Original articles
Jianglin Wang, Xueyan Jiang, Lixin Zha, Shengjia Zu, Xiantong Che, Lingmin Zhan, Zhongxiao Li, Xiaoya Zha, Yuyan Qi, Xinke Zho, Xi-Yong Yu. Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 313-326

Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators
Jianglin Wang, Xueyan Jiang, Lixin Zha, Shengjia Zu, Xiantong Che, Lingmin Zhan, Zhongxiao Li, Xiaoya Zha, Yuyan Qi, Xinke Zho, Xi-Yong Yu
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
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 in vitro. 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.
Key words:    Lineage reprogramming    Human foreskin fibroblasts    Induced cardiac progenitor cells    CRISPR/Cas9    SAM    Cardiac transcription factors   
Received: 2019-04-29     Revised: 2019-08-26
DOI: 10.1016/j.apsb.2019.09.003
Funds: This work was supported by the National Natural Science Foundation of China (grant numbers 81330007 and U1601227 to XiYong Yu; 81700382 to Lingmin Zhang), and the Science and Technology Programs of Guangdong Province (grant numbers 2015B020225006 to Xi-Yong Yu, China).
Corresponding author: Xi-Yong Yu     Email:yuxycn@aliyun.com
Author description:
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Jianglin Wang
Xueyan Jiang
Lixin Zha
Shengjia Zu
Xiantong Che
Lingmin Zhan
Zhongxiao Li
Xiaoya Zha
Yuyan Qi
Xinke Zho
Xi-Yong Yu

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