Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors

Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13016-21. doi: 10.1073/pnas.1120299109. Epub 2012 Jul 23.

Abstract

Unique insights for the reprograming of cell lineages have come from embryonic development in the ascidian Ciona, which is dependent upon the transcription factors Ci-ets1/2 and Ci-mesp to generate cardiac progenitors. We tested the idea that mammalian v-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and mesoderm posterior (MESP) homolog may be used to convert human dermal fibroblasts into cardiac progenitors. Here we show that murine ETS2 has a critical role in directing cardiac progenitors during cardiopoiesis in embryonic stem cells. We then use lentivirus-mediated forced expression of human ETS2 to convert normal human dermal fibroblasts into replicative cells expressing the cardiac mesoderm marker KDR(+). However, although neither ETS2 nor the purported cardiac master regulator MESP1 can by themselves generate cardiac progenitors de novo from fibroblasts, forced coexpression of ETS2 and MESP1 or cell treatment with purified proteins reprograms fibroblasts into cardiac progenitors, as shown by the de novo appearance of core cardiac transcription factors, Ca(2+) transients, and sarcomeres. Our data indicate that ETS2 and MESP1 play important roles in a genetic network that governs cardiopoiesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • Cell Transdifferentiation / genetics
  • Cell Transdifferentiation / physiology*
  • Fibroblasts / cytology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Knockout Techniques
  • Humans
  • Mice
  • Myoblasts, Cardiac / cytology*
  • Myoblasts, Cardiac / physiology
  • Polymerase Chain Reaction
  • Proto-Oncogene Protein c-ets-2 / genetics
  • Proto-Oncogene Protein c-ets-2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / cytology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • ETS2 protein, human
  • Ets2 protein, mouse
  • Mesp1 protein, mouse
  • Proto-Oncogene Protein c-ets-2

Associated data

  • GEO/GSE29710