Interleukin 10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure Overloaded Myocardium
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.
Conclusions—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.
- Received February 14, 2017.
- Revision received May 10, 2017.
- Accepted June 15, 2017.