Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with Light-Emitting Diode: Implications and Molecular Mechanisms

Abstract

This study evaluated the effects of light-emitting diode (LED) on mesenchymal stem cells (MSCs). An electronic search was conducted in PubMed/MEDLINE, Scopus, and Web of Science database for articles published from 1980 to February 2020. Ten articles met the search criteria and were included in this review. The risk of bias was evaluated to report quality, safety, and environmental standards. MSCs were derived from adipose tissue, bone marrow, dental pulp, gingiva, and umbilical cord. Protocols for cellular irradiation used red and blue light spectrum with variations of the parameters. The LED has been shown to induce greater cellular viability, proliferation, differentiation, and secretion of growth factors. The set of information available leads to proposing a complex signaling cascade for the action of photobiomodulation, including angiogenic factors, singlet oxygen, mitogen-activated protein kinase/extracellular signal-regulated protein kinase, Janus kinase/signal transducer, and reactive oxygen species. In conclusion, although our results suggest that LED can boost MSCs, a nonuniformity in the experimental protocol, bias, and the limited number of studies reduces the power of systematic review. Further research is essential to find the optimal LED irradiation parameters to boost MSCs function and evaluate its impact in the clinical setting.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Photobiomodulation (PBM) employs nonionizing forms of light sources, which encompass laser and light-emitting diode (LED) for a broad visible and infrared spectrum, and PBM-based therapy has been successfully applied in treatment of several diseases, injuries, and disorders [1]. Acquaintance with the mechanisms subjacent the effects of PBM has been of considerable interest, and a well-accepted view is that the light energy delivered to tissues is absorbed by the cell chromophores, favouring the production of adenosine triphosphate (ATP) [2, 3]. Nevertheless, beneficial effects on inflammation, oxidative stress, survival, and the regeneration of tissues have been reported by several researchers [4–7].

Concerning LED, when the first one was developed in 1998 by Harry Whelan and his group at the NASA space medicine laboratory [8], this technology had some characteristics that diverge them from laser devices. While LED are noncoherent and quasimonochromatic light sources [9] based on the phenomenon of electroluminescence of semiconductor materials [10], laser emits, in a stimulated manner, a monochromatic, and coherent light beam of low divergence [11]. Besides that, it is important to quote that those different properties would still photoactivate cells without causing heat changes or damage. Notwithstanding, benefits are perceptible in LED when compared to lasers, such as increased safety and durability, lower cost, ease of use, and more flexibility in the irradiated area size [11, 12], although the biological effects of light on irradiated cells are similar in both laser and LED [13, 14]. LED phototherapy has either been well-proven to have an effective benefit in a wide variety of clinical indications such as pain relief, skin injuries, rheumatological diseases, muscle disorders, and infections, suggesting as well that LED might have a powerful role to play in the clinical practice for a variety of conditions. [7, 15–27].

The LED has also emerged to have important effects on mesenchymal stem cells (MSCs) [28], easily cultivated multipotent stem cells which can be isolated from various adult tissues, therefore opening a new window for PBM application into strategies being currently pursued to improve therapy with MSCs. Among the advantages of MSCs usage, it is possible to observe the availability in ubiquitous sources, the extensive ability of proliferation and multilineage differentiation, easy isolation, low immunogenicity, and paracrine potential [29, 30]. In addition, it is important to cite the immunomodulatory proprieties of MSCs, which could be used in the treatment of many disorders like promoting maintenance of the ratio of Treg and T helper cells in systemic lupus erythematosus [31], and the proosteogenic capacity, mainly presented in oral tissue MSCs [31, 32].

MSCs reside in a complex microenvironment among other cell types and biochemical stimuli, which influence if the cell will differentiate or self-renew. Mechanical factors are also being recognized as regulators. Therefore, the microenvironment is significantly an influencer of the role and differentiation of MSCs through biochemical, biomechanical, and biophysical factors [33].

Although being a promising therapy, mostly to the poor engrafting of implanted cells, low survival rates are common for long periods and MSC therapy has generated unsatisfactory results in numerous clinical conditions [34, 35]. Hence, since LED was referred to have the biological effects mentioned above, it could be applied to overcome the current limitations of MSC therapy more easily. Thereby, preconditioning of MSCs with LEDs before transplantation may be a usual procedure to improve tissue engineering and cell therapy in the future [36, 37].

To the best of our knowledge, most of the articles evaluated the repercussion of PBM on MSCs, as illustrated in different systematic reviews [28, 38–40], and the MSC response to LED irradiation remains unclear. Therefore, based on the plethora of biology actions that make the MSCs promising to regenerative medicine [29] and the possible cytoprotective effect of the PBM, we aimed this systematic review to summarize the current evidence about the effects of LED in mesenchymal stem cells (MSCs) and to identify the underlying mechanisms found to underpin this effect.

2. Materials and Methods

2.1. Search Strategy

The study was carried out according to PRISMA guidelines (Figure 1). The search for published articles into the effect of LEDs on MSCs was conducted in PubMed, Scopus, and Web of Science databases. The articles retrieved were limited to the English language and were for the period from January 1980 to February 2020. The MeSH terms and Scopus international data lines were used to find keywords related to “photobiomodulation,” “phototherapy,” “light-emitting diode,” “stem cells,” and “mesenchymal stem cells.” MeSH terms were used individually or combined to increase the findings. Data extraction involved MSC experimental methodology, LED parameters, and results. Duplicate articles from the database search results were removed.

[figure omitted; refer to PDF]

Although LED therapy could bring benefits in MSCs engineering, there was no unanimity regarding the source, nor the quantity and passage used in the experiments. Moreover, quality guideline criteria revealed that many of the included manuscripts had a high risk for detection, performance, and selection bias. These bias categories may be associated with problems in adhering to the study protocol, systematic differences introduced during the study, and lack of blinding results to study group or exposure level [42]. It is intended that a high risk of bias can potentially compromise the confidentiality of studies and influence the translation of findings in vitro to experiments using animals or clinical trials in the future.

Furthermore, after analyzing the studies in this review, it is important to quote some perspectives and limitations. The lack of studies available in irradiating MSCs with LEDs such as in vitro studies that mimic a hostile microenvironment, commonly found in transplantation sites, as well as in vivo experimentation and clinical trials possibly hindered the definition of a more effective irradiation protocol. Besides that, the lack of dosimetric parameters in studies that were not included in this review impossibilities the reproducibility and replicability of the results by other authors, also hindering determining the best parameter of irradiation.

5. Conclusion

Although the small number of studies limits the power of systematic review on photobiomodulation, evidence was found to suggest that red LED with a radiant exposure up to 7.2 J/cm², which can be an effective approach to boost MSC therapy. Overall, MSCs exposed to LED have shown enhanced viability, proliferation, differentiation, cell metabolism, and secretion of angiogenic factors compared to nonirradiated MSCs.

Disclosure

Funding sources were not involved in the study design, collection, analysis, or interpretation of data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.

Acknowledgments

This work was supported by the São Paulo Research Foundation (FAPESP) (grant 2018/06865-7) and Brazilian National Council for Scientific and Technological Development (CNPq) (grant 305527/2017-7).

References

[1] S. R. Tsai, M. R. Hamblin, "Biological effects and medical applications of infrared radiation," Journal of Photochemistry and Photobiology. B, vol. 170, pp. 197-207, DOI: 10.1016/j.jphotobiol.2017.04.014, 2017.

[2] F. Ginani, D. M. Soares, M. P. . V. Barreto, C. A. G. Barboza, "Effect of low-level laser therapy on mesenchymal stem cell proliferation: a systematic review," Lasers in Medical Science, vol. 30 no. 8, pp. 2189-2194, DOI: 10.1007/s10103-015-1730-9, 2015.

[3] Y. Wang, Y. Y. Huang, Y. Wang, P. Lyu, M. R. Hamblin, "Photobiomodulation (blue and green light) encourages osteoblastic- differentiation of human adipose-derived stem cells: role of intracellular calcium and light-gated ion channels," Scientific Reports, vol. 6 no. 1, article 33719,DOI: 10.1038/srep33719, 2016.

[4] H. A. de Oliveira, E. L. Antonio, G. Arsa, E. T. Santana, F. A. Silva, D. A. Júnior, S. dos Santos, P. . T. C. de Carvalho, E. C. P. Leal-Junior, A. Araujo, K. de Angelis, D. S. Bocalini, J. A. S. Junior, P. J. F. Tucci, A. J. Serra, "Photobiomodulation leads to reduced oxidative stress in rats submitted to high-intensity resistive exercise," Oxidative Medicine and Cellular Longevity, vol. 2018,DOI: 10.1155/2018/5763256, 2018.

[5] M. T. Manchini, A. J. Serra, R. . S. Feliciano, E. T. Santana, E. L. Antônio, P. de Tarso Camillo de Carvalho, J. Montemor, R. O. Crajoinas, A. C. C. Girardi, P. J. F. Tucci, J. A. Silva, "Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy," PLoS One, vol. 9 no. 7, article e101270,DOI: 10.1371/journal.pone.0101270, 2014.

[6] M. P. O. Rosso, D. Buchaim, N. Kawano, G. Furlanette, K. Pomini, R. Buchaim, "Photobiomodulation therapy (PBMT) in peripheral nerve regeneration: a systematic review," Bioengineering, vol. 5 no. 2,DOI: 10.3390/bioengineering5020044, 2018.

[7] T. G. Stancker, S. S. Vieira, A. J. Serra, R. do Nascimento Lima, R. dos Santos Feliciano, J. A. Silva, S. A. dos Santos, M. A. dos Santos Vieira, M. C. B. Simões, E. C. Leal-Junior, P. de Tarso Camillo de Carvalho, "Can photobiomodulation associated with implantation of mesenchymal adipose-derived stem cells attenuate the expression of MMPs and decrease degradation of type II collagen in an experimental model of osteoarthritis?," Lasers in Medical Science, vol. 33 no. 5, pp. 1073-1084, DOI: 10.1007/s10103-018-2466-0, 2018.

[8] H. T. Whelan, E. V. Buchmann, A. Dhokalia, M. P. Kane, N. T. Whelan, M. T. T. Wong-Riley, J. T. Eells, L. J. Gould, R. Hammamieh, R. Das, M. Jett, "Effect of NASA light-emitting diode irradiation on molecular changes for wound healing in diabetic mice," Journal of Clinical Laser Medicine & Surgery, vol. 21 no. 2, pp. 67-74, DOI: 10.1089/104454703765035484, 2003.

[9] H. T. Whelan, R. L. Smits, E. V. Buchman, N. T. Whelan, S. G. Turner, D. A. Margolis, V. Cevenini, H. Stinson, R. Ignatius, T. Martin, J. Cwiklinski, A. F. Philippi, W. R. Graf, B. Hodgson, L. Gould, M. Kane, G. Chen, J. Caviness, "Effect of NASA light-emitting diode irradiation on wound healing," Journal of Clinical Laser Medicine & Surgery, vol. 19 no. 6, pp. 305-314, DOI: 10.1089/104454701753342758, 2001.

[10] K. F. Renk, Basics of Laser Physics,DOI: 10.1007/978-3-642-23565-8, 2012.

[11] V. Heiskanen, M. R. Hamblin, "Photobiomodulation: lasers vs. light emitting diodes?," Photochemical & Photobiological Sciences, vol. 17 no. 8, pp. 1003-1017, DOI: 10.1039/C8PP00176F, 2018.

[12] S. Y. Tam, V. C. W. Tam, S. Ramkumar, M. L. Khaw, H. K. W. Law, S. W. Y. Lee, "Review on the cellular mechanisms of low-level laser therapy use in oncology," Frontiers in Oncology, vol. 10,DOI: 10.3389/fonc.2020.01255, 2020.

[13] F. Peng, H. Wu, Y. Zheng, X. Xu, J. Yu, "The effect of noncoherent red light irradiation on proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells," Lasers in Medical Science, vol. 27 no. 3, pp. 645-653, DOI: 10.1007/s10103-011-1005-z, 2012.

[14] Y. Ruan, H. Kato, Y. Taguchi, N. Yamauchi, M. Umeda, "Irradiation by high-intensity red light-emitting diode enhances human bone marrow mesenchymal stem cells osteogenic differentiation and mineralization through Wnt/ β -catenin signaling pathway," Lasers in Medical Science, vol. 36 no. 1, pp. 55-65, DOI: 10.1007/s10103-020-03002-5, 2021.

[15] R. G. Calderhead, W. S. Kim, T. Ohshiro, M. A. Trelles, D. Vasily, "Adjunctive 830 nm light-emitting diode therapy can improve the results following aesthetic procedures," Laser Therapy, vol. 24 no. 4, pp. 277-289, DOI: 10.5978/islsm.15-OR-17, 2015.

[16] N. G. Yeh, C.-H. Wu, T. C. Cheng, "Light-emitting diodes—their potential in biomedical applications," Renewable and Sustainable Energy Reviews, vol. 14 no. 8, pp. 2161-2166, DOI: 10.1016/j.rser.2010.02.015, 2010.

[17] W. S. Kim, R. G. Calderhead, "Is light-emitting diode phototherapy (LED-LLLT) really effective?," Laser Therapy, vol. 20 no. 3, pp. 205-215, DOI: 10.5978/islsm.20.205, 2011.

[18] R. Serhal, N. Saliba, G. Hilal, M. Moussa, G. Hassan, O. E. Atat, N. Alaaeddine, "Effect of adipose-derived mesenchymal stem cells on hepatocellular carcinoma:In vitroinhibition of carcinogenesis," World Journal of Gastroenterology, vol. 25 no. 5, pp. 567-583, DOI: 10.3748/wjg.v25.i5.567, 2019.

[19] W. Jing, Y. Chen, L. Lu, X. Hu, C. Shao, Y. Zhang, X. Zhou, Y. Zhou, L. Wu, R. Liu, K. Fan, G. Jin, "Human umbilical cord blood-derived mesenchymal stem cells producing IL15 eradicate established pancreatic tumor in syngeneic mice," Molecular Cancer Therapeutics, vol. 13 no. 8, pp. 2127-2137, DOI: 10.1158/1535-7163.MCT-14-0175, 2014.

[20] T. C. Kao, H. H. C. Lee, A. Higuchi, Q. D. Ling, W. C. Yu, Y. H. Chou, P. Y. Wang, S. Suresh Kumar, Y. Chang, Y. Hung Chen, Y. Chang, D. C. Chen, S. T. Hsu, "Suppression of cancer-initiating cells and selection of adipose-derived stem cells cultured on biomaterials having specific nanosegments," Journal of Biomedical Materials Research. Part B, Applied Biomaterials, vol. 102 no. 3, pp. 463-476, DOI: 10.1002/jbm.b.33024, 2014.

[21] E. S. Iplik, B. Ertugrul, I. Kozanoglu, Y. Baran, B. Cakmakoglu, "An answer to colon cancer treatment by mesenchymal stem cell originated from adipose tissue," Iranian Journal of Basic Medical Sciences, vol. 21 no. 5, pp. 465-468, DOI: 10.22038/IJBMS.2018.26152.6420, 2018.

[22] Y. Yuan, C. Zhou, X. Chen, C. Tao, H. Cheng, X. Lu, "Suppression of tumor cell proliferation and migration by human umbilical cord mesenchymal stem cells: a possible role for apoptosis and Wnt signaling," Oncology Letters, vol. 15 no. 6, pp. 8536-8544, DOI: 10.3892/ol.2018.8368, 2018.

[23] S. Bruno, F. Collino, M. C. Deregibus, C. Grange, C. Tetta, G. Camussi, "Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth," Stem Cells and Development, vol. 22 no. 5, pp. 758-771, DOI: 10.1089/scd.2012.0304, 2013.

[24] A. E. Shafei, M. A. Ali, H. G. Ghanem, A. I. Shehata, A. A. Abdelgawad, H. R. Handal, K. A. Talaat, A. E. Ashaal, A. S. el-Shal, "Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction," The Journal of Gene Medicine, vol. 19 no. 12,DOI: 10.1002/jgm.2995, 2017.

[25] A. Karamini, A. Bakopoulou, D. Andreadis, K. Gkiouras, A. Kritis, "Therapeutic potential of mesenchymal stromal stem cells in rheumatoid arthritis: a systematic review of in vivo studies," Stem Cell Reviews and Reports, vol. 16 no. 2, pp. 276-287, DOI: 10.1007/s12015-020-09954-z, 2020.

[26] Y. Chen, J. Shen, K. Ke, X. Gu, "Clinical potential and current progress of mesenchymal stem cells for Parkinson's disease: a systematic review," Neurological Sciences, vol. 41 no. 5, pp. 1051-1061, DOI: 10.1007/s10072-020-04240-9, 2020.

[27] J. AdiwinataPawitan, "Exploring the most promising stem cell therapy in liver failure: a systematic review," Stem Cells International, vol. 2019,DOI: 10.1155/2019/2782548, 2019.

[28] M. M. Marques, I. M. A. Diniz, S. P. H. M. de Cara, A. C. F. Pedroni, G. L. Abe, R. S. D'Almeida-Couto, P. L. V. Lima, T. K. Tedesco, M. S. Moreira, "Photobiomodulation of dental derived mesenchymal stem cells: a systematic review," Photomedicine and Laser Surgery, vol. 34 no. 11, pp. 500-508, DOI: 10.1089/pho.2015.4038, 2016.

[29] W. Tsuji, J. P. Rubin, K. G. Marra, "Adipose-derived stem cells: implications in tissue regeneration," World J Stem Cells, vol. 6 no. 3, pp. 312-321, DOI: 10.4252/wjsc.v6.i3.312, 2014.

[30] A. Rühle, R. Lopez Perez, B. Zou, A. L. Grosu, P. E. Huber, N. H. Nicolay, "The therapeutic potential of mesenchymal stromal cells in the treatment of chemotherapy-induced tissue damage," Stem Cell Reviews and Reports, vol. 15 no. 3, pp. 356-373, DOI: 10.1007/s12015-019-09886-3, 2019.

[31] G. Spagnuolo, B. Codispoti, M. Marrelli, C. Rengo, S. Rengo, M. Tatullo, "Commitment of oral-derived stem cells in dental and maxillofacial applications," Dentistry Journal, vol. 6 no. 4,DOI: 10.3390/dj6040072, 2018.

[32] A. Ballini, S. Cantore, S. Scacco, D. Coletti, M. Tatullo, "Mesenchymal stem cells as promoters, enhancers, and playmakers of the translational regenerative medicine 2018," Stem Cells International, vol. 2018,DOI: 10.1155/2018/6927401, 2018.

[33] M. Marrelli, B. Codispoti, R. M. Shelton, B. A. Scheven, P. R. Cooper, M. Tatullo, F. Paduano, "Dental pulp stem cell mechanoresponsiveness: effects of mechanical stimuli on dental pulp stem cell behavior," Frontiers in Physiology, vol. 9,DOI: 10.3389/fphys.2018.01685, 2018.

[34] E. Samper, A. Diez-Juan, J. A. Montero, P. Sepúlveda, "Cardiac cell therapy: boosting mesenchymal stem cells effects," Stem Cell Reviews and Reports, vol. 9 no. 3, pp. 266-280, DOI: 10.1007/s12015-012-9353-z, 2013.

[35] J. Y. Wu, C. H. Chen, C. Z. Wang, M. L. Ho, M. L. Yeh, Y. H. Wang, "Low-power laser irradiation suppresses inflammatory response of human adipose-derived stem cells by modulating intracellular cyclic AMP level and NF- κ B activity," PLoS One, vol. 8 no. 1, article e54067,DOI: 10.1371/journal.pone.0054067, 2013.

[36] L. Wang, F. Wu, C. Liu, Y. Song, J. Guo, Y. Yang, Y. Qiu, "Low-level laser irradiation modulates the proliferation and the osteogenic differentiation of bone marrow mesenchymal stem cells under healthy and inflammatory condition," Lasers in Medical Science, vol. 34 no. 1, pp. 169-178, DOI: 10.1007/s10103-018-2673-8, 2019.

[37] A. Castilho-Fernandes, T. G. Lopes, F. U. Ferreira, N. Rezende, V. F. Silva, F. L. Primo, A. M. Fontes, A. Ribeiro-Silva, A. C. Tedesco, "Adipogenic differentiation of murine bone marrow mesenchymal stem cells induced by visible light via photo- induced biomodulation," Photodiagnosis and Photodynamic Therapy, vol. 25, pp. 119-127, DOI: 10.1016/j.pdpdt.2018.11.013, 2019.

[38] M. Bayat, A. Virdi, F. Rezaei, S. Chien, "Comparison of the in vitro effects of low-level laser therapy and low-intensity pulsed ultrasound therapy on bony cells and stem cells," Progress in Biophysics and Molecular Biology, vol. 133, pp. 36-48, DOI: 10.1016/j.pbiomolbio.2017.11.001, 2018.

[39] R. Fekrazad, S. Asefi, M. Allahdadi, K. A. M. Kalhori, "Effect of photobiomodulation on mesenchymal stem cells," Photomedicine and Laser Surgery, vol. 34 no. 11, pp. 533-542, DOI: 10.1089/pho.2015.4029, 2016.

[40] B. Ahrabi, M. Rezaei Tavirani, M. S. Khoramgah, M. Noroozian, S. Darabi, S. Khoshsirat, H. A. Abbaszadeh, "The effect of photobiomodulation therapy on the differentiation, proliferation, and migration of the mesenchymal stem cell: a review," J Lasers Med Sci, vol. 10 no. 5, pp. S96-s103, DOI: 10.15171/jlms.2019.S17, 2019.

[41] J. A. C. Sterne, J. Savović, M. J. Page, R. G. Elbers, N. S. Blencowe, I. Boutron, C. J. Cates, H.-Y. Cheng, M. S. Corbett, S. M. Eldridge, J. R. Emberson, M. A. Hernán, S. Hopewell, A. Hróbjartsson, D. R. Junqueira, P. Jüni, J. J. Kirkham, T. Lasserson, T. Li, A. McAleenan, B. C. Reeves, S. Shepperd, I. Shrier, L. A. Stewart, K. Tilling, I. R. White, P. F. Whiting, J. P. T. Higgins, "RoB 2: a revised tool for assessing risk of bias in randomised trials," BMJ, vol. 366, 2019.

[42] G. O. Samuel, S. Hoffmann, R. A. Wright, M. M. Lalu, G. Patlewicz, R. A. Becker, G. L. DeGeorge, D. Fergusson, T. Hartung, R. J. Lewis, M. L. Stephens, "Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: a scoping review," Environment International, vol. 92-93, pp. 630-646, DOI: 10.1016/j.envint.2016.03.010, 2016.

[43] A. A. Karpov, D. V. Udalova, M. G. Pliss, M. M. Galagudza, "Can the outcomes of mesenchymal stem cell-based therapy for myocardial infarction be improved? Providing weapons and armour to cells," Cell Proliferation, vol. 50 no. 2,DOI: 10.1111/cpr.12316, 2017.

[44] W. T. Li, Y. C. Leu, J. L. Wu, "Red-light light-emitting diode irradiation increases the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells," Photomedicine and Laser Surgery, vol. 28, pp. S-157-S-165, DOI: 10.1089/pho.2009.2540, 2010.

[45] M. J. Holder, M. R. Milward, W. M. Palin, M. A. Hadis, P. R. Cooper, "Effects of red light-emitting diode irradiation on dental pulp cells," Journal of Dental Research, vol. 91 no. 10, pp. 961-966, DOI: 10.1177/0022034512456040, 2012.

[46] I. S. Park, P. S. Chung, J. C. Ahn, A. Leproux, "Human adipose-derived stem cell spheroid treated with photobiomodulation irradiation accelerates tissue regeneration in mouse model of skin flap ischemia," Lasers in Medical Science, vol. 32 no. 8, pp. 1737-1746, DOI: 10.1007/s10103-017-2239-1, 2017.

[47] A. Babaee, S. N. Nematollahi-mahani, M. Shojaei, S. Dehghani-Soltani, M. Ezzatabadipour, "Effects of polarized and non-polarized red-light irradiation on proliferation of human Wharton's jelly-derived mesenchymal cells," Biochemical and Biophysical Research Communications, vol. 504 no. 4, pp. 871-877, DOI: 10.1016/j.bbrc.2018.09.010, 2018.

[48] K. L. D. Vale, D. A. Maria, L. C. Picoli, A. M. Deana, M. B. Mascaro, R. A. M. Ferrari, S. K. Bussadori, K. P. S. Fernandes, "The effects of photobiomodulation delivered by light-emitting diode on stem cells from human exfoliated deciduous teeth: a study on the relevance to pluripotent stem cell viability and proliferation," Photomedicine and Laser Surgery, vol. 35 no. 12, pp. 659-665, DOI: 10.1089/pho.2017.4279, 2017.

[49] A. Lipovsky, U. Oron, A. Gedanken, R. Lubart, "Low-level visible light (LLVL) irradiation promotes proliferation of mesenchymal stem cells," Lasers in Medical Science, vol. 28 no. 4, pp. 1113-1117, DOI: 10.1007/s10103-012-1207-z, 2013.

[50] A. Babaee, S. N. Nematollahi-Mahani, S. Dehghani-Soltani, M. Shojaei, M. Ezzatabadipour, "Photobiomodulation and gametogenic potential of human Wharton's jelly-derived mesenchymal cells," Biochemical and Biophysical Research Communications, vol. 514 no. 1, pp. 239-245, DOI: 10.1016/j.bbrc.2019.04.059, 2019.

[51] K. Kim, J. Lee, H. Jang, S. Park, J. Na, J. Myung, M. J. Kim, W. S. Jang, S. J. Lee, H. Kim, H. Myung, J. H. Kang, S. Shim, "Photobiomodulation enhances the angiogenic effect of mesenchymal stem cells to mitigate radiation-induced enteropathy," International Journal of Molecular Sciences, vol. 20 no. 5,DOI: 10.3390/ijms20051131, 2019.

[52] Y. Yuan, G. Yan, R. Gong, L. Zhang, T. Liu, C. Feng, W. du, Y. Wang, F. Yang, Y. Li, S. Guo, F. Ding, W. Ma, E. Idiiatullina, V. Pavlov, Z. Han, B. Cai, L. Yang, "Effects of blue light emitting diode irradiation on the proliferation, apoptosis and differentiation of bone marrow-derived mesenchymal stem cells," Cellular Physiology and Biochemistry, vol. 43 no. 1, pp. 237-246, DOI: 10.1159/000480344, 2017.

[53] S. Dehghani Soltani, A. Babaee, M. Shojaei, P. Salehinejad, F. Seyedi, M. JalalKamali, S. N. Nematollahi-Mahani, "Different effects of energy dependent irradiation of red and green lights on proliferation of human umbilical cord matrix-derived mesenchymal cells," Lasers in Medical Science, vol. 31 no. 2, pp. 255-261, DOI: 10.1007/s10103-015-1846-y, 2016.

[54] T. Zhu, Y. Wu, X. Zhou, Y. Yang, Y. Wang, "Irradiation by blue light-emitting diode enhances osteogenic differentiation in gingival mesenchymal stem cells in vitro," Lasers in Medical Science, vol. 34 no. 7, pp. 1473-1481, DOI: 10.1007/s10103-019-02750-3, 2019.

[55] W. T. Li, Y. C. Leu, "Effects of low level red-light irradiation on the proliferation of mesenchymal stem cells derived from rat bone marrow," Annu Int Conf IEEE Eng Med Biol Soc, vol. 2007, pp. 5830-5833, DOI: 10.1109/IEMBS.2007.4353673, 2007.

[56] B. Mvula, T. J. Moore, H. Abrahamse, "Effect of low-level laser irradiation and epidermal growth factor on adult human adipose-derived stem cells," Lasers in Medical Science, vol. 25 no. 1, pp. 33-39, DOI: 10.1007/s10103-008-0636-1, 2010.

[57] H. Tuby, L. Maltz, U. Oron, "Low-level laser irradiation (LLLI) promotes proliferation of mesenchymal and cardiac stem cells in culture," Lasers in Surgery and Medicine, vol. 39 no. 4, pp. 373-378, DOI: 10.1002/lsm.20492, 2007.

[58] M. R. Hamblin, "Mechanisms and mitochondrial redox signaling in photobiomodulation," Photochemistry and Photobiology, vol. 94 no. 2, pp. 199-212, DOI: 10.1111/php.12864, 2018.

[59] E. Priglinger, J. Maier, S. Chaudary, C. Lindner, C. Wurzer, S. Rieger, H. Redl, S. Wolbank, P. Dungel, "Photobiomodulation of freshly isolated human adipose tissue-derived stromal vascular fraction cells by pulsed light-emitting diodes for direct clinical application," Journal of Tissue Engineering and Regenerative Medicine, vol. 12 no. 6, pp. 1352-1362, DOI: 10.1002/term.2665, 2018.

[60] A. Ekizer, T. Uysal, E. Güray, Y. Yüksel, "Light-emitting diode photobiomodulation: effect on bone formation in orthopedically expanded suture in rats--early bone changes," Lasers in Medical Science, vol. 28 no. 5, pp. 1263-1270, DOI: 10.1007/s10103-012-1214-0, 2013.

[61] J. T. Eells, M. T. Wong-Riley, J. VerHoeve, M. Henry, E. V. Buchman, M. P. Kane, L. J. Gould, R. Das, M. Jett, B. D. Hodgson, D. Margolis, H. T. Whelan, "Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy," Mitochondrion, vol. 4 no. 5-6, pp. 559-567, DOI: 10.1016/j.mito.2004.07.033, 2004.

[62] A. Mamalis, D. Siegel, J. Jagdeo, "Visible red light emitting diode photobiomodulation for skin fibrosis: key molecular pathways," Curr Dermatol Rep, vol. 5 no. 2, pp. 121-128, DOI: 10.1007/s13671-016-0141-x, 2016.

[63] M. A. Dall Agnol, R. A. Nicolau, C. J. de Lima, E. Munin, "Comparative analysis of coherent light action (laser) versus non-coherent light (light-emitting diode) for tissue repair in diabetic rats," Lasers in Medical Science, vol. 24 no. 6, pp. 909-916, DOI: 10.1007/s10103-009-0648-5, 2009.

[64] X. Gao, D. Xing, "Molecular mechanisms of cell proliferation induced by low power laser irradiation," Journal of Biomedical Science, vol. 16 no. 1,DOI: 10.1186/1423-0127-16-4, 2009.

[65] S. W. Jere, N. N. Houreld, H. Abrahamse, "Photobiomodulation at 660 nm stimulates proliferation and migration of diabetic wounded cells via the expression of epidermal growth factor and the JAK/STAT pathway," Journal of Photochemistry and Photobiology. B, vol. 179, pp. 74-83, DOI: 10.1016/j.jphotobiol.2017.12.026, 2018.

[66] J. E. Kim, Y. J. Woo, K. M. Sohn, K. H. Jeong, H. Kang, "Wnt/ β -catenin and ERK pathway activation: a possible mechanism of photobiomodulation therapy with light-emitting diodes that regulate the proliferation of human outer root sheath cells," Lasers in Surgery and Medicine, vol. 49 no. 10, pp. 940-947, DOI: 10.1002/lsm.22736, 2017.

[67] Y. H. Rhee, J. H. Moon, J. Y. Jung, C. Oh, J. C. Ahn, P. S. Chung, "Effect of photobiomodulation therapy on neuronal injuries by ouabain: the regulation of Na, K-ATPase; Src; and mitogen-activated protein kinase signaling pathway," BMC Neuroscience, vol. 20 no. 1,DOI: 10.1186/s12868-019-0499-3, 2019.

[68] S. Maacha, H. Sidahmed, S. Jacob, G. Gentilcore, R. Calzone, J. C. Grivel, C. Cugno, "Paracrine mechanisms of mesenchymal stromal cells in angiogenesis," Stem Cells International, vol. 2020,DOI: 10.1155/2020/4356359, 2020.

[69] X. L. Fan, Y. Zhang, X. Li, Q. L. Fu, "Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy," Cellular and Molecular Life Sciences, vol. 77 no. 14, pp. 2771-2794, DOI: 10.1007/s00018-020-03454-6, 2020.

[70] T. S. de Oliveira, A. J. Serra, M. T. Manchini, V. Bassaneze, J. E. Krieger, P. de Tarso Camillo de Carvalho, D. E. Antunes, D. S. Bocalini, P. J. Ferreira Tucci, J. A. Silva, "Effects of low level laser therapy on attachment, proliferation, and gene expression of VEGF and VEGF receptor 2 of adipocyte-derived mesenchymal stem cells cultivated under nutritional deficiency," Lasers in Medical Science, vol. 30 no. 1, pp. 217-223, DOI: 10.1007/s10103-014-1646-9, 2015.

[71] H. Tuby, L. Maltz, U. Oron, "Modulations of VEGF and iNOS in the rat heart by low level laser therapy are associated with cardioprotection and enhanced angiogenesis," Lasers in Surgery and Medicine, vol. 38 no. 7, pp. 682-688, DOI: 10.1002/lsm.20377, 2006.

[72] J. Szymanska, K. Goralczyk, J. J. Klawe, M. Lukowicz, M. Michalska, B. Goralczyk, P. Zalewski, J. L. Newton, L. Gryko, A. Zajac, D. Rosc, "Phototherapy with low-level laser influences the proliferation of endothelial cells and vascular endothelial growth factor and transforming growth factor-beta secretion," Journal of Physiology and Pharmacology, vol. 64 no. 3, pp. 387-391, 2013.