Qishan Chen1, Mei Yang1, Hong Wu1, Jiaojiao Zhou2, Weina Wang1, Hongkun Zhang3, Lin Zhao4, Jianhua Zhu1, Bin Zhou5, Qingbo Xu6, Li Zhang7. 1. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 2. Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 3. Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 4. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 5. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 6. Cardiovascular Division, British Heart Foundation Centre, King's College London, London, United Kingdom. Electronic address: qingbo.xu@kcl.ac.uk. 7. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: li_zhang@zju.edu.cn.
Abstract
AIMS: Accumulating evidence indicates the presence of vascular stem/progenitor cells that may play a role in endothelial repair and lesion formation in the injured artery, in which c-kit+ stem/progenitor cells have been reported to differentiate into endothelial and smooth muscle cells in vitro and in ischemic tissue. In this study, we investigated whether and how endogenous c-kit+ stem/progenitor cells contribute to vascular injury and neointima formation in vivo. METHODS AND RESULTS: We created Kit-CreERxRosa26-RFP mice and performed genetic lineage tracing analysis of c-kit+ stem/progenitor cells in injury-induced neointima formation in vivo. We provide direct evidence that endogenous c-kit+ stem/progenitor cells minimally differentiate into endothelial or smooth muscle cells facilitating vascular repair, but predominantly generate monocytes/macrophages and granulocytes contributing to vascular immuno-inflammatory response to endothelial injury. Although c-kit+ cells reside in both bone marrow and vessel wall, bone marrow transplantation data indicate that bone marrow-derived c-kit+ cells are the main source for enhancing neointima formation. Furthermore, treatment of ACK2, a c-kit receptor antagonizer, attenuates neointimal hyperplasia after injury at least in part by depleting c-kit+ cells and their generated progeny. CONCLUSIONS: c-kit+ stem/progenitor cells are not a main source for endothelial regeneration and smooth muscle accumulation of the large artery injury, but a plausible interventional approach to reduce vascular immuno-inflammatory response and subsequently to ameliorate vascular lesions.
AIMS: Accumulating evidence indicates the presence of vascular stem/progenitor cells that may play a role in endothelial repair and lesion formation in the injured artery, in which c-kit+ stem/progenitor cells have been reported to differentiate into endothelial and smooth muscle cells in vitro and in ischemic tissue. In this study, we investigated whether and how endogenous c-kit+ stem/progenitor cells contribute to vascular injury and neointima formation in vivo. METHODS AND RESULTS: We created Kit-CreERxRosa26-RFP mice and performed genetic lineage tracing analysis of c-kit+ stem/progenitor cells in injury-induced neointima formation in vivo. We provide direct evidence that endogenous c-kit+ stem/progenitor cells minimally differentiate into endothelial or smooth muscle cells facilitating vascular repair, but predominantly generate monocytes/macrophages and granulocytes contributing to vascular immuno-inflammatory response to endothelial injury. Although c-kit+ cells reside in both bone marrow and vessel wall, bone marrow transplantation data indicate that bone marrow-derived c-kit+ cells are the main source for enhancing neointima formation. Furthermore, treatment of ACK2, a c-kit receptor antagonizer, attenuates neointimal hyperplasia after injury at least in part by depleting c-kit+ cells and their generated progeny. CONCLUSIONS: c-kit+ stem/progenitor cells are not a main source for endothelial regeneration and smooth muscle accumulation of the large artery injury, but a plausible interventional approach to reduce vascular immuno-inflammatory response and subsequently to ameliorate vascular lesions.
Authors: Mariana Di Luca; Emma Fitzpatrick; Denise Burtenshaw; Weimin Liu; Jay-Christian Helt; Roya Hakimjavadi; Eoin Corcoran; Yusof Gusti; Daniel Sheridan; Susan Harman; Catriona Lally; Eileen M Redmond; Paul A Cahill Journal: NPJ Regen Med Date: 2021-03-01