Abstract

Although cellular therapy has been proposed for inflammation‐related disorders such as periodontitis for decades, clinical application has been unsuccessful. One explanation for these disappointing results is that the functions of stem cells are substantially compromised when they are transplanted into an inflammatory in vivo milieu. Considering the previous finding that P2X7 receptor (P2X7R) gene modification is able to reverse inflammation‐mediated impairment of periodontal ligament stem cells (PDLSCs), we further hypothesized that cells subjected to P2X7R gene transduction also exert influences on other cells within an in vivo milieu via an exosome‐mediated paracrine mechanism. To define the paracrine ability of P2X7R gene‐modified cells, P2X7R gene‐modified stem cell‐derived conditional medium (CM‐Ad‐P2X7) and exosomes (Exs‐Ad‐P2X7) were used to incubate PDLSCs. In an inflammatory osteogenic microenvironment, inflammation‐mediated changes in PDLSCs were substantially reduced, as shown by quantitative real‐time PCR (qRT‐PCR) analysis, Western blot analysis, alkaline phosphatase (ALP) staining/activity assays, and Alizarin red staining. In addition, the Agilent miRNA microarray system combined with qRT‐PCR analysis revealed that miR‐3679‐5p, miR‐6515‐5p, and miR‐6747‐5p were highly expressed in Exs‐Ad‐P2X7. Further functional tests and luciferase reporter assays revealed that miR‐3679‐5p and miR‐6747‐5p bound directly to the GREM‐1 protein, while miR‐6515‐5p bound to the GREM‐1 protein indirectly; these effects combined to rescue inflammation‐compromised PDLSCs from dysfunction. Thus, in addition to maintaining their robust functionality under inflammatory conditions, P2X7R gene‐modified stem cells may exert positive influences on their neighbors via a paracrine mechanism, pointing to a novel strategy for modifying the harsh local microenvironment to accommodate stem cells and promote improved tissue regeneration.

Details

Title
Exosomes derived from P2X7 receptor gene‐modified cells rescue inflammation‐compromised periodontal ligament stem cells from dysfunction
Author
Xin‐Yue Xu 1   VIAFID ORCID Logo  ; Bei‐Min Tian 2 ; Yu, Xia 2 ; Yun‐Long Xia 3 ; Li, Xuan 1 ; Zhou, Huan 1 ; Yi‐Zhou Tan 2 ; Fa‐Ming Chen 2   VIAFID ORCID Logo 

 State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, People's Republic of China; Shaanxi Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environments, Fourth Military Medical University, Xi'an, People's Republic of China 
 State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, People's Republic of China 
 Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China 
Pages
1414-1430
Section
TISSUE ENGINEERING AND REGENERATIVE MEDICINE
Publication year
2020
Publication date
Nov 2020
Publisher
Oxford University Press
ISSN
21576564
e-ISSN
21576580
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2453328140
Copyright
© 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.