title: Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells.
abstract: We previously described a critical role for a fibroblast precursor population in the development of a murine fibrotic cardiomyopathy model (I/RC). These precursors arose from circulating bone marrow-derived cells of monocytic origin. Administration of serum amyloid P (SAP) prevented the presence of this cell population in the heart and the cardiomyopathy. Because SAP binds to Fc receptors (FcRs) expressed on monocytes, we investigated the involvement of FcR signaling. We chose mice lacking the FcRgamma chain protein (FcRgamma(-/-)), a common membrane-signaling component of activating FcRs. Like wild-type mice, FcRgamma(-/-) mice developed fibrosis and cardiac dysfunction when subjected to I/RC. However, unlike wild-type mice, SAP in FcRgamma(-/-) mice failed to inhibit the development of fibrosis and cardiac dysfunction and did not diminish the numbers of alpha-smooth muscle actin(+) and CD34(+), CD45(+) fibroblasts that were typical for I/RC. To further examine the role of SAP in monocyte-to-fibroblast transition, we performed in vitro assays in which human peripheral blood mononuclear cells (PBMCs) migrated through human umbilical vein endothelial cells (HUVECs). We found that MCP-1-dependent transendothelial migration of monocytes markedly accelerated their differentiation into fibroblasts. This monocyte differentiation to fibroblasts was eliminated when SAP was added to the PBMC suspension before endothelial transmigration. Adding SAP to cells after successful migration did not inhibit fibroblast maturation. These data indicate that SAP inhibits the differentiation of a blood-borne, myeloid cell population into fibroblasts by signaling through activating FcRs before transendothelial migration has occurred. We suggest that FcR activation of circulating precursor cells may represent a new treatment target for adverse remodeling and cardiac fibrosis.
authors.affiliation: DeBakey Heart Center, Baylor College of Medicine and The Methodist Hospital, Houston, TX 77030, USA.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Haudek
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trial
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Damon
authors.initials: D
authors.lastname: Gupta
authors.forename: Darrell
authors.initials: D
authors.lastname: Pilling
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D005355:Fibrosis; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009206:Myocardium / Q000166:cytology* / Q000276:immunology*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D000683:Serum Amyloid P-Component / Q000008:administration & dosage / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000276:immunology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; D000683:Serum Amyloid P-Component