title: The cardiac repair benefits of inflammation do not persist: evidence from mast cell implantation.
abstract: Multiple mechanisms contribute to progressive cardiac dysfunction after myocardial infarction (MI) and inflammation is an important mediator. Mast cells (MCs) trigger inflammation after MI by releasing bio-active factors that contribute to healing. c-Kit-deficient (Kit(W/W-v) ) mice have dysfunctional MCs and develop severe ventricular dilatation post-MI. We explored the role of MCs in post-MI repair. Mouse wild-type (WT) and Kit(W/W-v) MCs were obtained from bone marrow (BM). MC effects on fibroblasts were examined in vitro by proliferation and gel contraction assays. MCs were implanted into infarcted mouse hearts and their effects were evaluated using molecular, cellular and cardiac functional analyses. In contrast to WT, Kit(W/W-v) MC transplantation into Kit(W/W-v) mice did not improve cardiac function or scar size post-MI. Kit(W/W-v) MCs induced significantly reduced fibroblast proliferation and contraction compared to WT MCs. MC influence on fibroblast proliferation was Basic fibroblast growth factor (bFGF)-dependent and MC-induced fibroblast contractility functioned through transforming growth factor (TGF)-β. WT MCs transiently rescue cardiac function early post-MI, but the benefits of BM cell implantation lasted longer. MCs induced increased inflammation compared to the BM-injected mice, with increased neutrophil infiltration and infarct tumour necrosis factor-α (TNF-α) concentration. This augmented inflammation was followed by increased angiogenesis and myofibroblast formation and reduced scar size at early time-points. Similar to the functional data, these beneficial effects were transient, largely vanishing by day 28. Dysfunctional Kit(W/W-v) MCs were unable to rescue cardiac function post-MI. WT MC implantation transiently enhanced angiogenesis and cardiac function. These data suggest that increased inflammation is beneficial to cardiac repair, but these effects are not persistent.
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.|Department of Ophthalmology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zhengbo
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Mansoreh
authors.initials: M
authors.lastname: Nazari
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Lily
authors.initials: L
authors.lastname: Guo
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Yuan
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008407:Mast Cells / Q000378:metabolism* / Q000637:transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D019009:Proto-Oncogene Proteins c-kit
keywords: c-Kit-deficient mice; cell transplantation; inflammatory response; mast cells; myocardial infarction; myofibroblasts