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Updated: Jul 8, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Robust small molecule-aided cardiac reprogramming systems selective to cardiac fibroblasts
Yanmeng Tao1, Yang Yang1, Zhenghao Yang1
1State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Educational Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
Scientists discovered a new chemical combination (2C) that significantly improves direct cardiac reprogramming, enhancing heart cell regeneration and disease modeling. This breakthrough offers a more selective and efficient method for cardiac repair and research.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Chemical Biology
Background:
- Direct cardiac reprogramming using factors like GMT (Gata4, Mef2c, Tbx5) shows promise for heart regeneration and disease modeling.
- Enhancing reprogramming efficiency often involves additional factors or chemicals, posing challenges in selectivity and delivery for in situ applications.
Purpose of the Study:
- To identify chemical compounds that enhance direct cardiac reprogramming efficiency and selectivity.
- To investigate the efficacy of identified compounds in reprogramming cardiac fibroblasts into cardiomyocyte-like cells.
Main Methods:
- Screening of 2000 chemicals with known biological activities.
- Evaluating the combination of SB431542 and Baricitinib (2C) for enhancing GMT-mediated cardiac reprogramming.
- Assessing the selective reprogramming of cardiac fibroblasts by MT (Mef2c, Tbx5) combined with 2C.
- Investigating the molecular mechanisms of 2C-mediated enhancement, including target inhibition and gene expression changes.
Main Results:
- A combination of SB431542 and Baricitinib (2C) significantly enhanced cardiac reprogramming by GMT.
- MT (Mef2c, Tbx5) plus 2C selectively reprogrammed cardiac fibroblasts with improved efficiency, kinetics, and cardiomyocyte function, even without Gata4.
- 2C demonstrated enhanced cardiac reprogramming in human cardiac fibroblasts.
- 2C synergistically enhanced reprogramming by inhibiting Alk5, Tyk2, and downregulating Oas2, Oas3, Serpina3n, and Tgfbi.
Conclusions:
- The chemical combination 2C (SB431542 and Baricitinib) enables selective and robust direct cardiac reprogramming.
- This finding significantly facilitates in vitro disease modeling and advances in vivo clinical therapeutic heart regeneration.
