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FGF4 and ascorbic acid enhance the maturation of induced cardiomyocytes by activating JAK2–STAT3 signaling

황선욱|Park Jae Hyoung|Yoon Da Eun|Kim Kyoungmi|Jun Seongmin|Song Myeong-Hwa|Choi Seung-Cheol|Noh Ji-Min|Kim Kyung Seob|Kim Minseok|Lim Do-Sun
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 2231-2245|DOI 10.1038/s12276-024-01321-z

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주제분류생화학

초록

Direct cardiac reprogramming represents a novel therapeutic strategy to convert non-cardiac cells such as fibroblasts into cardiomyocytes (CMs). This process involves essential transcription factors, such as Mef2c, Gata4, Tbx5 (MGT), MESP1, and MYOCD (MGTMM). However, the small molecules responsible for inducing immature induced CMs (iCMs) and the signaling mechanisms driving their maturation remain elusive. Our study explored the effects of various small molecules on iCM induction and discovered that the combination of FGF4 and ascorbic acid (FA) enhances CM markers, exhibits organized sarcomere and T-tubule structures, and improves cardiac function. Transcriptome analysis emphasized the importance of ECM-integrin-focal adhesions and the upregulation of the JAK2–STAT3 and TGFB signaling pathways in FA-treated iCMs. Notably, JAK2–STAT3 knockdown affected TGFB signaling and the ECM and downregulated mature CM markers in FA-treated iCMs. Our findings underscore the critical role of the JAK2–STAT3 signaling pathway in activating TGFB signaling and ECM synthesis in directly reprogrammed CMs.

Abstract

Direct cardiac reprogramming represents a novel therapeutic strategy to convert non-cardiac cells such as fibroblasts into cardiomyocytes (CMs). This process involves essential transcription factors, such as Mef2c, Gata4, Tbx5 (MGT), MESP1, and MYOCD (MGTMM). However, the small molecules responsible for inducing immature induced CMs (iCMs) and the signaling mechanisms driving their maturation remain elusive. Our study explored the effects of various small molecules on iCM induction and discovered that the combination of FGF4 and ascorbic acid (FA) enhances CM markers, exhibits organized sarcomere and T-tubule structures, and improves cardiac function. Transcriptome analysis emphasized the importance of ECM-integrin-focal adhesions and the upregulation of the JAK2–STAT3 and TGFB signaling pathways in FA-treated iCMs. Notably, JAK2–STAT3 knockdown affected TGFB signaling and the ECM and downregulated mature CM markers in FA-treated iCMs. Our findings underscore the critical role of the JAK2–STAT3 signaling pathway in activating TGFB signaling and ECM synthesis in directly reprogrammed CMs.

참고문헌 (55)

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