Heart repair by reprogramming non-myocytes with cardiac transcription factors

Kunhua Song; Young Jae Nam; Xiang Luo; Xiaoxia Qi; Wei Tan; Guo N. Huang; Asha Acharya; Christopher L. Smith; Michelle D. Tallquist; Eric G. Neilson; Joseph A. Hill; Rhonda Bassel-Duby; Eric N. Olson

doi:10.1038/nature11139

Heart repair by reprogramming non-myocytes with cardiac transcription factors

Kunhua Song, Young Jae Nam, Xiang Luo, Xiaoxia Qi, Wei Tan, Guo N. Huang, Asha Acharya, Christopher L. Smith, Michelle D. Tallquist, Eric G. Neilson, Joseph A. Hill, Rhonda Bassel-Duby, Eric N. Olson^*

^*Corresponding author for this work

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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.

Original language	English (US)
Pages (from-to)	599-604
Number of pages	6
Journal	Nature
Volume	485
Issue number	7400
DOIs	https://doi.org/10.1038/nature11139
State	Published - 2012

Funding

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 Ca21 Imaging System,andD.Srivastavafor lentiviralplasmids.Wethankthe microarray core at Universityof Texas Southwestern MedicalCenter for collecting geneexpressiondata. 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).

ASJC Scopus subject areas

General

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10.1038/nature11139

Cite this

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title = "Heart repair by reprogramming non-myocytes with cardiac transcription factors",

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.",

author = "Kunhua Song and Nam, {Young Jae} and Xiang Luo and Xiaoxia Qi and Wei Tan and Huang, {Guo N.} and Asha Acharya and Smith, {Christopher L.} and Tallquist, {Michelle D.} and Neilson, {Eric G.} and Hill, {Joseph A.} and Rhonda Bassel-Duby and Olson, {Eric N.}",

note = "Funding Information: 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{\textquoteright}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 Ca21 Imaging System,andD.Srivastavafor lentiviralplasmids.Wethankthe microarray core at Universityof Texas Southwestern MedicalCenter for collecting geneexpressiondata. 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).",

year = "2012",

doi = "10.1038/nature11139",

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pages = "599--604",

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AU - Song, Kunhua

AU - Nam, Young Jae

AU - Luo, Xiang

AU - Qi, Xiaoxia

AU - Tan, Wei

AU - Huang, Guo N.

AU - Acharya, Asha

AU - Smith, Christopher L.

AU - Tallquist, Michelle D.

AU - Neilson, Eric G.

AU - Hill, Joseph A.

AU - Bassel-Duby, Rhonda

AU - Olson, Eric N.

N1 - Funding Information: 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 Ca21 Imaging System,andD.Srivastavafor lentiviralplasmids.Wethankthe microarray core at Universityof Texas Southwestern MedicalCenter for collecting geneexpressiondata. 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).

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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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Heart repair by reprogramming non-myocytes with cardiac transcription factors

Abstract

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