Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p
Background: Diabetic foot is caused by ischemic disease of lower extremities of diabetic patients, and the effective therapy is very limited. Mesenchymal stem cells (MSCs) based cell therapy had been developed into a new treatment strategy for diabetic foot clinically. However, the underlying molecu...
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Elsevier
2021-04-01
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Series: | Stem Cell Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506121000817 |
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doaj-869605bda13a44759317cf91b0d10434 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chen Huang Wenfeng Luo Qian Wang Yufeng Ye Jinghui Fan Li Lin Congying Shi Wei Wei Hanwei Chen Yangzhe Wu Yukuan Tang |
spellingShingle |
Chen Huang Wenfeng Luo Qian Wang Yufeng Ye Jinghui Fan Li Lin Congying Shi Wei Wei Hanwei Chen Yangzhe Wu Yukuan Tang Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p Stem Cell Research Diabetic foot Exosomes Mesenchymal stem cells miRNA Angiogenesis |
author_facet |
Chen Huang Wenfeng Luo Qian Wang Yufeng Ye Jinghui Fan Li Lin Congying Shi Wei Wei Hanwei Chen Yangzhe Wu Yukuan Tang |
author_sort |
Chen Huang |
title |
Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p |
title_short |
Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p |
title_full |
Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p |
title_fullStr |
Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p |
title_full_unstemmed |
Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5p |
title_sort |
human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome mirna-21-5p |
publisher |
Elsevier |
series |
Stem Cell Research |
issn |
1873-5061 |
publishDate |
2021-04-01 |
description |
Background: Diabetic foot is caused by ischemic disease of lower extremities of diabetic patients, and the effective therapy is very limited. Mesenchymal stem cells (MSCs) based cell therapy had been developed into a new treatment strategy for diabetic foot clinically. However, the underlying molecular mechanism remains to be fully addressed. Exosomes (extracellular vesicles) secreted by MSCs may play crucial role in the processes of MSCs mediated inhibition of inflammatory microenvironment as well as pro-angiogenesis of ischemic tissue of diabetic foot. Methods: Exosomes were isolated from MSCs using ultracentrifugation, and further characterized by the nanoparticle tracking analyzer and flow cytometry. Moreover, RNA sequencing, Western Blot, in vitro cell proliferation, in vivo pro-angiogenesis, as well as ischemic repairment of diabetic foot through rat model were performed to evaluate exosome physiological functions. Results: We found that inflammatory cytokines (tumor necrosis factor α and interleukin-6) and vascular cell adhesion molecule-1 induced MSCs to secrete exosomes heterogeneously, including exosome size and quantity. Through RNA sequencing, we defined a new proangiogenic miRNA, miRNA-21-5p. Further knockdown and overexpression of miRNA-21-5p by manipulating MSCs validated the biological activity of exosome miRNA-21-5p, including in vitro cell proliferation, in vivo pro-angiogenesis in Chick Chorioallantoic Membrane (CAM) assay, and in vivo pro-angiogenesis experiments (tissue injury and repair) in diabetic rat models. Furthermore, we discovered that exosomemiRNA-21-5p promoted angiogenesis through upregulations of vascular endothelial growth factor receptor (VEGFR) as well as activations of serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK). Together, our work suggested miRNA-21-5p could be a novel mechanism by which exosomes promote ischemic tissue repair and angiogenesis. Meanwhile, miRNA-21-5p could be potentially developed into a new biomarker for exosomes of MSCs to treat diabetic foot. Conclusions: miRNA-21-5p is a new biomarker and a novel mechanism by which exosomes promote ischemic tissue repair and angiogenesis of diabetic foot. Our work could not only provide new scientific evidences for revealing pro-angiogenesis mechanism of MSCs, but also eventually benefit MSCs-based clinical therapy for diabetic foot of diabetes patients. |
topic |
Diabetic foot Exosomes Mesenchymal stem cells miRNA Angiogenesis |
url |
http://www.sciencedirect.com/science/article/pii/S1873506121000817 |
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doaj-869605bda13a44759317cf91b0d104342021-03-25T04:27:46ZengElsevierStem Cell Research1873-50612021-04-0152102235Human mesenchymal stem cells promote ischemic repairment and angiogenesis of diabetic foot through exosome miRNA-21-5pChen Huang0Wenfeng Luo1Qian Wang2Yufeng Ye3Jinghui Fan4Li Lin5Congying Shi6Wei Wei7Hanwei Chen8Yangzhe Wu9Yukuan Tang10Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR China; Medical Imaging Institute of Panyu, Guangzhou 511400, Guangdong, PR ChinaGuangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR ChinaGuangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR ChinaGuangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR China; Medical Imaging Institute of Panyu, Guangzhou 511400, Guangdong, PR ChinaGuangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR ChinaZhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Zhuhai 519000, Guangdong, PR China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, Guangdong, PR ChinaInstitution of GuangDong Cord Blood Bank, Guangzhou 510700, PR ChinaInstitution of GuangDong Cord Blood Bank, Guangzhou 510700, PR ChinaGuangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR China; Medical Imaging Institute of Panyu, Guangzhou 511400, Guangdong, PR ChinaZhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Zhuhai 519000, Guangdong, PR China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, Guangdong, PR China; Corresponding authors at: Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Zhuhai 519000, Guangdong, PR China (Y. Wu). Guangzhou Panyu Central Hospital, Guangzhou,511400, Guangdong, P.R. China (Y. Tang).Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong, PR China; Corresponding authors at: Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Zhuhai 519000, Guangdong, PR China (Y. Wu). Guangzhou Panyu Central Hospital, Guangzhou,511400, Guangdong, P.R. China (Y. Tang).Background: Diabetic foot is caused by ischemic disease of lower extremities of diabetic patients, and the effective therapy is very limited. Mesenchymal stem cells (MSCs) based cell therapy had been developed into a new treatment strategy for diabetic foot clinically. However, the underlying molecular mechanism remains to be fully addressed. Exosomes (extracellular vesicles) secreted by MSCs may play crucial role in the processes of MSCs mediated inhibition of inflammatory microenvironment as well as pro-angiogenesis of ischemic tissue of diabetic foot. Methods: Exosomes were isolated from MSCs using ultracentrifugation, and further characterized by the nanoparticle tracking analyzer and flow cytometry. Moreover, RNA sequencing, Western Blot, in vitro cell proliferation, in vivo pro-angiogenesis, as well as ischemic repairment of diabetic foot through rat model were performed to evaluate exosome physiological functions. Results: We found that inflammatory cytokines (tumor necrosis factor α and interleukin-6) and vascular cell adhesion molecule-1 induced MSCs to secrete exosomes heterogeneously, including exosome size and quantity. Through RNA sequencing, we defined a new proangiogenic miRNA, miRNA-21-5p. Further knockdown and overexpression of miRNA-21-5p by manipulating MSCs validated the biological activity of exosome miRNA-21-5p, including in vitro cell proliferation, in vivo pro-angiogenesis in Chick Chorioallantoic Membrane (CAM) assay, and in vivo pro-angiogenesis experiments (tissue injury and repair) in diabetic rat models. Furthermore, we discovered that exosomemiRNA-21-5p promoted angiogenesis through upregulations of vascular endothelial growth factor receptor (VEGFR) as well as activations of serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK). Together, our work suggested miRNA-21-5p could be a novel mechanism by which exosomes promote ischemic tissue repair and angiogenesis. Meanwhile, miRNA-21-5p could be potentially developed into a new biomarker for exosomes of MSCs to treat diabetic foot. Conclusions: miRNA-21-5p is a new biomarker and a novel mechanism by which exosomes promote ischemic tissue repair and angiogenesis of diabetic foot. Our work could not only provide new scientific evidences for revealing pro-angiogenesis mechanism of MSCs, but also eventually benefit MSCs-based clinical therapy for diabetic foot of diabetes patients.http://www.sciencedirect.com/science/article/pii/S1873506121000817Diabetic footExosomesMesenchymal stem cellsmiRNAAngiogenesis |