Presentation Abstract

Session: 10-Outstanding Early Career Award Finalists
Wednesday, Jul 24, 2013, 1:00 PM - 1:45 PM
Presentation: 360 - IL-10-inhibits Pressure Overload-induced Homing, Proliferation And Differentiation Of Non-resident Fibroblast Progenitors And Improve Heart Function.
Location: Concorde B/C
Pres. Time: Wednesday, Jul 24, 2013, 1:30 PM - 1:45 PM
Category: Cardiac Regeneration, Stem Cells and Tissue Engineering
Keywords: Fibroblast Progenitor Cells; Cardiac Fibrosis; Cardiac Hypertrophy
Author(s): Suresh K Verma, Prasanna Krishnamurthy, Feinberg Cardiovascular Res Inst, Northwestern Univ, Chicago, IL; David Barefield, Dept of Cell and Molecular Physiology, Stritch Sch of Med, Loyola Univ, Chicago, IL; Alexander R Mackie, Erin E Vaughan, Tatian Abramova, Veronica Ramirez, Sol Misener, Feinberg Cardiovascular Res Inst, Northwestern Univ, Chicago, IL; Sakthivel Sadayappan, Dept of Cell and Molecular Physiology, Stritch Sch of Med, Loyola Univ, Chicago, IL; Gangjian Qin, Raj Kishore, Feinberg Cardiovascular Res Inst, Northwestern Univ, Chicago, IL
Abstract: Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited the pressure overload-induced cardiac fibrosis, however, antifibrotic mechanisms of IL-10 are largely unknown. In most of organs, including heart, extracellular matrix (ECM) remodeling is primarily mediated by excessive proliferation of activated fibroblasts and myofibroblasts. Here we hypothesized that IL-10 inhibits stress-induced homing, proliferation and differentiation of nonresident bone marrow-derived fibroblast progenitor cells and therefore, attenuates cardiac remodeling and improves of heart function. Methods and Results: Cardiac hypertrophy was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice compared to WT. TAC significantly increased TGF-β, collagen Iα and IIIα genes expression. Systemic recombinant mouse IL-10 administration markedly improved LV function, inhibited TAC-induced cardiac fibrosis and fibrosis associated genes expression. To identify the role of fibroblast progenitor cells (FPCs), we measured the mobilization of FPCs (Prominin1 positive cells) from bone marrow to heart by FACs. Exacerbated mobilization of FPCs in peripheral blood and heart in IL-10 KO mice were found 3 and 7 days after aortic constriction. Bone marrow transplantation experiments were performed where WT-GFP positive marrow was transplanted in BM depleted IL-10 KO mice. TAC-induced mobilization was significantly reduced in WT-transplanted marrow as compare to TAC-IL-10 KO mice. To identify the role IL-10 on TGFβ-induced endothelial cells trans-differentiation to myofibroblasts, we treated aortic endothelial cells with IL-10 and TGFβ2 for 96 hrs. Both Immunocytochemistry and Western blot analysis results suggested that TGF-β2-induced EndMT was significantly inhibited by IL-10 treatment. To understand the mechanisms, we found that TGF-β2-induced Notch1 signaling was reduced by IL-10. Conclusion: Taken together our observations suggest that the anti-fibrotic effects of IL-10 treatment are mediated by reduced proliferation and differentiation of non-resident myofibroblasts.
Disclosures:  S.K. Verma: None. P. Krishnamurthy: None. D. Barefield: None. A.R. Mackie: None. E.E. Vaughan: None. T.V. Abramova: None. V. Ramirez: None. S. Misener: None. S. Sadayappan: None. G. Qin: None. R. Kishore: None.



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