Cardiogenic small molecules that enhance myocardial repair by stem cells

Hesham A Sadek, Britta Hannack, Elizabeth Choe, Jessica Wang, Shuaib Latif, Mary G. Garry, Daniel J. Garry, Jamie Longgood, Doug E. Frantz, Eric N Olson, Jenny Hsieh, Jay W Schneider

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

The clinical success of stem cell therapy for myocardial repair hinges on a better understanding of cardiac fate mechanisms. We have identified small molecules involved in cardiac fate by screening a chemical library for activators of the signature gene Nkx2.5, using a luciferase knockin bacterial artificial chromosome (BAC) in mouse P19CL6 pluripotent stem cells. We describe a family of sulfonylhydrazone (Shz) small molecules that can trigger cardiac mRNA and protein expression in a variety of embryonic and adult stem/progenitor cells, including human mobilized peripheral blood mononuclear cells (M-PBMCs). Small-molecule-enhanced M-PBMCs engrafted into the rat heart in proximity to an experimental injury improved cardiac function better than control cells. Recovery of cardiac function correlated with persistence of viable human cells, expressing human-specific cardiac mRNAs and proteins. Shz small molecules are promising starting points for drugs to promote myocardial repair/regeneration by activating cardiac differentiation in M-PBMCs.

Original languageEnglish (US)
Pages (from-to)6063-6068
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number16
DOIs
StatePublished - Apr 22 2008

Keywords

  • Cardiogenesis
  • Chemical biology
  • High-throughput screen
  • Myocardial repair

ASJC Scopus subject areas

  • General

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    Sadek, H. A., Hannack, B., Choe, E., Wang, J., Latif, S., Garry, M. G., Garry, D. J., Longgood, J., Frantz, D. E., Olson, E. N., Hsieh, J., & Schneider, J. W. (2008). Cardiogenic small molecules that enhance myocardial repair by stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105(16), 6063-6068. https://doi.org/10.1073/pnas.0711507105