title: Angiogenesis, cardiomyocyte proliferation and anti-fibrotic effects underlie structural preservation post-infarction by intramyocardially-injected cardiospheres.
abstract: OBJECTIVE
  We sought to understand the cellular and tissue-level changes underlying the attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial infarction (MI).
  
  
  BACKGROUND
  Cardiospheres (CSps) are heart-derived multicellular clusters rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation improves left ventricular (LV) function and attenuates remodeling in both small and large animal studies. However, the mechanisms of benefit have not yet been fully elucidated.
  
  
  METHODS
  Four groups were studied: 1) "Sham" (Wistar Kyoto rats with thoracotomy and ligature without infarction); 2) "MI" (proximal LAD ligation with peri-infarct injection of vehicle); 3) "MI+CSp" (MI with cardiospheres injected in the peri-infarct area); 4) "Small MI" (mid-LAD ligation only).
  
  
  RESULTS
  In vivo 1 week after CSp transplantation, LV functional improvement was associated with an increase in cardiomyocyte proliferation. By 3 weeks, microvessel formation was enhanced, while cardiomyocyte hypertrophy and regional fibrosis were attenuated. Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated. The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection. In vitro, CSp-conditioned media reduced collagen production in coculture with fibroblasts and triggered neoangiogenesis in an ex vivo aortic ring assay.
  
  
  CONCLUSIONS
  Cardiospheres enhance cardiomyocyte proliferation and angiogenesis, and attenuate hypertrophy and fibrosis, in the ischemic myocardium. These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: de Couto
authors.affiliation: Third Department of Cardiology, University of Athens, Athens, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Terrovitis
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Baiming
authors.initials: B
authors.lastname: Sun
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Liu
authors.initials: L
authors.lastname: Weixin
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D017077:Culture Media, Conditioned / Q000737:chemistry; D004452:Echocardiography; D005260:Female; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology; D006984:Hypertrophy; D007249:Inflammation; D008833:Microcirculation; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D009389:Neovascularization, Pathologic; D051381:Rats; D011921:Rats, Inbred WKY; D013234:Stem Cells / Q000166:cytology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D003094:Collagen