Editors' ChoiceMyocardial Infarction

Not Enough Myocytes? Use Fibroblasts!

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Science Translational Medicine  20 Jun 2012:
Vol. 4, Issue 139, pp. 139ec109
DOI: 10.1126/scitranslmed.3004465

Heart failure after myocardial infarction is the most deadly, expensive problem in modern medicine. Such infarctions are caused by interruption of the heart’s blood supply (ischemia), which kills or damages cardiac tissue. Although the task for cardiologists might seem straightforward—to repair the damage that occurs after the ischemic death of contracting myocytes—it has escaped a real solution. Two recent studies from separate groups propose a conceptually simple remedy: Why not use fibroblasts, which naturally occur in the heart at a higher frequency than myocytes, as spare parts?

Expression of the appropriate transcription factors can convert fibroblasts to several cell types. Song et al. found that four transcription factors (GATA4, HAND2, MEF2C, and TBX5, together dubbed GHMT)—known regulators of cardiac gene expression—could reprogram fibroblasts into cardiomyocyte-like cells. Transduction of cardiac fibroblasts from adult mice with GHMT-expressing retroviruses induced the expression of proteins normally seen in cardiomyocytes in 6.8% of the cells; a small percentage of those (<0.1%) exhibited spontaneous contractions. Expression of GHMT for limited periods of time with inducible expression vectors resulted in a stable cardiomyocyte phenotype after expression ended, an important finding for in vivo applications. Song et al. then injected retroviruses encoding GHMT into the mouse heart after ligating a coronary artery, which causes myocardial infarction. This process resulted in GHMT expression in non-cardiomyocytes, generating at least 10,000 new myocytes in the injured area after 3 weeks. These myocytes coupled electrically with surrounding cells and were beating. Remarkably, magnetic resonance imaging showed that the treatment improved the ejection fraction—the portion of blood pumped out of the heart per beat—to near-normal values 12 weeks after myocardial infarction. Qian et al. independently reported similar results using only three of those transcription factors (GMT), albeit with a somewhat lower functional improvement.

Song et al. concede that the low in vitro reprogramming efficiency does not explain the spectacular improvements seen in mice and speculate that functional reprogramming of cells may simply work better in vivo. If so, repurposing fibroblasts as spare parts for rebuilding contractile units, with one shot of gene therapy, appears to be a promising new concept to repair the heart.

K. Song et al., Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012). [Abstract]

L. Qian et al., In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012). [Abstract]

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