Heart failure & cardiomyopathies
Overcoming Intrinsic Barriers in Myofibroblasts Permits Efficient Cardiac Reprogramming After Infarction
Authors' conclusion
Our study identifies pathological MEOX1 upregulation as a key mechanism underlying the reprogramming resistance of post-MI mouse MFs and activated human MFs.
Study context
- Population
- Post-MI mouse injury-activated myofibroblasts (Postn lineage-traced, PDGFRα+ cardiac fibroblasts (CFs)), human iPSC-derived myofibroblasts (MFs) and primary human MFs
- Comparison
- MEOX1 knockdown vs control in myofibroblasts undergoing cardiac reprogramming
- Outcome
- Molecular barrier to reprogramming of injury-activated MFs into induced cardiomyocytes (iCMs)
Methodological detailslineage tracing, single-cell RNA sequencing, targeted in vitro shRNA screen, dual-recombinase-mediated lineage tracing, mouse and human cells, in vitro and in vivo
- Lineage tracing
- Single-cell RNA sequencing
- Targeted in vitro shRNA screen
- Dual-recombinase-mediated lineage tracing
- Mouse and human cells
- In vitro and in vivo
Main finding
As reported in the abstract
MEOX1 as principal barrier to MF reprogramming
- Upregulated TF MEOX1, a fibrosis determinant downstream of transforming growth factor-beta 1 and interleukin-1 beta, identified as the principal molecular barrier responsible for profound reprogramming resistance of MFs
- MEOX1 knockdown markedly enhanced reprogramming efficiency in mouse and human MFs and enabled GATA4-free reprogramming combinations
- Inhibition depended on transcriptional activation activity of MEOX1: disrupting its DNA-binding domain or fusing it to a repressor domain rescued reprogramming
- MEOX1 binds and stabilizes a fibrotic, MF-defining transcriptional program antagonizing the cardiogenic program while modulating the inflammatory response; knockdown disrupted this fibrotic network to favor iCM fate acquisition
- MEOX1 knockdown enables highly efficient in vivo MF-to-iCM conversion, with significant reductions in cardiac fibrosis and substantial improvement in cardiac function after myocardial infarction (MI)
- Dual-recombinase lineage tracing used in vivo
Parts of this Brief are withheld: the automatic checks could not confirm them against the abstract.
Original publication
Overcoming Intrinsic Barriers in Myofibroblasts Permits Efficient Cardiac Reprogramming After Infarction. Circulation. Published 8 September 2026. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →