Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1 alpha/TGF-beta 1/SMAD pathway

作者全名："Shi, Yan; Wang, Shang; Zhang, Weiwei; Zhu, Yihan; Fan, Zhiqiang; Huang, Yuesheng; Li, Furong; Yang, Ronghua"

作者地址："[Shi, Yan; Zhang, Weiwei; Li, Furong] Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Translat Med Collaborat Innovat Ctr, Shenzhen 518055, Peoples R China; [Shi, Yan; Zhang, Weiwei; Li, Furong] Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518055, Peoples R China; [Shi, Yan; Zhang, Weiwei; Li, Furong] Guangdong Engn Technol Res Ctr Stem Cell & Cell T, Shenzhen Key Lab Stem Cell Res & Clin Transformat, Shenzhen 518020, Peoples R China; [Shi, Yan] Jinan Univ, Affiliated Hosp 1, Guangzhou 510632, Peoples R China; [Wang, Shang] Chongqing Med Univ, Chongqing Key Lab Tradit Chinese Med Prevent & Cu, Chongqing 400016, Peoples R China; [Zhu, Yihan] Jiangxi Maternal & Child Hlth Hosp, Dept Plast & Aesthet Surg, Nanchang 330006, Jiangxi, Peoples R China; [Fan, Zhiqiang] Nanchang Med Coll, Affiliated Hosp 1, Jiangxi Prov Peoples Hosp, Orthopaed Trauma, Nanchang 330006, Jiangxi, Peoples R China; [Huang, Yuesheng] Southern Univ Sci & Technol, Southern Univ Sci & Technol Hosp, Inst Wound Repair & Regenerat Med, Dept Wound Repair, Shenzhen 518055, Peoples R China; [Yang, Ronghua] South China Univ Technol, Guangzhou Peoples Hosp 1, Dept Burn & Plast Surg, Guangzhou 510180, Guangdong, Peoples R China"

通信作者："Li, FR (通讯作者)，Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Translat Med Collaborat Innovat Ctr, Shenzhen 518055, Peoples R China.; Li, FR (通讯作者)，Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518055, Peoples R China.; Li, FR (通讯作者)，Guangdong Engn Technol Res Ctr Stem Cell & Cell T, Shenzhen Key Lab Stem Cell Res & Clin Transformat, Shenzhen 518020, Peoples R China.; Huang, YS (通讯作者)，Southern Univ Sci & Technol, Southern Univ Sci & Technol Hosp, Inst Wound Repair & Regenerat Med, Dept Wound Repair, Shenzhen 518055, Peoples R China.; Yang, RH (通讯作者)，South China Univ Technol, Guangzhou Peoples Hosp 1, Dept Burn & Plast Surg, Guangzhou 510180, Guangdong, Peoples R China."

来源：STEM CELL RESEARCH & THERAPY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000826088500010

JCR分区：Q1

影响因子：7.5

年份：2022

卷号：13

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Bone marrow mesenchymal stem cells; TGF-beta 1; Autophagy; Diabetic wound

摘要："Background: The biological activity and regenerative medicine of bone marrow mesenchymal stem cells (BMSCs) have been focal topics in the broad fields of diabetic wound repair. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated during BMSC treatment. Our previous studies have shown that hypoxia is not only a typical pathological phenomenon of wounds but also exerts a vital regulatory effect on cellular bioactivity. In this study, the beneficial effects of hypoxic BMSCs on the cellular behaviors of epidermal cells and diabetic wound healing were investigated. Method: The viability and secretion ability of hypoxic BMSCs were detected. The autophagy, proliferation and migration of HaCaT cells cultured with hypoxic BMSCs-derived conditioned medium were assessed by estimating the expression of autophagy-related proteins, MTS, EdU proliferation and scratch assays. And the role of the SMAD signaling pathway during hypoxic BMSC-evoked HaCaT cell autophagy was explored through a series of in vitro gain- and loss-of-function experiments. Finally, the therapeutic effects of hypoxic BMSCs were evaluated using full-thickness cutaneous diabetic wound model. Results: First, we demonstrated that hypoxic conditions intensify HIF-1 alpha-mediated TGF-beta 1 secretion by BMSCs. Then, the further data revealed that BMSC-derived TGF-beta 1 was responsible for the activation of epidermal cell autophagy, which contributed to the induction of epidermal cell proliferation and migration. Here, the SMAD signaling pathway was identified as downstream of BMSC-derived TGF-beta 1 to regulate HaCaT cell autophagy. Moreover, the administration of BMSCs to diabetic wounds increased epidermal autophagy and the rate of re-epithelialization, leading to accelerated healing, and these effects were significantly attenuated, accompanied by the downregulation of Smad2 phosphorylation levels due to TGF-beta 1 interference in BMSCs. Conclusion: In this report, we present evidence that uncovers a previously unidentified role of hypoxic BMSCs in regulating epidermal cell autophagy. The findings demonstrate that BMSC-based treatment by restoring epidermal cell autophagy could be an attractive therapeutic strategy for diabetic wounds and that the process is mediated by the HIF-1 alpha/TGF-beta 1/SMAD pathway."

基金机构："National Natural Science Foundation of China [82060350]; GuangDong Basic and Applied Basic Research Foundation [2021A1515011453, 2022A1515011380]; Industry-universityresearch Innovation Fund of Higher Education of China [2021JH028]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (No. 82060350), GuangDong Basic and Applied Basic Research Foundation (No. 2021A1515011453, No. 2022A1515011380), Industry-universityresearch Innovation Fund of Higher Education of China (No. 2021JH028)."