Direct Reprogramming Improves Cardiac Function and Reverses Fibrosis in Chronic Myocardial Infarction

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Cardiology

Background:

• Adult cardiomyocytes exhibit limited regenerative capacity, leading to fibrosis and heart failure after myocardial infarction (MI).
• Existing therapies for chronic MI with established fibrosis are insufficient for myocardial regeneration.

Purpose of the Study:

• To investigate the efficacy of in vivo cardiac reprogramming of resident cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) for repairing chronic MI.
• To elucidate the mechanisms underlying cardiac repair through fibroblast reprogramming in chronic MI models.

Main Methods:

• Development of a novel transgenic mouse system (Tcf21^iCre/reporter/MGTH2A) for inducible cardiac reprogramming and lineage tracing.
• Assessment of in vivo reprogramming efficacy and mechanisms in acute and chronic MI models using techniques like microarray and single-cell RNA sequencing.

Main Results:

• In chronic MI, cardiac reprogramming converted approximately 2% of CFs into iCMs, significantly improving myocardial contraction and reducing fibrosis.
• MGTH overexpression activated cardiac gene programs, suppressed fibroblast and inflammatory signatures, and shifted profibrotic CFs to an antifibrotic state.
• Cardiac reprogramming suppressed Meox1, a key regulator of fibroblast activation, contributing to antifibrotic effects.

Conclusions:

• In vivo cardiac reprogramming can effectively repair chronic MI by promoting myocardial regeneration and mitigating fibrosis.
• These findings highlight the potential of cardiac reprogramming as a novel therapeutic strategy for chronic heart failure.