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MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.

Publication ,  Journal Article
Jayawardena, TM; Egemnazarov, B; Finch, EA; Zhang, L; Payne, JA; Pandya, K; Zhang, Z; Rosenberg, P; Mirotsou, M; Dzau, VJ
Published in: Circ Res
May 25, 2012

RATIONALE: Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ. OBJECTIVE: The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo. METHODS AND RESULTS: Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin. CONCLUSIONS: The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.

Duke Scholars

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

May 25, 2012

Volume

110

Issue

11

Start / End Page

1465 / 1473

Location

United States

Related Subject Headings

  • Transfection
  • S100 Proteins
  • Regeneration
  • Red Fluorescent Protein
  • Recovery of Function
  • Protein Kinase Inhibitors
  • Myocytes, Cardiac
  • Myocardial Ischemia
  • Myocardial Contraction
  • MicroRNAs
 

Citation

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Jayawardena, T. M., Egemnazarov, B., Finch, E. A., Zhang, L., Payne, J. A., Pandya, K., … Dzau, V. J. (2012). MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res, 110(11), 1465–1473. https://doi.org/10.1161/CIRCRESAHA.112.269035
Jayawardena, Tilanthi M., Bakytbek Egemnazarov, Elizabeth A. Finch, Lunan Zhang, J Alan Payne, Kumar Pandya, Zhiping Zhang, Paul Rosenberg, Maria Mirotsou, and Victor J. Dzau. “MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.Circ Res 110, no. 11 (May 25, 2012): 1465–73. https://doi.org/10.1161/CIRCRESAHA.112.269035.
Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012 May 25;110(11):1465–73.
Jayawardena, Tilanthi M., et al. “MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.Circ Res, vol. 110, no. 11, May 2012, pp. 1465–73. Pubmed, doi:10.1161/CIRCRESAHA.112.269035.
Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012 May 25;110(11):1465–1473.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

May 25, 2012

Volume

110

Issue

11

Start / End Page

1465 / 1473

Location

United States

Related Subject Headings

  • Transfection
  • S100 Proteins
  • Regeneration
  • Red Fluorescent Protein
  • Recovery of Function
  • Protein Kinase Inhibitors
  • Myocytes, Cardiac
  • Myocardial Ischemia
  • Myocardial Contraction
  • MicroRNAs