title: Cell therapy limits myofibroblast differentiation and structural cardiac remodeling: basic fibroblast growth factor-mediated paracrine mechanism.
abstract: BACKGROUND
  Experimental cell therapy attenuates maladaptive cardiac remodeling and improves heart function. Paracrine mechanisms have been proposed. The effect of cell therapy on post infarction cardiac fibroblast and extracellular matrix (ECM) regulation was examined.
  
  
  RESULTS
  Vascular smooth muscle cells (VSMC) were injected into the border zone of subacute infarcted syngeneic Fischer rat hearts and compared with medium-injected controls. Twelve weeks post injection, cell-treated hearts showed preserved ECM content and attenuated structural chamber remodeling. Myofibroblast activation (α-smooth muscle actin expression) was decreased significantly, while basic fibroblast growth factor (bFGF) expression, a known inhibitor of transforming growth factor β-1-induced fibroblast differentiation, was increased. Matrix metalloproteinase-2 expression and activation by gelatin zymography was unchanged between groups, while its endogenous inhibitor, tissue inhibitors of matrix metalloproteinase (TIMP)-2, showed both increased expression and enhanced inhibitory capacity in cell-treated hearts. To define paracrine mechanisms, in vitro effects of VSMC conditioned media on myofibroblast activation were assessed by 3-D collagen gel contraction assay. VSMC conditioned media significantly inhibited collagen contraction, while a specific bFGF inhibitor abolished this paracrine response. TIMP-2 induced collagen contraction, but the effect was suppressed in the presence of bFGF.
  
  
  CONCLUSIONS
  Extracellular matrix dysregulation post myocardial infarction is improved by cell therapy. These data suggest that cell transplantation attenuates myofibroblast activation and subsequent maladaptive structural chamber remodeling through paracrine mechanisms involving bFGF and TIMP-2.
authors.affiliation: Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Alberta, Canada. paul.fedak@gmail.com
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Liping
authors.initials: L
authors.lastname: Bai
authors.forename: Jeannine
authors.initials: J
authors.lastname: Turnbull
authors.forename: Janet
authors.initials: J
authors.lastname: Ngu
authors.forename: Kishan
authors.initials: K
authors.lastname: Narine
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000637:transplantation; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000199:Actins; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2; D019716:Tissue Inhibitor of Metalloproteinase-2; C498862:Acta2 protein, rat