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Background
Stem cell-based therapy, a crucial area of regenerative medicine, aims to enhance the body’s repair mechanisms by stimulating, modulating, and regulating endogenous stem cells or replenishing cell pools, thereby promoting tissue homeostasis and regeneration and offering promising treatments for numerous systemic diseases. This systematic review comprehensively summarizes animal studies investigating the efficacy of dental mesenchymal stem cells (DMSCs) in treating systemic diseases and promoting tissue regeneration compared to mesenchymal stem cells (MSCs) derived from other sources.
Methods
PICO question was, “What is the difference in efficacy between dental-derived mesenchymal stem cells and mesenchymal stem cells from other sources when used for the treatment of systemic diseases and/or tissue regeneration?” A comprehensive search, up to October 2024, across PubMed, Embase, and Scopus was conducted using a defined search strategy to identify relevant studies. Controlled animal studies were included, and the risk of bias was assessed using the SYRCLE tool.
Results
This systematic review included 29 studies published between 2008 and 2024, comparing the therapeutic efficacy of various dental-derived stem cells, including DPSCs (Dental Pulp Stem Cells), DPNCCs (Dental Pulp Neural Crest Cells), GMSCs (Gingival Mesenchymal Stem Cells), SHEDs (Stem Cells from Human Exfoliated Deciduous Teeth), and PDLSCs (Periodontal Ligament Stem Cells) with other stem cell sources in preclinical animal models. DMSCs demonstrated significant osteogenic potential, enhanced neuroprotection, angiogenesis, and robust immunomodulatory effects, showing superior performance compared to bone marrow mesenchymal stem cells (BMMSCs) and other sources in tissue repair, functional recovery, and inflammation modulation across multiple systems, including musculoskeletal, oral, ocular, neural, immune, dermal, metabolic, cardiovascular, and pulmonary. However, some studies reported similar or slightly better outcomes with other stem cell types, depending on the specific application or disease model.
Conclusion
DMSCs exhibit promising therapeutic potential, often outperforming traditional MSC sources such as bone marrow and adipose tissue in preclinical settings. Their accessibility through minimally invasive procedures and robust regenerative properties position them as a viable option for translational medicine. However, methodological heterogeneity and limited standardization across studies necessitate further rigorous research to validate these findings and optimize their clinical application.
Introduction
Stem cell-based therapy is a crucial area of regenerative medicine. It aims to enhance the body’s repair mechanisms by stimulating, modulating, and regulating endogenous stem cells or replenishing cell pools. This promotes tissue homeostasis and regeneration, offering promising treatments for various systemic diseases [1]. Mesenchymal stem cells (MSCs) are multipotent progenitor cells recognized for their capacity for self-renewal and differentiation into various mesenchymal lineages, as defined by the International Society for Cell and Gene Therapy (ISCT) [2]. Recent progress in clinical trials has underscored the potential of MSC therapies as innovative treatments for various diseases [3, 4, 5–6]. Bone marrow mesenchymal stem cells (BMMSCs) are the most widely studied and frequently used in clinical applications [7].
Additionally, stem cells can be isolated from various tissues, including dental tissues such as the tooth germ, dental follicle, apical papilla, dental pulp, human exfoliated deciduous teeth, periodontal ligament, alveolar bone, and gingiva, which constitute a specific subset of MSCs [8].
Dental mesenchymal stem cells (DMSCs) have shown significant potential in regenerative medicine. They exhibit high proliferative capacity, immunomodulatory effects that enable them to regulate the surrounding immune microenvironment, and multilineage differentiation potential similar to BMMSCs. DMSCs can differentiate into cells with characteristics of odontoblasts, cementoblasts, osteoblasts, chondrocytes, myocytes, epithelial cells, neural cells, hepatocytes, and adipocytes. This suggests that DMSCs may be particularly effective in clinical applications [9]. Many authors emphasize the non-invasive or minimally invasive characteristics of the DMSC harvesting technique, identifying it as an advantage over other methods of collecting adult mesenchymal stem cells from sources like bone marrow, adipose tissue, and peripheral blood, as well as time-sensitive or condition-dependent sources such as the umbilical cord, placenta, and amniotic fluid [10]. The comparative efficacy of DMSCs versus MSCs from other sources, such as bone marrow or adipose tissue, has not been fully elucidated. This systematic review comprehensively summarizes animal studies investigating the efficacy of DMSCs in treating systemic diseases and promoting tissue regeneration in comparison to MSCs derived from other sources. We will discuss the potential mechanisms of action of DMSCs and the challenges associated with translating preclinical findings into clinical applications. This information will contribute to a better understanding of the therapeutic potential of DMSCs and promote further development of these cells as novel treatments for various diseases and tissue injuries.
Materials and methods
This study was conducted following the PRISMA (preferred reporting items for systematic review and meta-analysis) statement [11]. The study protocol has been registered in the international prospective register of systematic reviews (PROSPERO) (number CRD42024552714).
The PICO format was used to formulate the research question, where the population (P) comprised experimental animals focusing on treatment for systemic diseases (e.g., autoimmune diseases, neurologic diseases, etc.) and/or tissue regeneration (e.g., bone regeneration, skin repair, etc.); the intervention (I) was treatment with dental mesenchymal stem cells (DMSCs); the comparison (C) was treatment with mesenchymal stem cells from other sources (e.g., bone marrow mesenchymal stem cells (BMMSCs), adipose-derived stem cells (ADSCs), etc.); and the outcome (O) was the efficacy in treating these conditions, as measured by relevant study outcomes (e.g., disease severity reduction, etc.).
Eligibility criteria
The articles screened were included in this study based on the following criteria: articles that reported the treatment with dental mesenchymal stem cells and compared their efficacy in treating systemic diseases and/or tissue regeneration in animal studies with stem cells from other sources in control groups. Studies must also be controlled trials and written in English. Exclusion criteria applied were articles that reported the use of preconditioned stem cells or stem cell secretome for treatment, articles that did not report stem cells from other sources in control groups or appropriate controls, articles with inappropriate outcomes reported or insufficient data on the outcome. Review articles, in vitro studies, conference abstracts, and protocols were also excluded.
Information sources and search strategy
In May 2024, a comprehensive electronic search was conducted by two independent reviewers (A.M., A.D.) across PubMed, Embase, and Scopus databases using the search queries specified in Table 1, and it was updated in October 2024, ensuring that all relevant studies were included up to the most recent available data. These databases were selected as they offer comprehensive coverage of biomedical and health sciences, and dental literature relevant to the scope of this review. The search was restricted to English language articles to ensure manageable resources for data extraction and analysis. There was no restriction on the publication date, allowing us to capture all relevant studies. Search terms were selected based on both MeSH terms and clinical keywords related to dental mesenchymal stem cells (DMSCs), other mesenchymal stem cells (MSCs) from various sources, and systemic diseases. The search terms were combined using the Boolean operators “AND” and “OR”, as detailed in Table 1. This strategy was designed to capture studies related to the therapeutic potential of DMSCs across different disease models. Additionally, references of the included articles were manually searched to identify any relevant publications not retrieved through electronic searches.
Table 1. Search queries made to each database
PubMed: 556 |
(“dental mesenchymal stem cells” OR "Tooth germ stem cells" OR "dental follicle stem cells" OR "stem cells from the apical papilla" OR "dental pulp stem cells" OR "stem cells from human exfoliated deciduous teeth" OR "Periodontal ligament stem cells" OR "alveolar bone-derived mesenchymal stem cells" OR "gingival mesenchymal stem cells") AND ("Nervous System Diseases" [Mesh] OR “Nervous System Diseases” [Title/Abstract] OR "Immune System Diseases" [Mesh] OR "Immune System Diseases" [Title/Abstract] OR "Cardiovascular Diseases" [Mesh] OR "Cardiovascular Diseases" [Title/Abstract] OR "Musculoskeletal Diseases" [Mesh] OR "Musculoskeletal Diseases" [Title/Abstract] OR "Lung Diseases" [Mesh] OR "Lung Diseases" [Title/Abstract] OR "Metabolic Diseases" [Mesh] OR "Metabolic Diseases" [Title/Abstract] OR "Endocrine System Diseases" [Mesh] OR "Endocrine System Diseases" [Title/Abstract] OR "Hematologic Diseases" [Mesh] OR "Hematologic Diseases" [Title/Abstract] OR "Skin Diseases" [Mesh] OR "Skin Diseases" [Title/Abstract] OR "Mouth Diseases" [Mesh] OR "Mouth Diseases" [Title/Abstract] OR "Eye Diseases" [Mesh] OR "Eye Diseases" [Title/Abstract] OR "Gastrointestinal Diseases" [Mesh] OR "Gastrointestinal Diseases" [Title/Abstract] OR "Communicable Diseases" [Mesh] OR "Communicable Diseases" [Title/Abstract] OR " Urogenital Diseases" [Mesh] OR " Urogenital Diseases" [Title/Abstract]) |
Embase: 1908 |
('dental mesenchymal stem cells' OR 'tooth germ stem cells' OR 'dental follicle stem cells' OR 'stem cells from the apical papilla' OR 'dental pulp stem cells'/exp OR 'dental pulp stem cells' OR 'stem cells from human exfoliated deciduous teeth'/exp OR 'stem cells from human exfoliated deciduous teeth' OR 'periodontal ligament stem cells'/exp OR 'periodontal ligament stem cells' OR 'alveolar bone-derived mesenchymal stem cells' OR 'gingival mesenchymal stem cells') AND ('neurologic disease'/exp OR 'neurologic disease' OR 'immunopathology'/exp OR 'immunopathology' OR 'cardiovascular disease'/exp OR 'cardiovascular disease' OR 'musculoskeletal disease'/exp OR 'musculoskeletal disease' OR 'lung disease'/exp OR 'lung disease' OR 'metabolic disorder'/exp OR 'metabolic disorder' OR 'endocrine disease'/exp OR 'endocrine disease' OR 'hematologic disease'/exp OR 'hematologic disease' OR 'skin disease'/exp OR 'skin disease' OR 'mouth disease'/exp OR 'mouth disease' OR 'eye disease'/exp OR 'eye disease' OR 'gastrointestinal disease'/exp OR 'gastrointestinal disease' OR 'communicable disease'/exp OR 'communicable disease' OR 'urogenital tract disease'/exp OR 'urogenital tract disease') AND [english]/lim |
Scopus: 154 |
( TITLE-ABS-KEY ( {dental mesenchymal stem cells} OR {Tooth germ stem cells} OR {dental follicle stem cells} OR {stem cells from the apical papilla} OR {dental pulp stem cells} OR {stem cells from human exfoliated deciduous teeth} OR {Periodontal ligament stem cells} OR {alveolar bone-derived mesenchymal stem cells} OR {gingival mesenchymal stem cells} ) AND ALL ( {Nervous System Diseases} OR {Immune System Diseases} OR {Cardiovascular Diseases} OR {Musculoskeletal Diseases} OR {Lung Diseases} OR {Metabolic Diseases} OR {Endocrine System Diseases} OR {Hematologic Diseases} OR {Skin Diseases} OR {Mouth Diseases} OR {Eye Diseases} OR {Gastrointestinal Diseases} OR {Communicable Diseases} OR {Urogenital Diseases} ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) ) |
Gray literature (e.g., preprints and conference abstracts) was not included due to the lack of detailed data, unclear methodologies, and ambiguous review process for these sources, which can limit the rigorousness of our review.
Selection process
All studies were transferred to EndNote 21 to remove duplicates and then exported to the Rayyan online systematic review web application for screening based on titles and abstracts. The process of study selection, guided by the inclusion and exclusion criteria, was conducted in two stages by two independent reviewers (A.M., A.D.). These reviewers were blinded to each other’s decisions. Initially, they screened titles and abstracts for relevance, followed by obtaining and filtering full-text articles in the second stage. Reviewers resolved any discrepancies through discussion and consultation with the corresponding author.
Data collection process and data items
Initially two reviewers (A.M., A.D.) were calibrated by the corresponding author; and, afterwards, they independently conducted data extraction, resolving any disagreements through discussion with the corresponding author and review of the articles. This systematic review involved extracting data from animal studies. Information extracted from the articles included general details such as author and year of publication, as well as technical information, including animal model, specific disease model, source of DMSCs (e.g., dental follicle stem cell, Periodontal ligament stem cells, etc.), treatment groups, analysis reported, and outcomes (disease model assessment: specific scoring system for evaluating disease severity or progression, and quantitative measures of disease markers such as inflammatory cytokines and tissue damage indicators - tissue regeneration measures such as histological analysis and imaging techniques).
Study risk of bias assessment
Initially two reviewers were calibrated by the corresponding author. After the calibration process, the two reviewers evaluated study quality, and the risk of bias in animal studies was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. All disagreements at any stage were resolved after a discussion with the corresponding author.
Data analysis
The assessment of the included studies outcomes primarily involved qualitative analysis due to insufficient quantitative data available for pooling and the noticeable heterogeneity.
Results
Study selection
The comprehensive electronic search initially identified 2,154 studies after duplicates were removed. Following a review of titles and abstracts, 70 studies were deemed relevant for further evaluation. After reading the full text of the articles, 29 studies met the criteria for inclusion. Figure 1 presents a flow diagram of the search and screening process.
[See PDF for image]
Fig. 1
PRISMA flow diagram of the present study
Study characteristics
The studies included were published from 2008 to 2024. In recent years, the comparison between dental mesenchymal stem cells and stem cells from other sources has increased in articles, indicating that DMSCs may be recognized as a viable alternative in therapeutic applications. This study investigates the efficacy of various dental-derived stem cells, including DPSCs (Dental Pulp Stem Cells), DPNCCs (Dental Pulp Neural Crest Cells), GMSCs (Gingival Mesenchymal Stem Cells), SHEDs (Stem Cells from Human Exfoliated Deciduous Teeth), and PDLSCs (Periodontal Ligament Stem Cells), in comparison to other types of stem cells such as BMMSCs (Bone Marrow Mesenchymal Stem Cells), iPSCs (Induced Pluripotent Stem Cells), ADSCs (Adipose-Derived Stem Cells), HUVECs (Human Umbilical Vein Endothelial Cells), UCMSCs (Umbilical Cord Mesenchymal Stem Cells), WJSCs (Wharton’s Jelly Stem Cells), and AFSCs (Amniotic Fluid Stem Cells). The focus is on the effectiveness in addressing various systemic diseases and their role in regeneration treatments, including those affecting the musculoskeletal system [12, 13, 14, 15, 16, 17, 18, 19, 20, 21–22], mouth [23, 24], eyes [25, 26], nervous system [27, 28, 29, 30–31], immune system [32, 33–34], skin [35, 36], metabolic processes [37], cardiovascular system [38, 39], and lungs [40].
Risk of bias and study quality
The studies were assessed for their risk of bias using the SYRCLE tool, and the results were illustrated in Fig. 2. Most studies lacked detailed information on random sequence generation, making it hard to confirm if allocation was truly random [12, 14, 18, 19, 21, 22–23, 25, 26–27, 29, 30, 32, 33, 34–35, 37, 38–39]. While most studies reported similar baseline characteristics, others did not [27, 33, 34, 37], so any observed effects may result from pre-existing differences rather than the intervention itself. Additionally, allocation concealment was sometimes reported [13, 15, 16, 28], raising the risk of selection bias if investigators potentially influenced group assignments. Random housing was mentioned in only a few studies [13, 15, 16, 28, 36, 40], and without this information, environmental factors could inadvertently impact outcomes, weakening result confidence. Blinding of caregivers and researchers was rarely noted [13, 15, 16, 26], which raises concerns about performance bias, as awareness of group assignments could unintentionally affect behavior and outcomes. Three articles explicitly followed the ARRIVE guidelines during the experiment; therefore, detection bias due to random outcome assessment is considered low risk for these articles [13, 15, 16]. Few studies mentioned blinding of outcome assessors [13, 15, 16], increasing the risk of detection bias, as knowledge of treatment could influence result interpretation.
[See PDF for image]
Fig. 2
Risk of bias assessment using Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias assessment tool
Comparative efficacy of DMSCs and other stem cells
A summary of the methods and outcomes reported by the included studies can be found in Tables 2, 3, 4, 5, 6, 7, 8, 9 and 10. Figure 3 provides a visual synthesis of DMSC-specific therapeutic mechanisms and effects across disease contexts.
Table 2. Comparative summary of included studies on the applications of mesenchymal stem cells in musculoskeletal diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Lyu et al. | 2021 | Congenital cleft-jaw model (mandibular defect) | F344 rats N = 9 per group | DPSCs | 1. Control 2. Undiffer-DPSC-CellSaic 3. Undiffer-BMMSC-CellSaic | µCT, histology | The undiffer-BMMSC-CellSaic group showed no bone formation, while the undiffer-DPSC-CellSaic group exhibited minimal bone formation at week 4, strengthening from week 6 onward; osteoblasts appeared only in the DPSC-CellSaic group by weeks 6 and 8, whereas the BMMSC-CellSaic group developed fibrous tissues. | DPSCs |
Shiu et al. | 2021 | Calvarial bone defect model | New Zealand white rabbits N = 24 | DPSCs | 1. Control 2. MBCP 3. MBCP + DPSCs/BMMSCs 4. Bio-Oss 5. Bio-Oss + DPSCs/BMMSCs 6. Autogenous bone | µCT, histology | Undifferentiated DPSCs and BMMSCs significantly increased new bone formation, bony bridges, and the number of osteoblastic cells compared to control or scaffold-only groups. However, no significant differences were observed between these two types of stem cells in (BV/TV) and histology values at various healing periods. | Comparable efficacy |
Johnson et al. | 2021 | Calvarial bone defect model | Yorkshire pigs (number NR) | DPNCCs | 1. Native bone 2. DPNCCs + HA/TCP scaffold 3. BMA + HA/TCP scaffold | µCT, histology | DPNCCs and BMA, combined with a 3D-printed HA/TCP scaffold, effectively regenerated calvarial bone in swine models, showing complete defect healing, comparable bone density and strength to native bone at 8 weeks, and further scaffold degradation with smooth, dense bone formation by 12 weeks. No adverse effects or ectopic bone formation were observed. BMA demonstrated slightly better scaffold degradation and integration over time. | Comparable efficacy |
Al-Qadhi et al. | 2020 | Tibia critical-size defect model | New Zealand white rabbits N = 27 | GMSCs | 1. Unloaded NanoBone Scaffold 2. GMSCs loaded on NanoBone Scaffold 3. BMMSCs loaded on NanoBone Scaffold | histology | Two weeks postoperatively, defects treated with GMSCs loaded on NanoBone scaffold (group II) exhibited thicker bone trabeculae mainly from the lateral sides, compared to thinner, irregular trabeculae in group I and group III. Histological evaluation indicated remnants of scaffold material within granulation tissue, with group II showing numerous dilated blood vessels congested with red blood cells, suggesting increased vascularization. By four weeks, group II exhibited more mature lamellated bone, whereas group III showed thinner woven bone trabeculae. At six weeks, group III demonstrated almost complete defect bridging with organized Haversian systems, whereas group II displayed a mix of lamellar and woven bone. Quantitatively, group II had the highest newly formed bone area at two and four weeks, shifting to group III at six weeks. Masson’s trichrome staining revealed more mature collagen fibers in group II initially, but by six weeks, group III showed greater maturation. | Both effective at different healing phases |
Lee et al. | 2019 | Calvarial bone defect model | New Zealand white rabbits N = 12 | DPSCs | 1. Empty control 2. Bio-Oss 3. Bio-Oss seeded with BMMSCs 4. Bio-Oss seeded with DPSCs | µCT, histology, immunohistochemical (IHC) | In a rabbit calvarial bone defect model, Bio-Oss grafts containing BMMSCs or DPSCs significantly improved bone defect bridging and new bone formation compared to control and scaffold-only groups. The BV/TV ratios in MSC-treated groups were significantly higher at both 3 and 6 weeks post-surgery. Histological analysis showed greater new bone formation and osteoconductivity in the Bio-Oss + BMMSCs and Bio-Oss + DPSCs groups. Immunohistochemical evaluations revealed more pronounced Collagen I and OPG staining in DPSCs and BMMSCs groups. | Comparable efficacy |
Jin et al. | 2019 | Mandibular bone defect model | (strain NR) rats N = 5 per group | DPSCs | 1. Puramatrix alone 2. Puramatrix/DPSC complex 3. Puramatrix/ADSC complex | µCT, histology, sequential fluorescence labeling | Micro-CT analysis revealed that the ADSC group exhibited robust new bone formation compared to the DPSCs and the control group. Quantitative evaluations indicated that the BV/TV, Tb.N, and Tb.Th metrics were significantly higher, while Tb.Sp was significantly lower in the ADSC group. Sequential fluorescence labeling indicated early mineralization in the ADSC group as early as one week, while the DPSC group showed weaker calcium deposition. Histological sections further supported these findings, with the ADSC group showing a significantly greater new bone area compared to the DPSC group. | ADSCs |
Nakajima et al. | 2018 | Calvarial bone defect model | BLAB/c-nu mice N = 5 per group | SHEDs, DPSCs | 1. Control group 2. SHEDs 3. DPSCs 4. BMMSCs | µCT, histology | All MSC-treated groups showed significantly more new bone formation than the control group, with no differences among them. Histological evaluations revealed minimal mineralized tissue in the control group, while the SHEDs group displayed prominent new bone formation with visible collagen fibers, osteoid, and mature lamellar bone. The DPSCs group had less bone than SHEDs but more collagen and osteoid than the control. The BMMSCs group showed limited bone formation at the center bottom and cell invasion into the membrane. Quantitative analysis confirmed larger collagen and osteoid areas in the SHEDs and DPSCs groups compared to the control, with no significant differences in scaffold degradation among the groups. | All effective; SHEDs slightly more prominent |
Moshaverinia et al. | 2014 | Calvarial bone defect model | Beige nude XID III (NU/NU) mice N = 4 per group | PDLSCs, GMSCs | 1. Cell-free alginate negative control group 2. PDLSCs + RGD-coupled alginate 3. GMSCs + RGD-coupled alginate 4. BMMSCs + RGD-coupled alginate | µCT, histology, immunohistochemical (IHC) | After 8 weeks, micro-CT and histological analyses demonstrated that PDLSCs significantly enhanced bone regeneration in defects compared to the negative control. Quantitative analysis showed that GMSCs had lower bone regenerative potential than PDLSCs and BMMSCs, with BMMSCs inducing the highest bone formation. Histological staining revealed mature bone formation with a lamellar pattern and osteocytes within lacunae in PDLSC- and GMSC-treated defects, while hematopoietic marrow elements were present only in BMMSC-treated defects. Additionally, BMMSCs produced significantly more mineralized tissue compared to PDLSCs and GMSCs. Immunohistochemical staining showed strong expression of osteogenic markers Runx2 and OCN in areas treated with PDLSCs and BMMSCs, whereas GMSCs exhibited milder expression. | BMMSCs |
Yu et al. | 2014 | Calvarial bone defect model | nude rats N = 6 per group | PDLSCs | 1. No-graft (negative control) 2. Bio-Oss (positive control) 3. BMMSC/Bio-Oss 4. PDLSC/Bio-Oss | µCT, histology, immunohistochemical (IHC) | In both ectopic and critical-size defect models, PDLSC/Bio-Oss constructs consistently showed superior bone formation compared to BMMSC/Bio-Oss and Bio-Oss alone. This was evident in higher bone volume ratios, trabecular thickness, and trabecular numbers, with lower trabecular separations. Histological assessments confirmed greater osteoblast activity and blood vessel formation in PDLSC-treated groups. While quantitative differences were noted between PDLSC and BMMSC constructs, both enhanced bone regeneration significantly compared to the control groups. | PDLSCs |
Liu et al. | 2014 | Ovariectomy-induced osteoporosis (distal metaphysis of the femur) | C3H/HeJ mice N = 5 per group | SHEDs | 1. OVX + Sham 2. OVX without treatment 3. OVX + SHEDs 4. OVX + hBMMSCs | µCT, histology, ELISA assay | Both SHEDs and hBMMSCs transplantation led to significant improvements in BV/TV, Tb.Th, Tb.N, BMD, Conn.D, and reductions in trabecular separation and structural model index compared to OVX mice. Additionally, cortical bone parameters such as Tt.Ar, Ct.Ar, Ct.Ar/Tt.Ar, and Ct.Th were also enhanced, albeit to a lesser extent. Both treatments markedly elevated trabecular bone volume and reduced osteoclast numbers. The levels of CTX-1, TRAP 5b, and RANKL in serum were markedly decreased in both SHEDs and hBMMSCs transplantation groups compared with the “OVX without transplantation” group, whereas OPG levels were markedly increased in both treatment groups. SHEDs ameliorates the osteoporotic phenotype in OVX mice by promoting T-cell apoptosis via the FasL/Fas pathway, enhancing regulatory T-cells, preserving BMMSCs, and inhibiting osteoclastogenesis to increase bone mass. | Both effective; SHEDs performed better by offering additional immunomodulatory effects that further ameliorated osteoporosis. |
Seo et al. | 2008 | Calvarial bone defect model | NIH-bg-nu-xid mice N = 6 per group | SHEDs | 1. TCP-HA 2. TCP-HA + SHEDs 3. TCP-HA + BMMSCs | histology, immunohistochemical (IHC), immunocytochemical | Both treatments effectively restored parietal continuity and formed bone tissue in transplanted mice. Semi-quantitative analysis showed robust mineralized tissue formation in SHEDs and BMMSCs groups, unlike controls. After six months, SHEDs achieved complete calvarial repair but lacked the hematopoietic marrow elements typical of BMMSCs-generated bone. SHEDs promoted recipient-cell differentiation into osteogenic cells and directly participated in bone formation, confirmed by human-specific markers. Multi-colony and single-colony SHEDs displayed similar regenerative potential without marrow formation. SHED-derived bone expressed osteogenic markers (ALP, BSP, type I collagen) and growth factor receptors (TGFß, FGF, VEGF), co-localizing with CC9/MUC18/CD146. | Comparable efficacy |
ADSCs Adipose-Derived Stem Cells, ALP Alkaline Phosphatase, BMA Bone Marrow Aspirate, BMD Bone Mineral Density, BMMSCs Bone Marrow Mesenchymal Stem Cells, BSP Bone Sialoprotein, BV/TV Bone Volume over Total Volume, CTX-1 C-Telopeptide of Type I Collagen, Conn.D Connectivity Density, Ct.Ar Cortical Area, Ct.Ar/Tt.Ar Cortical Area Fraction, Ct.Th Cortical Thickness, DMSCs Dental Mesenchymal Stem Cells, DPNCCs Dental Pulp Neural Crest Cells, DPSCs Dental Pulp Stem Cells, ELISA Enzyme-Linked Immunosorbent Assay, FGF Fibroblast Growth Factor, FasL/Fas Fas Ligand / Fas receptor, GMSCs Gingival Mesenchymal Stem Cells, HA/TCP Hydroxyapatite/Tricalcium Phosphate, IHC Immunohistochemistry, MBCP Micro/Macro Biphasic Calcium Phosphate, MSCs Mesenchymal Stem Cells, OCN Osteocalcin, OPG Osteoprotegerin, OVX Ovariectomized, PDLSCs Periodontal Ligament Stem Cells, RANKL Receptor Activator of Nuclear Factor-κB Ligand, RGD Arginine–Glycine–Aspartic Acid, RUNX2 Runt-Related Transcription Factor 2, SHEDs Stem Cells from Human Exfoliated Deciduous Teeth, TGF-β Transforming Growth Factor Beta, TRAP Tartrate-Resistant Acid Phosphatase, TRAP-5b Tartrate-Resistant Acid Phosphatase 5b, Tb.N Trabecular Number, Tb.Sp Trabecular Separation, Tb.Th Trabecular Thickness, Tt.Ar Total Cross-Sectional Area, VEGF Vascular Endothelial Growth Factor, hBMMSCs human bone marrow mesenchymal stem cells, μCT Micro-Computed Tomography
Table 3. Comparative summary of included studies on the applications of mesenchymal stem cells in oral diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Ma et al. | 2019 | Periodontitis | miniature pigs N = 6 (12 defects) | DPSCs | 1. Control group 2. BMMSCs 3. DPSCs | µCT, histology | Three-dimensional CT images showed marked bone regeneration in both the DPSC and BMMSC groups, while the control group exhibited limited bone formation. At 12 weeks post-transplantation, both MSC treatments significantly enhanced periodontal hard tissue regeneration compared to the control group. The height of the periodontal alveolar bone was greater in the DPSC group (2.72 ± 0.33 mm) than in the BMMSC group (2.28 ± 0.48 mm), both being significantly higher than in the control group (1.43 ± 0.41 mm). The volume of regenerative alveolar bone was similar in the DPSC (12.83 ± 4.41 mm³) and BMMSC (12.83 ± 4.34 mm³) groups, both significantly larger than in the control group (0.58 ± 0.32 mm³). The control group exhibited impaired sulcular epithelium and lymphocyte infiltration, which were absent in the DPSC and BMMSC groups. | DPSCs |
Kim et al. | 2009 | Peri-Implant defect model | Beagle dogs N = 4 | PDLSCs | 1. Cell-free HA/TCP (control group) 2. BMMSC - loaded HA/TCP 3. PDLSC - loaded HA/TCP | histology | At 8 weeks, the BMMSCs group demonstrated mature bone formation near the defect’s base, whereas the PDLSCs group showed immature bone, and the control group had partial bone with connective tissue surrounding HA/TCP particles. At 16 weeks, bone maturation progressed in all groups, with the BMMSCs group exhibiting the most extensive bone formation, extending beyond the implant platform. Both stem-cell groups displayed well-organized lamellar bone around HA/TCP particles, in contrast to the control group’s mixture of mature bone and connective tissue. Quantitatively, the BMMSCs group had the highest new bone formation at both time points, followed by the PDLSCs and control groups. No significant differences in BIC were observed among groups, except between BMMSCs and control groups at 16 weeks. | BMMSCs |
BIC Bone-to-Implant Contact, BMMSCs Bone Marrow Mesenchymal Stem Cells, DMSCs Dental Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, HA/TCP Hydroxyapatite/Tricalcium Phosphate, MSCs Mesenchymal Stem Cells, PDLSCs Periodontal Ligament Stem Cells, μCT Micro-Computed Tomography
Table 4. Comparative summary of included studies on the applications of mesenchymal stem cells in eye diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Liu et al. | 2023 | Retinal degenration | Royal College of Surgeons (RCS) Rats N = 6 per group | DPSCs | 1. ADSCs 2. AFSCs 3. BMMSCs 4. DPSCs 5. hiPSC-RPE 6. PBS(Negative control) 7. Blank control | Fundus photography, Optomotor response (OMR) evaluations, Light–dark box testing, Electroretinography (ERG), Histology | At four weeks, all MSC groups, exhibited significantly higher ERG wave amplitudes and qOMR index values than control groups, indicating improved visual function. However, only rats treated with hiPSC-derived RPE cells maintained visual function at eight weeks, highlighting their superior long-term efficacy. Histological analysis confirmed these findings, as ONL thickness in treated groups correlated with ERG and qOMR results. While MSCs preserved ONL thickness, hiPSC-derived RPE cells provided the most sustained protective effect. | hiPSC-RPE |
Mead et al., | 2013 | Optic nerve crush | SD rats N = 6 per group (36 eyes) | DPSCs | 1. ONC + DPSC Transplant (living cells, right eye; dead cells, left eye) 2. ONC + BMMSC Transplant (living cells, right eye; dead cells, left eye) 3. ONC (left eye)/intact control (right eye) + PBS (control injection) | OCT (retinal nerve fiber layer thickness), IHC (Brn-3a + RGC survival), Microscopy + Photoshop (GAP-43 + axon regeneration quantification) | RNFL thickness was measured to evaluate post-ONC RGC axonal atrophy. In uninjured animals, RNFL thickness remained stable, whereas ONC animals showed significant thinning. Transplants of dead DPSCs or BMMSCs had no protective effect, with RNFL thinning similar to the ONC group. However, living DPSCs and BMMSCs prevented RNFL thinning at 7 dpl, indicating a neuroprotective effect. By 14 dpl, RNFL thickness in DPSC-transplanted animals remained higher than in untreated animals but lower than in intact ones. At 21 dpl, RNFL thickness in DPSCs- and BMMSCs-treated animals declined to levels comparable to untreated animals. Viable DPSCs persisted in the vitreous humor at 21 dpl, correlating with elevated BDNF and NT-3 in the retina compared to eyes receiving dead DPSCs. Intravitreal DPSC transplantation significantly increased RGC survival at 21 dpl compared to BMMSCs, dead DPSCs, or untreated controls. BMMSCs transplantation also improved RGC survival compared to dead BMMSC transplants or untreated animals. The number of regenerating GAP-43-positive RGC axons was significantly higher in DPSC-transplanted animals than in BMMSC-treated, dead DPSC-treated, or untreated groups. BMMSCs also enhanced axonal regeneration compared to untreated and dead BMMSC-treated animals, particularly at 100 and 200 μm distal to the crush site. | DPSCs |
ADSCs Adipose-Derived Stem Cells, AFSCs Amniotic Fluid Stem Cells, BMMSCs Bone Marrow Mesenchymal Stem Cells, DMSCs Dental Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, MSCs Mesenchymal Stem Cells, hiPSC-RPE Human-Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium, RCS Royal College of Surgeons (a strain of rat), SD Sprague–Dawley, OMR Optomotor Response, qOMR Quantitative Optomotor Response, ERG Electroretinography, OCT Optical Coherence Tomography, IHC Immunohistochemistry, ONC Optic Nerve Crush, ONL Outer Nuclear Layer, RNFL Retinal Nerve Fiber Layer, RGC Retinal Ganglion Cell, RPE Retinal Pigment Epithelium, PBS Phosphate Buffered Saline, GAP-43 Growth-Associated Protein-43, BDNF Brain-Derived Neurotrophic Factor, NT-3 Neurotrophin-3, DPL Days Post-Lesion, Brn-3a Brain-specific homeobox/POU domain protein 3A
Table 5. Comparative summary of included studies on the applications of mesenchymal stem cells in nervous system diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Uzunlu et al. | 2024 | Sciatic Nerve Crush Injury | Wistar Albino rats N = 7 per group | DPSCs | 1. Sham 2. BMMSCs 3. DPSCs 4. BMMSCs + DPSCs | Functional recovery (SFI), Histology (H&E for tissue structure, S100 for Schwann cells), Inflammation analysis (IL-1β, TNF-α, IL-10, NF-kB), Gait analysis | Motor recovery was measured on days 7, 14, 21, and 28 post-injuries using the SFI, where the combined group showed the most significant improvement. By the 28th day its SFI score (−18.98) was significantly higher than the BMMSCs (−36.73) and DPSCs (−28.42) groups, while the sham group showed no significant recovery. Histopathological analysis revealed preserved perineurium and intact fascicular organization in all treatment groups, with the combined group exhibiting the most structural integrity. Edema was absent only in the combined group, while mild inflammatory infiltration was observed in all treatment groups except the control. Gait analysis showed significant hind limb recovery in the combined group, with smoother walking motion, while the DPSCs group demonstrated better coordination and fewer deficits in stride length and step frequency compared to the BMMSCs group. Schwann cell activity and nerve regenration, indicated by S100-positive cells, was 90% in the DPSCs and combined groups, compared to 70% in the BMMSCs group and none in the sham group. This indicates that DPSCs and the combined treatment group promoted nerve regeneration more effectively than BMMSCs alone. | Combination > DPSCs > BMMSCs |
Senthilkumar et al. | 2023 | Temporal Lobe Epilepsy (Kainic Acid-induced Status Epilepticus) | CF-1 Albino mice N = 34 | DPSCs | 1. Sham DPSCs 2. Sham BMMSCs 3. KA group 4. KA + DPSCs 5. KA + BMMSCs | Behavioral tests (EPM, OFT, NOR, Radial Arm Maze, Self-grooming Behaviour, FST), Immunohistochemistry for GFAP, Cresyl violet staining, ELISA | The DPSC group showed a significant reduction in time spent in open arms and fewer open-arm entries, indicating effective alleviation of anxiety-like behavior, while BMMSC treatment did not produce statistically significant changes. Elevated anxiety-related behaviors in KA mice, including head dips and unprotected body stretches, were significantly reduced by both treatments, with DPSCs showing a stronger effect on head dips. The frequency of rearing, an indicator of hyperactivity, was higher in KA mice but normalized to sham levels in both treatment groups. Hyperactivity, as measured by rearing frequency, normalized to sham levels in both groups, and both treatments decreased zone transitions and reversed abnormal center-zone exploration. KA-treated mice spent more time in the center zone, indicating abnormal exploratory behavior. KA mice exhibited impaired object recognition, with a lower recognition index compared to sham controls. Both treatments restored object recognition, with showing a higher preference for novel objects, suggesting preserved cognitive function, with no clear superiority between the two treatments. In the Radial Arm Maze, sham controls demonstrated 80% correct choices, while the KA group showed significant learning impairment. Treatment groups achieved spatial learning performance comparable to sham controls. Finally, while KA mice showed reduced self-grooming—a marker of stress and depression—DPSCs significantly increased grooming frequency, indicating stronger anti-depressive effects compared to BMMSCs, although both improved stress-related behaviors. | DPSCs |
Krakenes et al. | 2023 | Multiple sclerosis (MS) | C57BL/6 mice N = 35 (10 or 5 per group) | SHEDs | 1. Saline Injection group 2. Healthy control (n = 5) 3. BMMSCs 4. SHEDs | Myelin staining (Luxol), Light Microscopy, Immunohistochemistry (MAC-3, GFAP, NOGO-A, NEFL), Human cell marker detection | The BMMSCs group exhibited significantly higher myelin levels than the saline-treated group, indicating a protective effect against demyelination. In contrast, the SHEDs exhibited increased myelination without statistical significance. In healthy contros, minimal microglial activation was observed in the corpus callosum. Both BMMSCs and SHEDs significantly reduced microglial activation compared to saline, demonstrating anti-inflammatory effects with no difference between them. Astrocytic activation, measured by GFAP staining, was significantly reduced in SHEDs, suggesting a stronger anti-inflammatory response, whereas BMMSCs had no significant effect The average density of oligodendrocytes (NOGO-A positive cells) in healthy control mice was 732 cells/cm². Oligodendrocyte density decreased across all cuprizone-treated groups, with no significant difference between BMMSCs and SHEDs. Neurofilament (NEFL) staining, a marker of neuronal integrity, showed no significant differences across groups, indicating neither treatment affected neuronal integrity in this demyelination model. | Both effective (different aspects) |
Song et al. | 2017 | Cerebral Ischemic Injury (Stroke) | SD rats N = 9 per group | DPSCs | 1. MCAo + PBS 2. MCAo + DPSCs 3. MCAo + BMMSCs | Modified neurological severity score (mNSS), Nissl staining for infarct volume, Immunohistochemistry for human nuclei (hNuA), neuronal marker (NeuN), and glial fibrillary acidic protein (GFAP), von Willebrand factor (vWF) and GFAP/nestin and GFAP/Musashi-1 | DPSCs improved neurological function compared to both the PBS and BMMSC groups, as indicated by lower mNSS over 28 days, with the greatest recovery observed in the DPSC group. Nissl staining showed that DPSCs more effectively reduced infarct volume than BMMSCs, though both treatments were superior to PBS. Histological analysis revealed that DPSCs migrated to the lesion boundary in the ischemic brain and differentiated into neurons and astrocytes, as indicated by the presence of hNuA, NeuN, and GFAP in the brain sections, with more pronounced neurodifferentiation than BMMSCs. Furthermore, DPSCs enhanced angiogenesis, as evidenced by a larger vWF-stained area, and significantly inhibited astrogliosis, reducing GFAP/nestin + and GFAP/Musashi-1 + cells compared to BMMSCs and PBS. Astrogliosis can lead to the formation of a glial scar, which inhibits neural regeneration. | DPSCs |
Sakai et al. | 2012 | Spinal Cord Injury (SCI) | SD rats (number NR) | DPSCs/SHEDs | 1. Skin-derived Fibroblasts 2. PBS (control) 3. DPSCs 4. SHEDs 5. BMMSCs | Basso, Beattie, Bresnahan (BBB) locomotor rating scale, Immunohistochemistry for neurofilament M (NF-M), Anterograde neuronal tracing for corticospinal tract (CST) and serotonergic raphespinal axons, Pull-down assay for Rho GTPase activity, Immunohistochemical staining for myelination (FluoroMyelin), TUNEL assay for apoptosis | DPSCs and SHEDs significantly enhance locomotor recovery post-SCI, with higher Basso, BBB scores compared to BMMSCs, skin-derived fibroblasts, or PBS controls. This recovery is driven by neuroregenerative mechanisms, including inhibition of apoptosis in neurons and glial cells, and preservation of neuronal structures and myelin. Both DPSCs and SHEDs promote axonal growth by blocking growth inhibitors like chondroitin sulfate proteoglycan through paracrine signaling and differentiate into mature oligodendrocytes, aiding remyelination and suppressing Rho GTPase for axon regeneration. Notably, DPSCs and SHEDs demonstrate superior survival and differentiation into oligodendrocytes compared to BMMSCs or fibroblasts, underscoring their potential for SCI treatment. | DPSCs/SHEDs |
BMMSCs Bone Marrow Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, SHEDs Stem Cells from Human Exfoliated Deciduous Teeth, DMSCs Dental Mesenchymal Stem Cells, MS Multiple Sclerosis, SCI Spinal Cord Injury, SD Sprague–Dawley, KA Kainic Acid, MCAo Middle Cerebral Artery Occlusion, SFI Sciatic Functional Index, mNSS modified Neurological Severity Score, BBB Basso, Beattie, and Bresnahan, EPM Elevated Plus Maze, OFT Open Field Test, NOR Novel Object Recognition, RAM Radial Arm Maze, FST Forced Swim Test, H&E Hematoxylin and Eosin, S100 S100 Calcium-Binding Protein, IL-1β Interleukin-1 beta, TNF-α Tumor Necrosis Factor alpha, IL-10 Interleukin-10, NF-κB Nuclear Factor kappa B, ELISA Enzyme-Linked Immunosorbent Assay, MAC-3 Macrophage antigen-3, GFAP Glial Fibrillary Acidic Protein, NOGO-A Neurite Outgrowth Inhibitor A, NEFL Neurofilament Light Chain, NF-M Neurofilament M, CST Corticospinal Tract, hNuA human nuclear antigen, NeuN Neuronal Nuclei, vWF von Willebrand Factor, Rho Ras homolog family GTPase, TUNEL Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling, PBS Phosphate Buffered Saline, NR Not Reported
Table 6. Comparative summary of included studies on the applications of mesenchymal stem cells in immune system diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Dai et al. | 2019 | Allergic Rhinitis (AR) | BALB/c mice N = 6 per group | SHEDs | 1. Control group, sensitized and challenged with PBS and injected with PBS 2. sham-SHED group, sensitized and challenged with PBS and injected with SHEDs 3. OVA group, sensitized and challenged with OVA and injected with PBS 4. SHED group, sensitized and challenged with OVA and injected with SHEDs 5. BMMSC group, sensitized and challenged with OVA and injected with BMMSCs | Nasal allergic symptoms (frequencies of sneezing and nasal rubbing), Histological analysis (HE & PAS stains), ELISA, Flow cytometry, Real-time PCR | Allergic symptoms, including sneezing and nasal rubbing, were significantly higher in the OVA group than in the control and sham-SHED groups. Both SHED and BMMSC treatments significantly reduced these symptoms, with SHEDs demonstrating superior anti-inflammatory effects. Histological analysis revealed reduction in eosinophil infiltration, goblet cell hyperplasia, and T lymphocyte infiltration in the nasal mucosa of the SHED-treated group, while inflammatory cells were nearly absent in the control and sham-SHED groups. ELISA results confirmed that SHEDs significantly lowered OVA-specific IgE and IgG1 levels, similar to BMMSCs. Cytokine analysis revealed that both treatments downregulated IL-4, IL-5, IL-13, and IL-17 A while increasing IFN-γ, with SHEDs inducing a stronger IL-4 and IL-13 reduction, promoting a more balanced Th1/Th2 response. PCR analysis showed inhibited IL-4 and GATA-3 expression in both groups, along with increased IFN-γ, T-bet, and Foxp3 levels. While MSCs reduced IL-17 A expression, RORγt levels remained comparable to the OVA group. SHEDs demonstrated a greater reduction in IL-4 and GATA-3 than BMMSCs. | SHEDs |
Tang et al. | 2019 | Systemic Lupus Erythematosus (SLE) | B6.MRL-Faslpr/J (B6/lpr) mice N = 40 | DPSCs/PDLSCs | 1. Control group (PBS) 2. UCMSCs 3. DPSCs 4. PDLSCs | Measurement of proteinuria, Measurement of serum anti-dsDNA antibodies, and ANA, Histopathology analysis, Flow cytometry, Measurement of serum cytokines | All MSCs treatments significantly reduced proteinuria and serum anti-dsDNA antibody levels, along with a decrease in glomerular IgG/IgM deposition, though ANA levels declined only in the UCMSC group. DPSCs demonstrated superior efficacy in ameliorating glomerular lesions and reducing perivascular cell accumulation in the kidneys. Histological analysis confirmed that DPSC-treated mice showed reduced glomerular hypercellularity and less severe perivascular inflammation compared to those treated with PDLSCs and UCMSCs. In terms of immune modulation, both DPSCs and PDLSCs significantly downregulated Th1 cells (CD4 + IFNγ+) and plasma cells in the spleen, while UCMSCs were slightly less effective. No significant changes were observed in Th2, Th17, Tfh, or Treg populations, and cytokine levels (IL-6, IL-10, IL-17, MCP-1) remained unchanged across all groups. | DPSCs |
Yamaza et al. | 2010 | Systemic Lupus Erythematosus (SLE) | MRL/lpr mice N = 6 per group | SHEDs | 1. PBS infusion 2. SHEDs 3. BMMSCs | ELISA, Histological analysis of renal function and bone tissue, Flow cytometry for Treg and Th17 cell ratio, Histomorphometric analysis | SHEDs transplantation significantly reduced serum levels of autoantibodies (anti-dsDNA IgG, IgM, ANA) compared to controls, with a greater reduction in anti-dsDNA IgG than BMMSCs. Histological analysis showed that SHEDs improved SLE-related renal dysfunction by reducing nephritis and glomerular disorder, similar to BMMSCs, with both treatments showing decreased basal membrane disorder and mesangial cell overgrowth. ELISA analysis revealed that both treatments reduced urine C3 levels and increased serum C3 levels. SHEDs also more effectively reduced urine protein levels compared to BMMSCs. Both treatments elevated urine creatinine and reduced serum creatinine levels compared to controls. Flow cytometry showed no significant change in CD25 + Foxp3 + Treg levels within CD4 + T cells in the spleen, but both treatments reduced CD4 + IL17 + cells, with a more significant reduction in SHED-treated mice, leading to a higher Treg/Th17 ratio. Although serum IL10 and IL6 levels remained unchanged, IL17 was significantly downregulated in both groups. | SHEDs |
DMSCs Dental Mesenchymal Stem Cells, SHEDs Stem Cells from Human Exfoliated Deciduous Teeth, BMMSCs Bone Marrow Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, PDLSCs Periodontal Ligament Stem Cells, UCMSCs Umbilical Cord Mesenchymal Stem Cells, MSCs Mesenchymal Stem Cells, AR Allergic Rhinitis, SLE Systemic Lupus Erythematosus, OVA Ovalbumin, PBS Phosphate Buffered Saline, ELISA Enzyme-Linked Immunosorbent Assay, PAS Periodic Acid–Schiff, IgE Immunoglobulin E, IgG Immunoglobulin G, IgG1 Immunoglobulin G1, IgM Immunoglobulin M, IL-4 Interleukin-4, IL-5 Interleukin-5, IL-6 Interleukin-6, IL-10 Interleukin-10, IL-13 Interleukin-13, IL-17 Interleukin-17, IL-17A Interleukin-17A, IFN-γ Interferon-gamma, Th1 T helper 1, Th2 T helper 2, Th17 T helper 17, Tfh T follicular helper, Treg Regulatory T cell, GATA-3 GATA-binding Protein 3, T-bet T-box Transcription Factor TBX21, Foxp3 Forkhead box P3, RORγt RAR-related Orphan Receptor gamma t, dsDNA Double-Stranded DNA, ANA Antinuclear Antibody, C3 Complement Component 3, MCP-1 Monocyte Chemoattractant Protein-1 (CCL2)
Table 7. Comparative summary of included studies on the applications of mesenchymal stem cells in skin diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Martin-Piedra et al. | 2019 | Burn-wounds | Foxn1nu Athymic nude mice N = 4 per group | DPSCs | 1. NHS (Control) 2. DPSCs 3. ADSCs 4. WJSCs 5. BMMSCs | Histological analysis, ECM synthesis (collagen, GAGs, proteoglycans), Immunofluorescence for cytokeratins, HLA I and II expression | DPSCs generated a multi-layered, epithelial-like structure resembling native skin, with significant collagen deposition in the dermal substitute by day 30. ECM analysis showed that DPSCs promoted the synthesis of collagen, glycosaminoglycans (GAGs), and proteoglycans, essential components for skin regeneration. DPSCs also expressed cytokeratin markers CK5 and CK10, indicating differentiation into keratinocytes, and positive Filaggrin expression confirmed the formation of a functional epithelial barrier. Among MSC types, WJSCs demonstrated the highest epithelial differentiation potential, forming the thickest epithelial layers with strong CK10 expression, which indicates superior epidermal differentiation. BMMSCs exhibited mild HLA II expression at 30 days, suggesting minimal immunogenicity, while no MSC group showed HLA I expression, keeping the overall immunogenic risk low. | WJSCs |
Lv et al. | 2017 | Diabetic foot ulcer | SD rats N = 65 | SHEDs | 1. Control group 2. SHEDs 3. BMMSCs | Histopathology (H&E staining), Immunohistochemistry (collagen, CD31, VEGF), Western blot (VEGF, eNOS, MMP2, MMP9), ELISA (VEGF, IL-1β, TNF-α, IL-10) | Both SHEDs and BMMSCs accelerated diabetic ulcer closure compared to controls, with BMMSCs showing a slight advantage. By day 7, wound areas measured 6.97 ± 0.34 mm² in the SHEDs group and 5.70 ± 0.35 mm² in the BMMSCs group, decreasing to 4.58 ± 0.23 mm² and 3.92 ± 0.19 mm², respectively, by day 14. Both treatments reduced inflammatory cell infiltration, increased granulation tissue, and promoted faster epithelialization, with BMMSCs yielding slightly thicker granulation tissue. Immunohistochemical staining showed that SHEDs and BMMSCs significantly upregulated VEGF and CD31, enhancing angiogenesis, with BMMSCs producing marginally more blood vessels. Both treatments elevated MMP-2 and MMP-9 for matrix remodeling and significantly increased VEGF levels at days 3, 7, and 14, with BMMSCs showing slightly higher expression. SHEDs significantly reduced pro-inflammatory cytokines (IL-1β and TNF-α), while BMMSCs also reduced them, though not significantly. | BMMSCs |
DMSCs Dental Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, ADSCs Adipose-Derived Stem Cells, WJSCs Wharton’s Jelly Stem Cells, BMMSCs Bone Marrow Mesenchymal Stem Cells, SHEDs Stem Cells from Human Exfoliated Deciduous Teeth, MSCs Mesenchymal Stem Cells, Foxn1nu Athymic nude Foxn1nu mouse strain, SD Sprague–Dawley, NHS Native Human Skin, ECM Extracellular Matrix, GAGs Glycosaminoglycans, HLA Human Leukocyte Antigen, H&E Hematoxylin and Eosin, CK5 Cytokeratin 5, CK10 Cytokeratin 10, CD31 Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), VEGF Vascular Endothelial Growth Factor, eNOS Endothelial Nitric Oxide Synthase, MMP2 Matrix Metalloproteinase-2, MMP9 Matrix Metalloproteinase-9, ELISA Enzyme-Linked Immunosorbent Assay, IL-1β Interleukin-1 beta, TNF-α Tumor Necrosis Factor alpha, IL-10 Interleukin-10
Table 8. Comparative summary of included studies on the applications of mesenchymal stem cells in metabolic diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Rao et al. | 2019 | Type II Diabetes Mellitus (T2DM) | GK rats N = 8 per group Wistar rats (as normal control) N = 8 | SHEDs | 1. Control 2. PBS infusion into GK rats 3. SHEDs infusion into GK rats 4. BMMSCs infusion into GK rats | Biochemical and Physical assessment, IPITTs and IRTs, Histological analysis of pancreatic islets, Immunohistochemistry, Liver histology, PCR/Western blotting for liver metabolism markers | SHEDs infusion had the most significant impact on lowering blood glucose levels. Both fasting and non-fasting blood glucose levels were significantly reduced in SHEDs-treated rats compared to PBS-treated controls and BMMSCs-treated rats. SHEDs-treated rats experienced a faster and more sustained reduction in blood glucose than those treated with BMMSCs, which were effective but to a lesser extent. Additionally, SHEDs improved pancreatic islet structure. Histological analysis revealed more regular and intact β-cells in SHEDs-treated islets. While BMMSCs also helped restore islet morphology, they were less effective overall. SHEDs treatment reduced the number of irregular islets and enhanced insulin secretion capacity, as shown by insulin release tests. SHEDs also significantly improved liver function, as evidenced by PAS staining, which showed increased glycogen storage compared to the PBS group with reduced glycogen levels. SHEDs reversed diabetic-induced increases in gluconeogenesis markers (G-6-Pase, Pck1) and restored the expression of glycolysis and glycogen synthesis markers (GSK3B, GLUT2, PFKL). Although BMMSCs similarly improved liver function, they were less effective than SHEDs in normalizing these metabolic markers. | SHEDs |
DMSCs Dental Mesenchymal Stem Cells, SHEDs Stem Cells from Human Exfoliated Deciduous Teeth, BMMSCs Bone Marrow Mesenchymal Stem Cells, T2DM Type 2 Diabetes Mellitus, GK Goto-Kakizaki, PBS Phosphate Buffered Saline, IPITTs Intraperitoneal Insulin Tolerance Tests, IRTs Insulin Release Tests, PAS Periodic Acid–Schiff, PCR Polymerase Chain Reaction, G-6-Pase Glucose-6-Phosphatase, Pck1 Phosphoenolpyruvate Carboxykinase 1, GLUT2 Glucose Transporter 2, GSK3B Glycogen Synthase Kinase-3 Beta, PFKL Phosphofructokinase, Liver type
Table 9. Comparative summary of included studies on the applications of mesenchymal stem cells in cardiovascular diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Kim et al. | 2022 | Critical Limb Ischemia (CLI) | BALB/c nude mice (number NR) | DPSCs | 1. HBSS (negative control) 2. DPSCs 3. HUVECs 4. DPSCs + HUVECs (1 : 1 ratio) | Ischemic clinical score, Laser Doppler imaging (LDI), Histology (H&E, Masson’s trichrome), Immunohistochemistry (CD31) | The ischemia score was significantly lower in both the co-injection and DPSCs groups, with the co-injection group showing the lowest score among all treatment groups. LDI confirmed enhanced blood flow in the ischemic limb after 14 days in both groups, outperforming HUVECs. Histological analysis revealed that the co-injection group had the least fibrosis, inflammation, and muscle damage, while the DPSCs group showed moderate benefits. HUVECs alone were the least effective. Immunohistochemical staining for CD31 indicated the highest microvessel density in the co-injection group, highlighting superior angiogenesis. The DPSCs group had some angiogenic effects but was less effective than the combination, while HUVECs alone had minimal impact. | Co-injection |
Li et al. | 2021 | Critical Limb Ischemia (CLI) | Wistar rats N = 10 per group | DPSCs | 1. Control (non-ligated + non-treated) 2. Buffer (PBS) 3. DPSCs 4. BMMSCs 5. ADSCs 6. UCMSCs | Functional scoring, Laser Doppler perfusion imaging, X-ray angiography, Histopathology, ELISA, RT-PCR for cytokines | DPSCs exhibited the most pronounced effect on limb function improvement and tissue regeneration. Over four weeks, both DPSCs and BMMSCs accelerated recovery in ischemic limbs compared to other MSCs. Laser Doppler imaging showed that by three weeks post-treatment, DPSCs (on a larger scale) and BMMSCs restored blood flow to nearly 20% of normal levels. Histological analysis revealed that DPSCs and BMMSCs promoted greater capillary proliferation and increased vessel density compared to other treatment groups. DPSCs group exhibited a higher density of CD31-positive microvessels (indicating lumen formation) and greater muscle regeneration. Immunohistochemistry showed reduced infiltration of inflammatory cells (CD14 + and CD68+) in the limbs treated with DPSCs and BMMSCs, reflecting stronger anti-inflammatory effects. | DPSCs |
Table 10. Comparative summary of included studies on the applications of mesenchymal stem cells in lung diseases
Author | Year | Specific Disease Model | Animal Model (species/number) | Source of DMSCs | Treatment Groups | Analysis | Outcome | Which Cell Performed Better? |
|---|---|---|---|---|---|---|---|---|
Gao et al. | 2023 | Elastase-induced Pulmonary Emphysema | C57BL/6 mice N = 6 per group | DPSCs | 1. Control 2. COPD (PPE only) 3. COPD + DPSCs 4. COPD + BMMSCs | Lung function (FEV0.1/FVC, RL, Cydn), Histopathology (H&E and Victoria Blue staining), Oxidative stress (MDA, CAT, GSH), Inflammation markers (IL-1β, TNF-α, IL-6) | The DPSCs group showed marked improvements in FEV0.1/FVC, lung resistance (RL), and respiratory dynamic compliance (Cydn) compared to the untreated COPD and BMMSCs groups, indicating better lung function preservation. H&E staining revealed fewer emphysematous changes in the DPSCs group compared to the BMMSCs group, with reduced alveolar space enlargement and destruction. The mean linear intercept (MLI) and alveolar space proportion were also significantly lower in the DPSCs group. Victoria Blue staining demonstrated greater restoration of elastic fibers around small airways and lung parenchyma in the DPSCs group, improving lung elasticity and preventing airflow obstruction. In the DPSCs group, levels of malondialdehyde (MDA) were significantly lower than in the BMMSCs group, while catalase (CAT) and glutathione (GSH) levels were significantly higher, indicating superior antioxidative effects. Furthermore, DPSCs were more effective than BMMSCs in reducing IL-1β, TNF-α, and IL-6, as confirmed by ELISA and RT-qPCR analyses. | DPSCs |
ADSCs Adipose-Derived Stem Cells, BALB/c Bagg Albino Laboratory-bred strain c, BMMSCs Bone Marrow Mesenchymal Stem Cells, CD14 Cluster of Differentiation 14, CD31 Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), CD68 Cluster of Differentiation 68, CLI Critical Limb Ischemia, DMSCs Dental Mesenchymal Stem Cells, DPSCs Dental Pulp Stem Cells, ELISA Enzyme-Linked Immunosorbent Assay, H&E Hematoxylin and Eosin, HBSS Hanks’ Balanced Salt Solution, HUVECs Human Umbilical Vein Endothelial Cells, LDI Laser Doppler Imaging, MSCs Mesenchymal Stem Cells, NR Not Reported, PBS Phosphate Buffered Saline, RT-PCR Reverse Transcription Polymerase Chain Reaction, UCMSCs Umbilical Cord Mesenchymal Stem Cells
[See PDF for image]
Fig. 3
Dental mesenchymal stem cell (DMSC)-specific therapeutic mechanisms and effects across disease contexts. BMMSCs: Bone Marrow Mesenchymal Stem Cells, DPSCs: Dental Pulp Stem Cells, GMSCs: Gingival Mesenchymal Stem Cells, DPNCCs: Dental Pulp Neural Crest Cells, PDLSCs: Periodontal Ligament Stem Cells, SHEDs: Stem Cells from Human Exfoliated Deciduous Teeth, DMSCs: Dental Mesenchymal Stem Cells, ONC: Optic Nerve Crush, RNFL: Retinal Nerve Fiber Layer, RGC: Retinal Ganglion Cell, GAP-43: Growth-Associated Protein-43, BDNF: Brain-Derived Neurotrophic Factor, NT-3: Neurotrophin-3, SCI: Spinal Cord Injury, TLE: Temporal Lobe Epilepsy, GFAP: Glial Fibrillary Acidic Protein, vWF: von Willebrand Factor, mNSS: modified Neurological Severity Score, BBB: Basso, Beattie, and Bresnahan, SFI: Sciatic Functional Index, S100: S100 Calcium-Binding Protein, SLE: Systemic Lupus Erythematosus, CLI: Critical Limb Ischemia, CD31: Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), CD14: Cluster of Differentiation 14, CD68: Cluster of Differentiation 68, COPD: Chronic Obstructive Pulmonary Disease, FEV0.1/FVC: Forced Expiratory Volume in 0.1 s over Forced Vital Capacity, RL: Lung Resistance, Cydn: Dynamic Lung Compliance, MLI: Mean Linear Intercept, IL-1β: Interleukin-1 beta, TNF-α: Tumor Necrosis Factor alpha, IL-6: Interleukin-6, MDA: Malondialdehyde, CAT: Catalase, GSH: Glutathione, OVX: Ovariectomized, FasL/Fas: Fas Ligand/Fas receptor, BV/TV: Bone Volume over Total Volume, Tb.Th: Trabecular Thickness, Tb.N: Trabecular Number, Conn.D: Connectivity Density, Tb.Sp: Trabecular Separation, SMI: Structure Model Index, Tt.Ar: Total Cross-Sectional Area, Ct.Ar: Cortical Area, Ct.Ar/Tt.Ar: Cortical Area Fraction, Ct.Th: Cortical Thickness, BMD: Bone Mineral Density, TRAP: Tartrate-Resistant Acid Phosphatase, TRAP-5b: Tartrate-Resistant Acid Phosphatase 5b, CTX-1: C-Terminal Telopeptide of type I Collagen, RANKL: Receptor Activator of Nuclear Factor-κB Ligand, OPG: Osteoprotegerin, Treg: Regulatory T cell, ANA: Antinuclear Antibody, IgG: Immunoglobulin G, IgM: Immunoglobulin M, IgE: Immunoglobulin E, IgG1: Immunoglobulin G1, C3: Complement Component 3, Th1: T helper 1, Th2: T helper 2, Th17: T helper 17, GATA-3: GATA-binding Protein 3, T-bet: T-box Transcription Factor TBX21, Foxp3: Forkhead box P3, RORγt: RAR-related Orphan Receptor gamma t, VEGF: Vascular Endothelial Growth Factor, MMP-2: Matrix Metalloproteinase-2, MMP-9: Matrix Metalloproteinase-9, PAS: Periodic Acid–Schiff, G-6-Pase: Glucose-6-Phosphatase, Pck1: Phosphoenolpyruvate Carboxykinase 1, GLUT2: Glucose Transporter 2, GSK3B: Glycogen Synthase Kinase-3 Beta, PFKL: Phosphofructokinase, Liver type, CSPG: Chondroitin Sulfate Proteoglycan, Rho: Ras homolog family GTPase, RGD: Arginine–Glycine–Aspartic Acid, Tfh: T follicular helper, MCP-1: Monocyte Chemoattractant Protein-1 (CCL2), NOR: Novel Object Recognition, RAM: Radial Arm Maze
Musculoskeletal diseases
In mandibular defect models, Lyu et al. [12] reported that DPSC–CellSaic supported bone formation with osteoblasts, whereas BMMSC–CellSaic produced fibrous tissue without osteoblasts. In another study, ADSCs on a PuraMatrix scaffold outperformed DPSCs, as evidenced by superior trabecular microarchitectural parameters, earlier mineralization, and a larger area of new bone [17]. In calvarial defect models, Shiu et al. [13] demonstrated that both DPSCs and BMMSCs significantly increased new bone formation, bony bridging, and osteoblast numbers compared with the control and scaffold-only groups, with comparable efficacy between the two cell sources. Similarly, Lee et al. [16] reported comparable outcomes when Bio-Oss grafts were combined with either cell type. Johnson et al. [14] showed that DPNCCs and bone marrow aspirate (BMA), combined with a 3D-printed HA/TCP scaffold, effectively regenerated calvarial bone, with BMA showing slightly better scaffold integration and degradation. Nakajima et al. [18] reported that SHEDs, DPSCs, and BMMSCs similarly increased new bone formation, with SHEDs showing the most prominent bone and collagen deposition. Moshavernia et al. [19] reported that PDLSCs and BMMSCs significantly enhanced bone regeneration in RGD-coupled alginate scaffolds, with BMMSCs showing the highest bone formation and distinct hematopoietic marrow elements, while PDLSCs formed mature lamellar bone with osteocytes embedded in lacunae. Yu et al. [20] demonstrated that PDLSCs/Bio-Oss constructs produced greater bone volume, osteoblast activity, and vascularization than BMMSCs/Bio-Oss and Bio-Oss alone. Seo et al. [22] reported that SHEDs combined with HA/TCP achieved complete calvarial repair, with robust mineralized tissue and a direct contribution to bone formation, but lacked the hematopoietic marrow observed in BMMSC-derived bone. In tibial defect models, Al-Qadhi et al. [15] highlighted that GMSCs exhibited earlier osteogenic differentiation, scaffold integration, and immunomodulation when seeded on the NanoBone scaffold, thereby accelerating early-phase bone formation. In contrast, BMMSCs led to more substantial late-stage mineralization and collagen maturation. Liu et al. [21] reported that the transplantation of SHEDs and BMMSCs significantly improved bone microarchitecture and reduced osteoclast activity in ovariectomized mice. SHEDs specifically promoted T-cell apoptosis and enhanced regulatory T-cell function via the FasL/Fas pathway, thereby increasing bone mass and ameliorating the osteoporotic phenotype.
Mesenchymal stem cells derived from diverse sources hold significant promise for bone regeneration in musculoskeletal diseases. While BMMSCs remain the gold standard, evidence indicates that alternative sources, such as DPSCs, SHEDs, PDLSCs, and GMSCs, often achieve comparable regenerative outcomes, particularly when combined with appropriate scaffolds. Selection of the optimal MSC source should be guided by the specific clinical application, taking into account factors such as the anatomical defect location, the desired healing phase, scaffold choice, and the potential need for unique biological properties (e.g., immunomodulation in osteoporosis by SHEDs, hematopoietic marrow formation by BMMSCs, or rapid early integration by GMSCs).
Oral diseases
Ma et al. [23] demonstrated that in a periodontitis model, DPSCs exhibited superior periodontal bone regeneration compared to BMMSCs, with greater alveolar bone height and similar bone volume in both MSC groups, while the control group showed limited bone formation and tissue inflammation. Kim et al. [24] found that in HA/TCP-loaded peri-implant defects, BMMSCs produced the most extensive, mature lamellar bone, outperforming PDLSCs and controls, and were the only group with a significant increase in bone-to-implant contact.
Eye diseases
Liu et al. [25] found that while various MSCs provide short-term neuroprotection and functional benefits in retinal degeneration, human induced pluripotent stem cell–derived retinal pigment epithelium (hiPSC-RPE) cells offer a more durable therapeutic effect, maintaining retinal structure and function over an extended period. In optic nerve crush (ONC) models, Mead et al. [26] reported that living DPSCs delivered neurotrophin-mediated neuroprotection and pro-regenerative signalling, sustaining retinal structural integrity and neuronal survival. BMMSCs produced moderate improvements, whereas transplants of dead cells (DPSCs or BMMSCs) showed no benefit over untreated ONC animals.
Nervous system diseases
In a sciatic nerve crush model, Uzunlu et al. [31] reported that combined DPSCs + BMMSCs therapy yielded superior motor recovery, structural integrity, and Schwann cell activity compared with either therapy alone or sham controls. While DPSCs alone provided better gait coordination than BMMSCs, the combined group showed minimal edema and more complete histopathological preservation, suggesting a synergistic effect on nerve regeneration. Senthilkumar et al. [27] found that in temporal lobe epilepsy (TLE), DPSCs more effectively reduced anxiety- and depression-like behaviors than BMMSCs, while both treatments restored cognition to sham levels without between-group differences. In multiple sclerosis (MS) models, Krakenes et al. [28] reported that BMMSCs significantly increased myelination and reduced microglial activation. SHEDs also reduced microglial activation and more strongly suppressed astrocytic activation, but had no significant effect on myelination. Neither treatment restored oligodendrocyte density nor altered neuronal integrity. In cerebral ischemic injury models, Song et al. [29] reported that DPSCs outperformed BMMSCs and phosphate-buffered saline (PBS) in promoting functional recovery, reducing infarct volume, and enhancing neuronal and astrocytic differentiation. DPSCs also promoted angiogenesis and suppressed astrogliosis, thereby mitigating glial scar formation, a key factor in neural regeneration. Sakai et al. [30] demonstrated that DPSCs and SHEDs outperformed BMMSCs and fibroblasts in locomotor recovery after spinal cord injury, accompanied by neuroprotection, reduced apoptosis, increased axonal growth, and oligodendrocyte differentiation, contributing to improved remyelination and axon regeneration.
Collectively, these studies highlight DPSCs as a promising therapeutic modality, particularly when neuroregeneration, anti-inflammatory effects, or functional integration are required. At the same time, the complementary strengths of BMMSCs, especially in promoting myelination, support tailored strategies that use either a single cell type or a combinatorial approach, depending on disease-specific pathology.
Immune system diseases
In systemic lupus erythematosus (SLE), Tang et al. [33] reported that MSC therapy exerted immunoregulatory, renal anti-inflammatory effects that attenuated autoimmune renal injury and improved renal histopathology; among MSC sources, DPSCs showed the most consistent histopathologic improvement, and DPSCs and PDLSCs demonstrated stronger overall immunomodulatory activity than UCMSCs. Yamaza et al. [34] found that SHEDs and BMMSCs ameliorated autoimmune renal injury and improved renal histopathology; overall tissue recovery was comparable, but SHEDs delivered greater overall benefit and more pronounced immune modulation, characterised by Th17 suppression and a shift toward regulatory balance. In allergic rhinitis models, Dai et al. [32] demonstrated that both SHEDs and BMMSCs alleviated allergic symptoms and nasal inflammation. Mechanistically, both shifted immunity from a type 2 profile toward a more type 1/regulatory balance, with SHEDs providing consistently stronger modulation and overall benefit than BMMSCs.
Collectively, DMSCs, particularly SHEDs and DPSCs, show superior therapeutic activity across immune-mediated diseases compared with other MSC sources. SHEDs preferentially reduce autoantibodies, suppress Th17 cells, shift the Treg/Th17 balance toward regulation, and attenuate Th2-driven inflammation, whereas DPSCs demonstrate strong renoprotective effects in SLE. Both cell types consistently attenuate pathogenic immune responses, reduce inflammation, and promote immune homeostasis, underscoring their translational potential as regenerative immunotherapies.
Skin diseases
Martin-Piedra et al. [35] found that DPSCs generated skin-like constructs with robust collagen deposition, extracellular matrix synthesis, and keratinocyte differentiation, whereas WJSCs exhibited superior epidermal differentiation. In diabetic wound-healing models, Lv et al. [36] reported that both SHEDs and BMMSCs accelerated wound closure, enhanced angiogenesis, improved matrix remodeling, and reduced inflammation; BMMSCs were marginally more efficacious overall, whereas SHEDs exerted a stronger anti-inflammatory effect.
Metabolic diseases
In Type 2 Diabetes Mellitus (T2DM), a study by Rao et al. [37] demonstrated that infusion of SHEDs significantly reduced both fasting and non-fasting blood glucose levels more effectively than BMMSCs or PBS controls. SHEDs also restored pancreatic islet structure, enhanced insulin secretion, and improved liver function by modulating markers of gluconeogenesis and glycogen synthesis.
Cardiovascular diseases
In critical limb ischemia (CLI), Li et al. [39] found that DPSCs produced the greatest improvements in limb function and tissue regeneration compared with other MSCs. Both DPSCs and BMMSCs increased blood flow and capillary density, promoted muscle regeneration, and reduced inflammation. In another study, Kim et al. [38] showed that co-injection of DPSCs and HUVECs yielded the best outcomes, with the lowest ischemia scores, reduced fibrosis and inflammation, and the highest microvessel density, whereas DPSCs alone provided moderate benefit and HUVECs alone were minimally effective.
Lung diseases
In chronic obstructive pulmonary disease (COPD) models, Gao et al. [40] demonstrated that DPSCs were more effective than BMMSCs at preserving lung function, reducing emphysematous changes, and restoring elastic fibers, and that they exerted stronger antioxidative and anti-inflammatory effects than both the untreated COPD group and the BMMSC-treated group.
Discussion
This systematic review assessed the therapeutic potential of dental mesenchymal stem cells compared to other MSC sources, using data from 29 preclinical animal studies. Our findings suggest that DMSCs demonstrate comparable or superior efficacy to other MSC types across diverse disease models, including BMMSCs and adipose-derived stem cells. One of the key advantages of DMSCs is their accessibility through minimally invasive procedures, unlike BMMSCs, which require bone marrow aspiration. Their robust biological properties, including high proliferative capacity and multilineage differentiation potential, further enhance their therapeutic utility. In musculoskeletal disorders, DMSCs exhibited significant osteogenic potential. While some studies showed enhanced bone formation with DMSCs compared to BMMSCs in mandibular defects [12], others reported similar bone regeneration capabilities between the two cell types in calvarial defects [13]. However, it’s important to note that variability exists, with some studies indicating the superior performance of ADSCs over DMSCs in certain bone regeneration metrics [17]. DMSCs consistently demonstrated superior efficacy in neurological models. For instance, in optic nerve injury, DMSCs provided superior neuroprotection and axonal regeneration compared to BMMSCs. Similarly, enhanced recovery in spinal cord and cerebral ischemic injuries was observed with DMSCs, attributed to mechanisms such as reduced inflammation, apoptosis inhibition, and angiogenesis [29, 30]. Among DMSCs, certain subtypes, such as stem cells from human exfoliated deciduous teeth, often exhibit superior regenerative and immunomodulatory properties compared to other dental stem cells, particularly concerning immune modulation and angiogenesis [41]. Furthermore, when compared to BMMSCs, some DMSCs, like dental pulp stem cells and SHEDs, demonstrate more pronounced neuroprotective and anti-inflammatory effects in specific models [42]. These enhanced properties highlight the potential advantages of specific DMSC subtypes in targeted therapies.
The varying efficacy of dental mesenchymal stem cells across different diseases can be attributed to distinct underlying mechanisms, notably differences in their secretome and homing capabilities. The DMSC secretome is characterized by a unique profile of exosomes and bioactive molecules, including growth factors and cytokines, which play critical roles in promoting tissue repair, modulating immune responses, and enhancing angiogenesis [43]. Furthermore, DMSCs demonstrate enhanced homing capabilities, potentially mediated by a higher expression of chemokine receptors such as CXCR4, which facilitates their migration to sites of injury [44]. These molecular features may explain their superior efficacy in certain models, such as neurological and immune-related diseases. However, in some contexts, such as specific bone regeneration metrics, the secretome or homing efficiency of other MSC types, such as adipose-derived stem cells, may provide advantages. Comparatively, this systematic review aligns with other reviews in recognizing the promising therapeutic potential of DMSCs. However, it distinguishes itself by emphasizing the variability in outcomes across disease models and the need for standardized methodologies to better delineate their relative advantages [45, 46–47]. This systematic review offers a novel perspective on the current research landscape by specifically evaluating the therapeutic potential DMSCs. This subset is often underrepresented in comparative analyses. In contrast to previous reviews that primarily focus on bone marrow- or adipose-derived MSCs, our study highlights the distinct biological advantages of DMSCs, including their neuroprotective, angiogenic, and immunomodulatory properties. By systematically comparing DMSCs to other MSC sources across diverse disease models and examining unique mechanisms such as their secretome and homing abilities, this review emphasizes their emerging relevance and translational promise in regenerative medicine.
Rodríguez-Lozano et al. [46] demonstrated that DMSCs, including DPSCs, SHEDs, PDLSCs, dental follicle progenitor cells (DFPCs), and stem cells from the apical papilla (SCAPs), have the capacity to differentiate into odontoblasts, cementoblasts, and osteoblasts, making them highly suitable for dental tissue regeneration. They also showed that when combined with biocompatible scaffolds and growth factors such as BMPs, these stem cells can effectively promote the formation of dentin, periodontal ligament, and other dental structures in vitro and in vivo.
In another study by Bakopoulou et al. [45] they showed that DPSCs and SCAPs can both differentiate into odontoblast-like cells and form mineralized dentin-like structures in vitro. SCAPs, however, exhibit a significantly higher proliferation rate and mineralization potential compared to DPSCs. This makes SCAPs promising candidates for dental tissue regeneration, as they may be more effective in forming new dentin and promoting tissue repair in dental applications.
The unique immunomodulatory properties of DMSCs were also highlighted in immune system diseases. Studies showed that DMSCs, particularly stem cells from human exfoliated deciduous teeth, were more effective than BMMSCs in modulating immune responses in lupus nephritis models [33, 34]. Furthermore, in cardiovascular and metabolic diseases, DMSCs demonstrated superior angiogenesis, tissue regeneration, and reduced inflammation compared to BMMSCs. This was observed in models of critical limb ischemia and type 2 diabetes mellitus.
Dental mesenchymal stem cells offer advantages in regenerative medicine due to their accessibility through minimally invasive procedures, contrasting with the more invasive harvesting of BMMSCs. This ease of access potentially translates to reduced patient morbidity and wider applicability. However, DMSC isolation and expansion present challenges, often yielding lower cell numbers than BMMSCs, which can hinder large-scale clinical use [48]. The rationale for mesenchymal stem cell therapy lies in their regenerative and immunomodulatory properties, enabling differentiation into various cell types and secretion of bioactive molecules, including exosomes, which mediate therapeutic effects [49, 50]. Exosomes, nano-sized vesicles, facilitate intercellular communication and deliver therapeutic cargo, influencing target cell behavior and promoting tissue regeneration [49]. While some studies suggest enhanced proliferative capacity and unique immunomodulatory properties for DMSCs compared to other sources [51], definitive evidence of their superiority requires further investigation using standardized protocols and diverse disease models. The heterogeneity of DMSC populations, originating from various dental tissues, can also introduce variability, necessitating careful characterization and standardization [49]. While this review highlights the promising therapeutic potential of DMSCs, several limitations warrant consideration. Methodological rigor was a concern across the included studies, with the SYRCLE risk of bias assessment revealing significant shortcomings in areas such as random sequence generation, allocation concealment, and blinding. Few studies, such as Shiu et al. [13] and Al-Qadhi et al. [15], demonstrated low risk of bias across multiple domains. This heterogeneity in methodological quality introduces potential bias and limits the strength of the conclusions. Furthermore, substantial variability in DMSC sources (e.g., DPSCs, SHED, PDLSCs), experimental designs, and outcome measures hindered direct comparisons and limited the generalizability of findings. The predominance of qualitative or semi-quantitative outcomes, coupled with insufficient quantitative data, precluded meta-analysis, further restricting the ability to draw robust, pooled conclusions.
Translating preclinical findings to clinical applications presents additional challenges. Differences in immunogenicity, scalability, and long-term safety between animal models and humans underscore the need for rigorous preclinical and clinical research to bridge this translational gap. For instance, while DMSCs have shown promise in animal models, their long-term safety and efficacy in humans remain to be established. Furthermore, scaling up DMSC production for clinical use while maintaining consistent quality and efficacy presents a significant hurdle. To fully realize the therapeutic potential of DMSCs, future research should prioritize addressing these limitations. Standardized protocols for DMSC isolation, expansion, and characterization are crucial for enhancing reproducibility and enabling direct comparisons across studies. Well-designed comparative studies evaluating DMSCs against other MSC sources in diverse disease models are needed to clarify their relative advantages and disadvantages. Further investigation into the molecular mechanisms underlying DMSC-mediated tissue repair and immunomodulation is crucial. Understanding the specific pathways involved will pave the way for optimizing DMSC-based therapies and tailoring treatment strategies to individual patient needs. Rigorous clinical trials are essential to validate the safety, efficacy, and scalability of these therapies in humans, employing robust methodological designs, including appropriate blinding, randomization, and control groups, to ensure reliable and generalizable findings.
Despite their promising therapeutic potential, the clinical translation of DMSCs faces several challenges, including the risk of immune rejection in allogeneic applications and difficulties in large-scale production due to variability in cell yield and quality [52]. Limited data on long-term safety, such as tumorigenicity and ectopic tissue formation, also pose concerns. Compared to bone marrow mesenchymal stem cells and adipose-derived stem cells, which are more advanced in clinical applications with established protocols and numerous trials validating their efficacy in conditions like osteoarthritis, cardiovascular diseases, and wound healing [53], DMSCs remain relatively underexplored [54]. To bridge this gap, future efforts should focus on developing standardized protocols for DMSC isolation and expansion, conducting long-term safety studies, and leveraging lessons from the clinical success of BMMSCs and ADSCs to optimize the clinical application of DMSCs in regenerative medicine [55, 56]. As the clinical translation of stem cells faces challenges such as immune rejection, tumorigenicity, and scalability, alternatives like exosomes, secretomes, synthetic biomaterials, and gene therapy are being explored [57, 58]. Exosomes and secretomes, which are cell-free products, can replicate the therapeutic effects of stem cells [59, 60]. However, they face hurdles related to standardized production methods and ensuring long-term safety [61]. Synthetic biomaterials and small molecules offer the advantage of targeted regeneration but might lack the complex functionality of cellular therapies. Gene therapies also present a path for precision treatments but raises concerns regarding cost, delivery efficiency, and potential off-target effects. Overcoming these limitations is essential to advance the clinical application of these alternative therapeutic approaches [62, 63].
Several methodological shortcomings significantly impact the reliability and generalizability of findings on the therapeutic potential of DMSC. Common issues include inadequate allocation concealment, insufficient randomization, and a lack of blinding, all of which introduce risks of selection, performance, and detection biases that compromise internal validity and weaken the robustness of conclusions. The absence of proper randomization and allocation concealment can lead to systematic differences between study groups, while the lack of blinding may introduce subjective influences during outcome assessment. Furthermore, heterogeneity in study designs, such as variations in outcome measures, follow-up durations, and definitions of success, further complicates the interpretation and comparability of results, making it challenging to synthesize findings across studies.
Small sample sizes are another critical limitation, as they reduce statistical power and increase the likelihood of type I and type II errors, further undermining confidence in reported outcomes. The frequent reliance on animal models, though valuable for early-stage research, often fails to replicate the complexity of human pathophysiology and immune responses, limiting the translational applicability of preclinical findings. Additionally, incomplete adherence to established reporting guidelines, such as ARRIVE and CONSORT, undermines transparency and reproducibility, with key details on randomization methods, allocation concealment, and blinding often omitted. Addressing these methodological limitations is essential to ensuring more reliable and generalizable evidence in this field.
The overall methodological quality of the included studies was limited. Despite using the SYRCLE tool to systematically evaluate risk of bias, only 3 out of 29 studies demonstrated low risk in more than five domains, indicating that the vast majority were either at unclear or high risk across multiple areas. This raises concerns regarding the internal validity of the evidence base. In particular, critical aspects such as random sequence generation and allocation concealment were often poorly reported or entirely absent, making it difficult to ascertain whether group allocation was truly unbiased. Similarly, random housing and blinding of caregivers or outcome assessors were rarely implemented, introducing potential for performance and detection bias. While a few studies [12, 14, 15] adhered to the ARRIVE guidelines and implemented appropriate blinding, these were exceptions rather than the norm. Taken together, the predominance of studies with methodological limitations substantially weakens the confidence with which the findings can be interpreted and highlights the need for more comprehensive reporting and study design in future preclinical research.
Furthermore, while DMSCs have demonstrated promise in various applications, numerous areas and diseases, such as infertility, remain underexplored, representing significant opportunities to expand their therapeutic potential in regenerative medicine. Addressing these areas through well-designed studies will enhance the reliability and facilitate the translation of DMSCs into effective clinical therapies.
Conclusion
Dental mesenchymal stem cells present a promising, minimally invasive therapeutic option for various diseases and tissue regeneration. They exhibit distinct advantages in nerve injury models by enhancing neuroprotection and axonal regeneration, and in immune-related diseases by demonstrating robust immunomodulatory effects. In bone regeneration, DMSCs show favorable outcomes, particularly in mandibular and calvarial defects, although results vary depending on the specific disease model and evaluation criteria. However, their comparative efficacy against other mesenchymal stem cell sources remains inconclusive. Some studies suggest comparable or superior results to BMMSCs in specific applications, while others indicate greater efficacy for alternative sources. Methodological limitations, particularly in randomization and blinding, necessitate more rigorous research with standardized protocols for DMSC isolation, characterization, and application. Future studies should also prioritize mechanistic investigations to elucidate the molecular pathways underlying DMSC-mediated tissue repair and immunomodulation. Additionally, comparative studies in diverse disease models and rigorous clinical trials are essential to validate their safety, efficacy, and scalability for clinical use.
By addressing these challenges, DMSCs can be further optimized as a reliable and versatile therapeutic option in the broader context of regenerative medicine.
Acknowledgements
None.
Artificial intelligence generated materials
The authors declare that they have not used AI-generated work in this manuscript.
Systematic review registration
CRD42024552714.
Authors’ contributions
Alireza Daneshvar: Conceptualization, Project Administration, Investigation, Methodology, Software, Visualization, Writing – Original Draft, Writing – Review and EditingArman MomeniAmjadi: Methodology, Investigation, Validation, Writing – Original Draft, Writing – Review and EditingAli Azadi: Conceptualization, Methodology, Visualization, Investigation, Validation, Writing – Original Draft, Writing – Review and EditingSahar Baniameri: Investigation, Validation, Writing – Original Draft, Writing – Review and EditingMahdi Kadkhodazadeh: Conceptualization, Methodology, Supervision, Resources, Writing – Original Draft, Writing – Review and Editing.
Funding
No funding has been received for this study.
Data availability
The data that support the findings of this study are available from the corresponding author.
Declarations
Ethical approval consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Abbreviations
Adipose-derived stem cells
Amniotic fluid stem cells
Bone marrow mesenchymal stem cells
Dental pulp stem cells
Induced pluripotent stem cells
Human-induced pluripotent stem cell-derived retinal pigment epithelium
Mesenchymal stem cells
Gingival mesenchymal stem cells
Dental pulp neural crest cells
Bone marrow aspirate
Periodontal ligament stem cells
Stem cells from human exfoliated deciduous teeth
Wharton’s jelly stem cells
Human umbilical vein endothelial cells
Umbilical cord mesenchymal stem cells
Micro-computed tomography
Bone volume over total volume
Bone volume
Bone mineral density
Connectivity density
Trabecular number
Trabecular thickness
Trabecular separation
Cortical thickness
Cortical bone area
Total cross-sectional area
Cortical area fraction
Receptor activator of nuclear factor-κb ligand
Tartrate-resistant acid phosphatase
Bone sialoprotein
Osteocalcin
Osteoprotegerin
Runt-related transcription factor 2
Vascular endothelial growth factor
Growth-associated protein-43
Brain-derived neurotrophic factor
Neurotrophin-3
Transforming growth factor beta
Fibroblast growth factor
Middle cerebral artery occlusion
Retinal ganglion cell
Enzyme-linked immunosorbent assay
Immunohistochemistry
Optical coherence tomography
Room temperature
Laser doppler imaging
Terminal deoxynucleotidyl transferase dutp nick end labeling
Electroretinography
Ovalbumin
Ovariectomized
Systemic lupus erythematosus
Chronic obstructive pulmonary disease
Multiple sclerosis
Spinal cord injury
Optic nerve crush
Critical limb ischemia
Porcine pancreatic elastase
Extracellular matrix
Matrix metalloproteinase
Basso beattie and bresnahan
Retinal pigment epithelium
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Neurofilament
Neurofilament light chain
Glial fibrillary acidic protein
Neurite outgrowth inhibitor
Royal college of surgeons (a strain of rat)
Murphy roths large (a strain of mouse)
Forced swim test
Forced vital capacity
Sciatic functional index
Optomotor response
Quantitative optomotor response
Hydroxyapatite/tricalcium phosphate
Micro/macro biphasic calcium phosphate
C-telopeptide of type i collagen
Outer nuclear layer
Retinal nerve fiber layer
Days post-lesion
Alkaline phosphatase
Phosphate buffered saline
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