title: Mast cells promote proliferation and migration and inhibit differentiation of mesenchymal stem cells through PDGF.
abstract: Mast cells (MCs) dynamically participate in wound healing after myocardial infarction (MI) by releasing cytokines. Indeed, MC-deficient mice undergo rapid left ventricular dilation post-MI. Mesenchymal stem cells (MSCs) are recruited to the injured region following an MI and have potential for cardiac repair. In the current study, we evaluate the effect of MCs on MSC proliferation and myogenic differentiation.
  
  
  
  MCs were cultured from mouse bone marrow and MC granulate (MCG) was extracted from MCs via freeze-thaw cycles followed by filtration. α-SMA (smooth muscle actin) expression was examined as an indicator of myogenic differentiation. MSC/MC co-culture resulted in decreased MSC differentiation indicated by α-SMA suppression in MSCs. MCG also suppressed α-SMA expression and increased MSC migration and proliferation in a dose-dependent manner. Removal of MCG rescued α-SMA expression and MSC differentiation. Platelet derived growth factor (PDGF) receptor blockade using AG1296 also rescued MSC differentiation even after MCG treatment. Real-time PCR and Western blot showed that MCG exerted its effects on MSCs via downregulation of miR-145 and miR-143, downregulation of myocardin, upregulation of Klf4, and increased Erk and Elk1 phosphorylation.
  
  
  
  MCs promote MSC proliferation and migration by suppressing their myogenic differentiation. MCs accomplish this via activation of the PDGF pathway, downregulation of miR-145/143, and modulation of the myocardin-Klf4 axis. These data suggest a potential role for MSC/MC interaction in the infarcted heart where MCs may inhibit MSCs from differentiation and promote their proliferation whereby increased cardiac MSC accumulation promotes eventual cardiac regeneration after MCs cease activity.
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada.
authors.forename: Mansoreh
authors.initials: M
authors.lastname: Nazari
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Ni
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Lüdke
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: renkeli@uhnres.utoronto.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D003594:Cytoplasmic Granules / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D016130:Immunophenotyping; D000090062:Kruppel-Like Factor 4; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D000199:Actins; D015415:Biomarkers; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D010982:Platelet-Derived Growth Factor; D050807:ets-Domain Protein Elk-1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Differentiation; Mast cells; Mesenchymal stem cells; Myocardial infarction; PDGF; Proliferation