Small molecule regulators of postnatal Nkx2.5 cardiomyoblast proliferation and differentiation.
While recent data have supported the capacity for a neonatal heart to undergo cardiomyogenesis, it is unclear whether these new cardiomyocytes arise from an immature cardiomyoblast population or from the division of mature cardiomyocytes. By following the expression of enhanced Green Fluorescent Protein (eGFP) in an Nkx2.5 enhancer-eGFP transgenic mice, we have identified a population of immature cells that can undergo cardiomyogenic as well as smooth muscle cell differentiation in the neonatal heart. Here, we examined growth factors and small molecule regulators that potentially regulate the proliferation and cardiomyogenic versus smooth muscle cell differentiation of neonatal Nkx2.5-GFP (+) cells in vitro. We found that A83-01 (A83), an inhibitor of TGF-βRI, was able to induce an expansion of neonatal Nkx2.5-eGFP (+) cells. In addition, the ability of A83 to expand eGFP (+) cells in culture was dependent on signalling from the mitogen-activated protein kinase kinase (MEK) as treatment with a MEK inhibitor, PD0325901, abolished this effect. On the other hand, activation of neonatal Nkx2.5-eGFP (+) cells with TGF-β1, but not activin A nor BMP2, led to smooth muscle cell differentiation, an effect that can be reversed by treatment with A83. In summary, small molecule inhibition of TGF-β signalling may be a promising strategy to induce the expansion of a rare population of postnatal cardiomyoblasts.
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wen-Pin
WP
Chen
Sean M
SM
Wu
D028341:Activins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D024510:Muscle Development / Q000187:drug effects / Q000502:physiology*; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013859:Thiocarbamates / Q000494:pharmacology*; D013882:Thiosemicarbazones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
C507011:A-83-01; D001549:Benzamides; D055396:Bone Morphogenetic Protein 2; D004791:Enzyme Inhibitors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C484469:Nkx2-5 protein, mouse; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D013859:Thiocarbamates; D013882:Thiosemicarbazones; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; C506614:mirdametinib; D004159:Diphenylamine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020929:Mitogen-Activated Protein Kinase Kinases