Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

Abstract

Background Activated fibroblasts (myofibroblasts; myoFBs) play critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. We have earlier shown that interleukin-10 (IL10) suppresses PO-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits PO-induced homing of BM-FPCs to the heart and their trans-differentiation to myoFBs and thus attenuates cardiac fibrosis. Methods Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction (TAC). To determine the bone marrow origin, chimeric mice were created using eGFP WT mice marrow to the IL10KO mice. For mechanistic studies, fibroblast progenitor cells were isolated from mouse bone marrow. Results Pressure overload enhanced bone marrow fibroblast progenitor cell (BM-FPC) mobilization and homing in IL10KO mice compared to WT mice. Furthermore, WT bone marrow (from eGFP mice) transplantation in BM-depleted IL10KO mice (IL10KO chimeric mice) reduced TAC-induced BM-FPC mobilization compared to IL10KO mice. GFP co-staining with αSMA or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggest that myofibroblasts were derived from bone marrow post-TAC. Finally, WT-BMT in IL10KO mice inhibited TAC-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited TGFβ-induced transdifferentiation and fibrotic signaling in WT BM-FPC in vitro. Furthermore, fibrosis-associated miRNAs expression was highly upregulated in IL10KO-FPCs compared to WT-FPCs. PCR-based selective miRNA analysis revealed that TGFβ-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145 and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on TGFβ-induced fibrotic signaling in BM-FPC. Conclusion Our findings suggest that IL10 inhibits BM-FPC homing and trans-differentiation to myofibroblasts in pressure overloaded myocardium. Mechanistically for the first time we showed that IL10 suppresses Smad-miRNA-21 mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

IL-10 targets myofibroblasts and dampens cardiac fibrosis

“…activated downstream of TGF-β receptors I and II, TGF-β can also promote some non-canonical signaling pathways including the activation of extracellular signal-regulated kinase (ERK)/cJun/p38 mitogen activated protein kinases. Whether IL-10 can also inhibit this pathway has not been assessed in Verma et al (1). Likewise, since growth factors including platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) also contribute to the activation of myofibroblasts, it would be interesting to study the effect of IL-10 on these pathways.…”

“…In a recent issue of Circulation, Verma et al (1) uncover a new interleukin-10 (IL-10)-dependent mechanism inhibiting fibrosis in pressure overloaded mouse myocardium. In this study, pressure overload was achieved in wild-type (WT) and IL-10 knockout (IL-10KO) mice by transverse aortic constriction (TAC), a widely used experimental mouse model that creates pressure overloadinduced left ventricular hypertrophy, leading to heart failure.…”

“…Chimeric IL-10KO mice with WT BM were protected against TAC-induced cardiac fibrosis and presented improved heart function. Verma et al (1) found out that IL-10 inhibits homing and trans-differentiation of BM-derived fibroblast progenitor cells (FPC) in myofibroblasts, major effector cells of cardiac fibrosis. In vitro experiments performed on FPC isolated from mouse BM (prominin 1 + CD45 + cells) indicated that IL-10 could suppress the expression of the fibrosis-associated miR-21 in response to transforming growth factor-β (TGF-)β.…”

“…Verma et al (1) show that TAC induces homing of FPC to the heart and their trans-differentiation into myofibroblasts, which can be inhibited by IL-10. They identified a TGFβ-Smad2/3 signaling-mediated miRNA-21 maturation as a novel mechanism by which IL-10 might inhibit BM-FPC-mediated cardiac fibrosis in the pressureoverloaded myocardium.…”

Use of Growth Factors and Cytokines to Treat Injuries Resulting from a Radiation Public Health Emergency

“…The FDA Animal Rule (9) was used for the approval of filgrastim (Neupogen, 2015; Amgent, Thousand Oaks, CA), 2 pegfilgrastim (Neulasta, 2015; Amgen) 3 and sargramostim (Leukine, 2018; Partner Therapeutics, Lexington, MA). 4 These drugs are indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (hematopoietic sub-syndrome of ARS, H-ARS).…”