Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators.

Jianglin Wang; Xueyan Jiang; Lixin Zhao; Shengjia Zuo; Xiantong Chen; Lingmin Zhang; Zhongxiao Lin; Xiaoya Zhao; Yuyan Qin; Xinke Zhou; Xi-yong YU

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Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators.

Author: Jianglin WANG ¹ ; Xueyan JIANG ¹ ; Lixin ZHAO ¹ ; Shengjia ZUO ¹ ; Xiantong CHEN ¹ ; Lingmin ZHANG ¹ ; Zhongxiao LIN ¹ ; Xiaoya ZHAO ¹ ; Yuyan QIN ¹ ; Xinke ZHOU ¹ ; Xi-Yong YU ¹
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1. Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
Publication Type:Journal Article
Keywords: CRISPR/Cas9; Cardiac transcription factors; Human foreskin fibroblasts; Induced cardiac progenitor cells; Lineage reprogramming; SAM
From: Acta Pharmaceutica Sinica B 2020;10(2):313-326
CountryChina
Language:English
Abstract: Overexpression of exogenous lineage-determining factors succeeds in directly reprogramming fibroblasts to various cell types. Several studies have reported reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs). CRISPR/Cas9-mediated gene activation is a potential approach for cellular reprogramming due to its high precision and multiplexing capacity. Here we show lineage reprogramming to iCPCs through a dead Cas9 (dCas9)-based transcription activation system. Targeted and robust activation of endogenous cardiac factors, including GATA4, HAND2, MEF2C and TBX5 (G, H, M and T; GHMT), can reprogram human fibroblasts toward iCPCs. The iCPCs show potentials to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells . Addition of MEIS1 to GHMT induces cell cycle arrest in G2/M and facilitates cardiac reprogramming. Lineage reprogramming of human fibroblasts into iCPCs provides a promising cellular resource for disease modeling, drug discovery and individualized cardiac cell therapy.