Reprogramming of human fibroblasts toward a cardiac fate

Young Jae Nam, Kunhua Song, Xiang Luo, Edward Daniel, Kaleb Lambeth, Katherine West, Joseph A Hill, J. Michael Di Maio, Linda A Baker, Rhonda S Bassel-Duby, Eric N Olson

Research output: Contribution to journalArticle

296 Scopus citations

Abstract

Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and twomicroRNAs,miR-1 andmiR-133, activated cardiacmarker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-likemyocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.

Original languageEnglish (US)
Pages (from-to)5588-5593
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number14
DOIs
StatePublished - Apr 2 2013

Keywords

  • Cardiogenesis
  • Cell fate specification
  • Phenotypic switching
  • Regeneration

ASJC Scopus subject areas

  • General

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