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Conversion of human fibroblasts into functional cardiomyocytes by small molecules

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Science  03 Jun 2016:
Vol. 352, Issue 6290, pp. 1216-1220
DOI: 10.1126/science.aaf1502

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Making cardiac cells from fibroblasts

Reprogramming noncardiac cells into functional cardiomyocytes without any genetic manipulation could open up new avenues for cardiac regenerative therapies. Cao et al. identified a combination of nine small molecules that could epigenetically activate human fibroblasts, efficiently reprogramming them into chemically induced cardiomyocytes (ciCMs). The ciCMs contracted uniformly and resembled human cardiomyocytes. This method may be adapted for reprogramming multiple cell types and have important implications in regenerative medicine.

Science, this issue p. 1216

Abstract

Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells into specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds that we term 9C. The chemically induced cardiomyocyte-like cells uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters and enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to chemically induced cardiomyocyte-like cells. This pharmacological approach to lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.

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