Abstract 14014: IL-10 Reduces Pressure Overload-induced Fibrotic Remodeling by Inhibiting Homing and Differentiation of Bone Marrow-derived Fibroblasts Progenitor Cells- A Novel Mechanism
Recently we have shown that IL-10 markedly inhibited the pressure overload (PO)-induced cardiac fibrosis, however, antifibrotic mechanisms of IL-10 are largely unknown. Here we hypothesized that IL-10 inhibits PO-induced mobilization, homing and myofibroblast differentiation of bone marrow (BM)-derived fibroblast progenitor cells (FPCs) and therefore, attenuates cardiac fibrosis and adverse remodeling by PO. 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 FPCs, we measured the mobilization of FPCs (Prominin1+, CD45+ double+ cells) from BM to heart by FACs. Exacerbated mobilization of FPCs in peripheral blood and heart in KO mice were found 3 and 7 days after aortic constriction. BMT experiments were performed where WT-GFP positive marrow was transplanted in BM depleted KO mice. TAC-induced mobilization was significantly reduced in WT-transplanted marrow as compare to TAC KO mice. Furthermore, FPCs were isolated from WT and KO mice BM and treated with TGFβ2 to induce their differentiation. Both Immunocytochemistry and Western blot analysis results suggested that IL10-KO FPCs are more prone to differentiate into myofibroblasts as compare to WT-PPC. Interestingly, IL-10 treatment markedly reduced the differentiation of IL-10 KO derived FPCs to myofibroblasts. To understand the mechanisms, we found that TGF-β2-induced Notch1 signaling was reduced by IL-10.
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. Ongoing investigations will provide a better understanding on the mechanistic and therapeutic aspects of IL-10 and contribution for FPCs in PO-induced hypertrophic remodeling and heart failure.
- © 2013 by American Heart Association, Inc.