miR-214-3p-Sufu-GLI1 is a novel regulatory axis controlling inflammatory smooth muscle cell differentiation from stem cells and neointimal hyperplasia

Stem Cell Research & Therapy

Rui Xiao¹  Wei Wu¹  Weiwei An¹  Eithne Margaret Maguire¹  Mei Yang²  Feng Yang²  Qishan Chen²  Shiping He³  Qingzhong Xiao⁴  Li Zhang⁵  Wen Wang⁶ 

[1] Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, London, UK;Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, London, UK;Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, 310003, Hangzhou, Zhejiang, China;Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, London, UK;Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, EC1M 6BQ, London, UK;Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, London, UK;Key Laboratory of Cardiovascular Diseases at The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou, 511436, Guangdong, China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Panyu District, 511436, Guangzhou, Guangdong, China;Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, 310003, Hangzhou, Zhejiang, China;Department of Cardiology, and Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 200092, Shanghai, China;Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, EC1M 6BQ, London, UK;

关键词: Adventitia stem/progenitor cells;    Neointima formation;    Inflammatory smooth muscle cell;    Smooth muscle cell differentiation;    MicroRNA-214;    MicroRNAs;    Suppressor of fused (Sufu);   

DOI  :  10.1186/s13287-020-01989-w

来源: Springer

【 摘 要 】

BackgroundInflammatory smooth muscle cells (iSMCs) generated from adventitial stem/progenitor cells (AdSPCs) have been recognised as a new player in cardiovascular disease, and microRNA-214-3p (miR-214-3p) has been implicated in mature vascular SMC functions and neointimal hyperplasia. Here, we attempted to elucidate the functional involvements of miR-214-3p in iSMC differentiation from AdSPCs and unravel the therapeutic potential of miR-214-3p signalling in AdSPCs for injury-induced neointimal hyperplasia.MethodsThe role of miR-214-3p in iSMC differentiation from AdSPCs was evaluated by multiple biochemistry assays. The target of miR-214-3p was identified through binding site mutation and reporter activity analysis. A murine model of injury-induced arterial remodelling and stem cell transplantation was conducted to study the therapeutic potential of miR-214-3p. RT-qPCR analysis was performed to examine the gene expression in healthy and diseased human arteries.ResultsmiR-214-3p prevented iSMC differentiation/generation from AdSPCs by restoring sonic hedgehog-glioma-associated oncogene 1 (Shh-GLI1) signalling. Suppressor of fused (Sufu) was identified as a functional target of miR-214-3p during iSMC generation from AdSPCs. Mechanistic studies revealed that miR-214-3p over-expression or Sufu inhibition can promote nuclear accumulation of GLI1 protein in AdSPCs, and the consensus sequence (GACCACCCA) for GLI1 binding within smooth muscle alpha-actin (SMαA) and serum response factor (SRF) gene promoters is required for their respective regulation by miR-214-3p and Sufu. Additionally, Sufu upregulates multiple inflammatory gene expression (IFNγ, IL-6, MCP-1 and S100A4) in iSMCs. In vivo, transfection of miR-214-3p into the injured vessels resulted in the decreased expression level of Sufu, reduced iSMC generation and inhibited neointimal hyperplasia. Importantly, perivascular transplantation of AdSPCs increased neointimal hyperplasia, whereas transplantation of AdSPCs over-expressing miR-214-3p prevented this. Finally, decreased expression of miR-214-3p but increased expression of Sufu was observed in diseased human arteries.ConclusionsWe present a previously unexplored role for miR-214-3p in iSMC differentiation and neointima iSMC hyperplasia and provide new insights into the therapeutic effects of miR-214-3p in vascular disease.

【 授权许可】

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