Making Steady Progress on Direct Cardiac Reprogramming Toward Clinical Application
Reprogramming of Human Fibroblasts Toward a Cardiac Fate
Nam et al
Proc Natl Acad Sci USA. 2013;110:5588–5593.
A new report demonstrates direct cardiac reprogramming in human cells for the first time and points to the possibility of moving this technology toward clinical applications.
Direct reprogramming to somatic cells by forced expression of a combination of lineage-specific transcription factors or micro RNAs (miRNAs) has been demonstrated in a variety of rodent cell types, such as neurons,1 neural stem cells,2 hepatocyte-like cells,3,4 β-cells,5 and cardiomyocytes.6–10 Three groups have reported the direct neuronal reprogramming of human fibroblast into neuronal cells.11–13 Pang et al11 demonstrated that the same 3 transcription factors used for mouse cells, Brn2, Ascl1, and Myt1l, are insufficient to induce functional neurons from human fetal fibroblasts, but that Brn2, Ascl1, and Myt1l plus the addition of NenroD1 can convert human fetal and postnatal fibroblasts into functional neurons. Yoo et al13 also reported that a combination of neuronal transcription factors and 2 miRNAs, micro RNA (miR)-9/9* and miR-124, can efficiently convert human fibroblasts into functional neurons. These findings suggest that, compared with mouse cells, additional factors might be required to direct the reprogramming of human somatic cells into other lineage cells.
More recently, Nam et al14 reported the direct reprogramming of human fibroblasts into cardiac-like cells (iCLMs). They first tested whether the same cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT) or GMT+Hand2, which were previously reported to be useful for the direct reprogramming of mouse fibroblasts into cardiomyocytes,6–8,10 could reprogram neonatal human foreskin fibroblasts into iCLMs. However, GMT and GMT+Hand2 both failed to induce cardiac marker expression in human foreskin fibroblasts. …