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

  1. Robert J. Schwartzb,c,2,3
  1. aGraduate School of Biomedical Sciences, Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77030;
  2. bStem Cell Engineering Laboratory, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, TX 77030;
  3. dDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030;
  4. cDepartment of Biology and Biochemistry, University of Houston, Houston, TX 77204; and
  5. eSanford-Burnham Medical Research Institute, La Jolla, CA 92037

  1. Edited* by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved June 25, 2012 (received for review December 12, 2011)

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, Ca2+ transients, and sarcomeres. Our data indicate that ETS2 and MESP1 play important roles in a genetic network that governs cardiopoiesis.

Footnotes

  • ↵1J.F.I., Y.L., and K.-C.W. contributed equally to this work.

  • ↵2V.N.P. and R.J.S. contributed equally to this work.

  • ↵3To whom correspondence should be addressed. E-mail: rjschwartz{at}uh.edu.

  • Author contributions: J.F.I., Y.L., K.-C.W., M.J.R., A.P., J.H., D.T., M.C., V.N.P., and R.J.S. designed research; J.F.I., Y.L., K.-C.W., M.J.R., A.P., J.H., D.T., M.C., and V.N.P. performed research; K.-C.W., D.I., R.G.O., and V.N.P. contributed new reagents/analytic tools; J.F.I., Y.L., M.J.R., S.Z., A.P., J.H., D.T., M.C., M.M., J.T.W., V.N.P., and R.J.S. analyzed data; Y.L., M.M., J.T.W., V.N.P., and R.J.S. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: The sequences reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE29710).

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1120299109/-/DCSupplemental.

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