title: Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration.
abstract: OBJECTIVE
  Our previous study found that A83-01, a small molecule type 1 TGFβ receptor inhibitor, could induce proliferation of postnatal Nkx2.5(+) cardiomyoblasts in vitro and enhance their cardiomyogenic differentiation. The present study addresses whether A83-01 treatment in vivo could increase cardiomyogenesis and improve cardiac function after myocardial infarction through an Nkx2.5(+) cardiomyoblast-dependent process.
  
  
  RESULTS
  To determine the effect of A83-01 on the number of Nkx2.5(+) cardiomyoblasts in the heart after myocardial injury, we treated transgenic Nkx2.5 enhancer-GFP reporter mice for 7 days with either A83-01 or DMSO and measured the number of GFP(+) cardiomyoblasts in the heart at 1 week after injury by flow cytometry. To determine the degree of new cardiomyocyte formation after myocardial injury and the effect of A83-01 in this process, we employed inducible Nkx2.5 enhancer-Cre transgenic mice to lineage label postnatal Nkx2.5(+) cardiomyoblasts and their differentiated progenies after myocardial injury. We also examined the cardiac function of each animal by intracardiac haemodynamic measurements. We found that A83-01 treatment significantly increased the number of Nkx2.5(+) cardiomyoblasts at baseline and after myocardial injury, resulting in an increase in newly formed cardiomyocytes. Finally, we showed that A83-01 treatment significantly improved ventricular elastance and stroke work, leading to improved contractility after injury.
  
  
  CONCLUSIONS
  Pharmacological inhibition of TGFβ signalling improved cardiac function in injured mice and promoted the expansion and cardiomyogenic differentiation of Nkx2.5(+) cardiomyoblasts. Direct modulation of resident cardiomyoblasts in vivo may be a promising strategy to enhance therapeutic cardiac regeneration.
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan smwu@stanford.edu chenwenpin@ntu.edu.tw.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Jin
authors.initials: YJ
authors.lastname: Ho
authors.affiliation: Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lokey Stem Cell Research Building, G1120A, 265 Campus Drive, Stanford, CA 94305, USA smwu@stanford.edu chenwenpin@ntu.edu.tw.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C507011:A-83-01; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D011720:Pyrazoles; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D013882:Thiosemicarbazones; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Cardiomyoblast; Myocardial infarction; Nkx2.5; Regeneration; TGFβ