Targeting native adult heart progenitors with cardiogenic small molecules

Jamie L. Russell, Sean C. Goetsch, Hector R. Aguilar, Doug E. Frantz, Jay W. Schneider

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Targeting native progenitors with small molecule pharmaceuticals that direct cell fate decisions is an attractive approach for regenerative medicine. Here, we show that 3,5-disubstituted isoxazoles (Isx), stem cell-modulator small molecules originally recovered in a P19 embryonal carcinoma cell-based screen, directed cardiac muscle gene expression in vivo in target tissues of adult transgenic reporter mice. Isx also stimulated adult mouse myocardial cell cycle activity. Narrowing our focus onto one target cardiac-resident progenitor population, Isx directed muscle transcriptional programs in vivo in multipotent Notch-activated epicardium-derived cells (NECs), generating Notch-activated adult cardiomyocyte-like precursors. Myocardial infarction (MI) preemptively differentiated NECs toward fibroblast lineages, overriding Isxs cardiogenic influence in this cell population. Isx dysregulated gene expression in vivo in Notch-activated repair fibroblasts, driving distinctive (pro-angiogenesis) gene programs, but failed to mitigate fibrosis or avert ventricular functional decline after MI. In NECs in vitro, Isx directed partial muscle differentiation, which included biosynthesis and assembly of sarcomeric α-actinin premyofibrils, beaded structures pathognomonic of early developing cardiomyocytes. Thus, although Isx small molecules have promising in vivo efficacy at the level of cardiac muscle gene expression in native multipotent progenitors and are first in class in this regard, a greater understanding of the dynamic interplay between fibrosis and cardiogenic small molecule signals will be required to pharmacologically enable regenerative repair of the heart.

Original languageEnglish (US)
Pages (from-to)1067-1076
Number of pages10
JournalACS Chemical Biology
Volume7
Issue number6
DOIs
StatePublished - Jun 15 2012

Fingerprint

Isoxazoles
Molecules
Muscle
Pericardium
Gene expression
Cells
Fibroblasts
Gene Expression
Cardiac Myocytes
Myocardium
Fibrosis
Repair
Myocardial Infarction
Embryonal Carcinoma Stem Cells
Actinin
Muscles
Regenerative Medicine
Biosynthesis
Stem cells
Modulators

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Russell, J. L., Goetsch, S. C., Aguilar, H. R., Frantz, D. E., & Schneider, J. W. (2012). Targeting native adult heart progenitors with cardiogenic small molecules. ACS Chemical Biology, 7(6), 1067-1076. https://doi.org/10.1021/cb200525q

Targeting native adult heart progenitors with cardiogenic small molecules. / Russell, Jamie L.; Goetsch, Sean C.; Aguilar, Hector R.; Frantz, Doug E.; Schneider, Jay W.

In: ACS Chemical Biology, Vol. 7, No. 6, 15.06.2012, p. 1067-1076.

Research output: Contribution to journalArticle

Russell, JL, Goetsch, SC, Aguilar, HR, Frantz, DE & Schneider, JW 2012, 'Targeting native adult heart progenitors with cardiogenic small molecules', ACS Chemical Biology, vol. 7, no. 6, pp. 1067-1076. https://doi.org/10.1021/cb200525q
Russell, Jamie L. ; Goetsch, Sean C. ; Aguilar, Hector R. ; Frantz, Doug E. ; Schneider, Jay W. / Targeting native adult heart progenitors with cardiogenic small molecules. In: ACS Chemical Biology. 2012 ; Vol. 7, No. 6. pp. 1067-1076.
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