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Heart repair by reprogramming non-myocytes with cardiac transcription factors

Nature volume 485, pages 599–604 (2012)Cite this article

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Abstract

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

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Figure 1: Reprogramming fibroblasts towards a cardiac phenotype in vitro by GHMT.
Figure 2: Reprogramming non-cardiomyocytes towards a cardiac fate in vivo by GHMT.
Figure 3: Lineage tracing of GHMT-induced iCLMs in vivo.
Figure 4: Ameliorated cardiac function of injured hearts by GHMT.
Figure 5: Attenuation of fibrosis in response to myocardial infarction by GHMT.

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Gene Expression Omnibus

Data deposits

Microarray data were deposited in the Gene Expression Omnibus database (accession number GSE37057).

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Acknowledgements

We thank J. Cabrera for graphics. We are grateful to members of the Olson lab for critical reading of the manuscript. We thank D. Sosic, W. Tang, J. O’Rourke, N. Liu, M. Xin, A. Johnson and J. McAnally for discussions; J. Shelton and J. A. Richardson for histology. We are grateful to I. Bezprozvanny for the PTI Ca2+ Imaging System, and D. Srivastava for lentiviral plasmids. We thank the microarray core at University of Texas Southwestern Medical Center for collecting gene expression data. E.N.O. is supported by grants from NIH, the Donald W. Reynolds Center for Clinical Cardiovascular Research, the Robert A. Welch Foundation (grant I-0025), the Leducq Fondation-Transatlantic Network of Excellence in Cardiovascular Research Program, the American Heart Association-Jon Holden DeHaan Foundation and the Cancer Prevention & Research Institute of Texas (CPRIT).

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Authors and Affiliations

  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9148, USA,

    Kunhua Song, Young-Jae Nam, Xiaoxia Qi, Guo N. Huang, Asha Acharya, Christopher L. Smith, Michelle D. Tallquist, Joseph A. Hill, Rhonda Bassel-Duby & Eric N. Olson

  2. Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9148, USA,

    Young-Jae Nam, Xiang Luo, Wei Tan & Joseph A. Hill

  3. Department of Medicine, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Eric G. Neilson

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Contributions

K.S. and E.N.O. conceived the project. K.S., Y.-J.N. and E.N.O. designed the experiments. K.S., Y.-J.N., X.L., X.Q., W.T., G.N.H., C.L.S. and A.A. performed experiments. J.A.H. contributed to surgical experiments; E.G.N. made the Fsp1-Cre mouse line. K.S. and R.B.-D. wrote the animal protocol. M.D.T. and R.B.-D. contributed scientific discussion. K.S., Y.-J.N., X.L., M.D.T., R.B.-D. and E.N.O. analysed data and prepared the manuscript.

Corresponding author

Correspondence to Eric N. Olson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-21. (PDF 1479 kb)

Supplementary Movie 1

This movie shows beating induced cardiac-like myocytes (iCLM) generated from adult cardiac fibroblasts (CFs) 6 weeks post-infection of retroviruses expressing GHMT transcription factors. (MOV 2392 kb)

Supplementary Movie 2

This movie shows beating induced cardiac-like myocytes (iCLM) generated from adult cardiac fibroblasts (CFs) 6 weeks post-infection of retroviruses expressing GHMT transcription factors. (MOV 1796 kb)

Supplementary Movie 3

This movie shows beating induced cardiac-like myocytes (iCLM) generated from adult tail tip fibroblasts (TTFs) 6 weeks post-infection of retroviruses expressing GHMT transcription factors. (MOV 2004 kb)

Supplementary Movie 4

This movie shows beating induced cardiac-like myocytes (iCLM) that were isolated from mouse heart at 5 weeks post-MI and injection of retroviruses expressing GHMT transcription factors. (MOV 2628 kb)

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Song, K., Nam, YJ., Luo, X. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012). https://doi.org/10.1038/nature11139

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