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Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction.

ABSTRACT: Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair.To demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI.This report shows that presence of CPCs correlates with the expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery were evident at the end of a 12-week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via ??-integrin-focal adhesion kinase-signal transducer and activator of transcription 3-Pim1 independent of Akt.Fn is essential for endogenous CPC expansion and repair required for stabilization of cardiac function after MI.

SUBMITTER: Konstandin MH

PROVIDER: S-EPMC3815660 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction.

Konstandin Mathias H MH Toko Haruhiro H Gastelum Grady M GM Quijada Pearl P De La Torre Andrea A Quintana Mercedes M Collins Brett B Din Shabana S Avitabile Daniele D Völkers Mirko M Gude Natalie N Fässler Reinhard R Sussman Mark A MA

Circulation research 20130507 2

<h4>Rationale</h4>Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair.<h4>Objective</h4>To demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI.<h4>Methods and res ...[more]

PMID: 23652800

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Project description:Background We previously reported that osteopontin plays an essential role in accelerating both reparative fibrosis and clearance of dead cells (efferocytosis) during tissue repair after myocardial infarction (MI) and galectin-3hiCD206+ macrophages is the main source of osteopontin in post-MI heart. Interleukin-10- STAT3 (signal transducer and activator of transcription 3)-galectin-3 axis is essential for Spp1 (encoding osteopontin) transcriptional activation in cardiac macrophages after MI. Here, we investigated the more detailed mechanism responsible for functional maturation of osteopontin-producing macrophages. Methods and Results In post-MI hearts, Spp1 transcriptional activation occurred almost exclusively in MerTK (Mer tyrosine kinase)+ galectin-3hi macrophages. The induction of MerTK on galectin-3hi macrophages is essential for their functional maturation including efferocytosis and Spp1 transcriptional activity. MerTK+galectin-3hi macrophages showed a strong activation of both STAT3 and ERK (extracellular signal-regulated kinase). STAT3 inhibition suppressed the differentiation of osteopontin-producing MerTK+galectin-3hi macrophages, however, STAT3 activation was insufficient at inducing Spp1 transcriptional activity. ERK inhibition suppressed Spp1 transcriptional activation without affecting MerTK or galectin-3 expression. Concomitant activation of ERK is required for transcriptional activation of Spp1. In Il-10 knockout enhanced green fluorescent protein-Spp1 knock-in mice subjected to MI, osteopontin-producing macrophages decreased but did not disappear entirely. Interleukin-10 and macrophage colony-stimulating factor synergistically activated STAT3 and ERK and promoted the differentiation of osteopontin-producing MerTK+galectin-3hi macrophages in bone marrow-derived macrophages. Coadministration of anti-interleukin-10 plus anti-macrophage colony-stimulating factor antibodies substantially reduced the number of osteopontin-producing macrophages by more than anti-interleukin-10 antibody alone in post-MI hearts. Conclusions Interleukin-10 and macrophage colony-stimulating factor act synergistically to activate STAT3 and ERK in cardiac macrophages, which in turn upregulate the expression of galectin-3 and MerTK, leading to the functional maturation of osteopontin-producing macrophages.

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Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction.

Publications

Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction.

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