Conversion of human fibroblasts into functional cardiomyocytes by small molecules

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 Heart-like cells can be generated from human skin cells by using small molecules and without genetic manipulation. 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.

[1]  Xiaoxia Qi,et al.  Heart repair by reprogramming non-myocytes with cardiac transcription factors , 2012, Nature.

[2]  Gang Wang,et al.  Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy , 2011, Nature Cell Biology.

[3]  Li Qian,et al.  In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes , 2011, Nature.

[4]  Keiichi Fukuda,et al.  Induction of Cardiomyocyte-Like Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5 , 2012, Circulation research.

[5]  Sean P. Palecek,et al.  Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling , 2012, Proceedings of the National Academy of Sciences.

[6]  Chad A. Cowan,et al.  A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. , 2010, The Journal of clinical investigation.

[7]  G. Lyons,et al.  Extracellular Matrix Promotes Highly Efficient Cardiac Differentiation of Human Pluripotent Stem Cells: The Matrix Sandwich Method , 2012, Circulation research.

[8]  Gordon Keller,et al.  Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. , 2011, Cell stem cell.

[9]  I. Pogribny,et al.  Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents. , 2013, International journal of oncology.

[10]  Upendarrao Golla,et al.  Depletion of Cellular Iron by Curcumin Leads to Alteration in Histone Acetylation and Degradation of Sml1p in Saccharomyces cerevisiae , 2013, PloS one.

[11]  R. Passier,et al.  Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells , 2015, Nature Biotechnology.

[12]  D. Srivastava,et al.  Recent advances in direct cardiac reprogramming. , 2015, Current opinion in genetics & development.

[13]  Robert Passier,et al.  Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology , 2015, EMBO molecular medicine.

[14]  Li Qian,et al.  Direct Reprogramming of Human Fibroblasts toward a Cardiomyocyte-like State , 2013, Stem cell reports.

[15]  C. I. Spencer,et al.  Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. , 2014, Cell reports.

[16]  Jane Synnergren,et al.  Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue. , 2012, Physiological genomics.

[17]  J Michael DiMaio,et al.  Making steady progress on direct cardiac reprogramming toward clinical application. , 2013, Circulation research.

[18]  E. Finch,et al.  MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. , 2015, Circulation research.

[19]  Sean P. Palecek,et al.  Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells , 2009, Circulation research.

[20]  A. McCulloch,et al.  Lentiviral Vectors and Protocols for Creation of Stable hESC Lines for Fluorescent Tracking and Drug Resistance Selection of Cardiomyocytes , 2009, PloS one.

[21]  V. Vedantham,et al.  Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors , 2010, Cell.

[22]  Gordon Keller,et al.  Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. , 2012, Cell stem cell.

[23]  D. Roberts,et al.  Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages , 2009, Nature.

[24]  E. Finch,et al.  MicroRNA-Mediated In Vitro and In Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes , 2012, Circulation research.

[25]  Yang Shi,et al.  Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. , 2010, Annual review of biochemistry.

[26]  Shinsuke Yuasa,et al.  Induction of human cardiomyocyte-like cells from fibroblasts by defined factors , 2013, Proceedings of the National Academy of Sciences.