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J Cell Mol Med. 2019 Apr;23(4):2943-2953. doi: 10.1111/jcmm.14202. Epub 2019 Feb 7.

Critical role of Lin28-TNFR2 signalling in cardiac stem cell activation and differentiation.

Xiang Q1,2,3,4, Yang B1, Li L1,2,3, Qiu B1, Qiu C1, Gao XB5, Zhou HJ1, Min W1.

Author information

1
Yale Stem Center, Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
2
Translational Medicine Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
3
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
4
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
5
Department of Comparative Medicine and Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.

Abstract

Tumour necrotic factor receptor-2 (TNFR2) has been to be cardiac-protective and is expressed in cardiac progenitor cells. Our goal is to define the mechanism for TNFR2-mediated cardiac stem cell activation and differentiation. By employing a protocol of in vitro cardiac stem cell (CSC) differentiation from human inducible pluripotent stem cell (hiPSC), we show that expression of TNFR2 precedes expression of CSC markers followed by expression of mature cardiomyocyte proteins. Activation of TNFR2 by a specific agonist promotes whereas inhibition of TNFR2 by neutralizing antibody diminishes hiPSC-based CSC differentiation. Interestingly, pluripotent cell factor RNA-binding protein Lin28 enhances TNFR2 protein expression in early CSC activation by directly binding to a conserved Lin28-motif within the 3'UTR of Tnfr2 mRNA. Furthermore, inhibition of Lin28 blunts TNFR2 expression and TNFR2-dependent CSC activation and differentiation. Our study demonstrates a critical role of Lin28-TNFR2 axis in CSC activation and survival, providing a novel strategy to enhance stem cell-based therapy for the ischaemic heart diseases.

KEYWORDS:

Lin28; TNFR2; cardiac stem cell; differentiation

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