Article

The transplantation of rapamycin-treated senescent human mesenchymal stem cells with enhanced proangiogenic activity promotes neovascularization and ischemic limb salvage in mice

Yu-lin Cao1, Wen-lan Chen1, Qian Lei2, Fei Gao3, Wen-xiang Ren1, Li Chen3, Hong-xiang Wang3, Ting Chen4, Qiu-bai Li1,4, Zhi-chao Chen1
1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2 Department of Laboratory Medicine, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
3 Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
4 Hubei Engineering Research Center for Application of Extracelluar Vesicle, Hubei University of Science and Technology, Xianning 437100, China
Correspondence to: Qiu-bai Li: qiubaili@hust.edu.cn, Zhi-chao Chen: chenzhichao@hust.edu.cn,
DOI: 10.1038/s41401-022-00896-5
Received: 17 December 2021
Accepted: 6 March 2022
Advance online: 1 April 2022

Abstract

Few therapies can reverse the proangiogenic activity of senescent mesenchymal stromal/stem cells (MSCs). In this study, we investigated the effects of rapamycin on the proangiogenic ability of senescent human umbilical cord MSCs (UCMSCs). An in vitro replicative senescent cell model was established in cultured UCMSCs. We found that late passage (P25 or later) UCMSCs (LP- UCMSCs) exhibited impaired proangiogenic abilities. Treatment of P25 UCMSCs with rapamycin (900 nM) reversed the senescent phenotype and notably enhanced the proangiogenic activity of senescent UCMSCs. In a nude mouse model of hindlimb ischemia, intramuscular injection of rapamycin-treated P25 UCMSCs into the ischemic limb significantly promoted neovascularization and ischemic limb salvage. We further analyzed the changes in the expression of angiogenesis-associated genes in rapamycin-primed MSCs and found higher expression of several genes related to angiogenesis, such as VEGFR2 and CTGF/CCN2, in primed cells than in unprimed MSCs. Taken together, our data demonstrate that rapamycin is a potential drug to restore the proangiogenic activity of senescent MSCs, which is of importance in treating ischemic diseases and tissue engineering.
Keywords: rapamycin; mesenchymal stem cells; cellular senescence; ischemic disease; hindlimb ischemia; UCMSCs

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