Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice

Jiaqi Sun,Xiaoyong Chen,Jiancheng Wang,Weijun Huang,Yubao Fan,Jianye Cai,Tao Wang,Ke Qin ,Yinong Huang,Jianbin Gong ,Wei Zhang,Bin Wang,Yi Wang,Yuanchen Ma,Yuan Qiu,Yili Wei,Lihua Hu ,Jierui Chen,Shuwei Zheng,Chuanfeng Xiong,Xiaoping Li,Andy Peng Xiang,Weiqiang Li

doi:10.1038/s41467-020-19042-y

Abstract

Pericytes play essential roles in blood–brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRβ, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.

Highlights

Pericytes play essential roles in blood–brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders the underlying mechanism remains largely unknown
It has long been recognized that brain microvascular endothelial cells (BMECs) play an essential role in the maintenance of the BBB3 and the tight junctions (TJs), which are composed of claudin-5, Occludin, and zonula occludens-1 (ZO-1) formed by BMECs are critical for modulating the structural integrity of the BBB5,6
In this study, we successfully derived pericyte-like cells with cranial neural crest origin from human pluripotent stem cells

Summary

Introduction

Pericytes play essential roles in blood–brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders the underlying mechanism remains largely unknown. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases. The major contribution of pericytes to the BBB was reported in 2010 by two studies using pericyte-deficient mouse models They revealed that pericyte–endothelial cell interactions were critical in the establishment and maintenance of the BBB, and pericytes could influence BBB-specific gene expression patterns in BMECs and induce the polarization of astrocyte end-feet surrounding CNS blood vessels[7,8]. Recent transcriptomic studies suggest that pericytes express multiple transporters, receptors, and ion channels[1,11,12] These results indicate that pericytes play a fundamental role in regulating the chemical composition of the extracellular fluid surrounding the brain cells and cerebral blood flow[1]. The in vivo functional characteristics and therapeutic potential of hPSC-derived pericyte-like cells still need to be clarified

Methods

Results

Conclusion