Mesenchymal stem cells attenuate liver fibrosis by targeting Ly6C(hi/lo) macrophages through activating the cytokine-paracrine and apoptotic pathways

Mesenchymal stem cell (MSC) therapy has become a promising treatment for liver fibrosis due to its predominant immunomodulatory performance in hepatic stellate cell inhibition and fibrosis resolution. However, the cellular and molecular mechanisms underlying these processes remain limited. In the present study, we provide insights into the functional role of bone marrow-derived MSCs (BM-MSCs) in alleviating liver fibrosis by targeting intrahepatic Ly6C(hi) and Ly6C(lo) macrophage subsets in a mouse model. Upon chronic injury, the Ly6C(hi) subset was significantly increased in the inflamed liver. Transplantation of BM-MSCs markedly promoted a phenotypic switch from pro-fibrotic Ly6C(hi) subset to restorative Ly6C(lo) subpopulation by secreting paracrine cytokines IL-4 and IL-10 from the BM-MSCs. The Ly6C(hi)/Ly6C(lo) subset switch significantly blocked the source of fibrogenic TGF-β, PDGF, TNF-α, and IL-1β cytokines from Ly6C(hi) macrophages. Unexpectedly, BM-MSCs experienced severe apoptosis and produced substantial apoptotic bodies in the fibrotic liver during the 72 h period of transplantation. Most apoptotic bodies were engulfed by Ly6C(lo) macrophages, and this engulfment robustly triggered MMP12 expression for fibrosis resolution through the PtdSer-MerTK-ERK signaling pathway. This paper is the first to show previously unrecognized dual regulatory functions of BM-MSCs in attenuating hepatic fibrosis by promoting Ly6C(hi)/Ly6C(lo) subset conversion and Ly6C(lo) macrophage restoration through secreting antifibrogenic-cytokines and activating the apoptotic pathway.