Endogenous Follistatin-like 1 guarantees the immunomodulatory properties of mesenchymal stem cells during liver fibrotic therapy

Abstract

Background Mesenchymal stem cell (MSC) therapy has been shown to be a promising option for liver fibrosis treatment. However, critical factors affecting the efficacy of MSC therapy for liver fibrosis remain unknown. Follistatin-like 1 (FSTL1), a TGF-β-induced matricellular protein, is documented as an intrinsic regulator of proliferation and differentiation in MSCs. In the present study, we characterized the potential role of FSTL1 in MSC-based anti-fibrotic therapy and further elucidated the mechanisms underlying its action. Methods Human umbilical cord-derived MSCs were characterized by flow cytometry. FSTL1low MSCs were achieved by FSTL1 siRNA. Migration capacity was evaluated by wound-healing and transwell assay. A murine liver fibrotic model was created by carbon tetrachloride (CCl4) injection, while control MSCs or FSTL1low MSC were transplanted via intravenous injection 12 weeks post CCl4 injection. Histopathology, liver function, fibrosis degree, and inflammation were analysed thereafter. Inflammatory cell infiltration was evaluated by flow cytometry after hepatic nonparenchymal cell isolation. An MSC-macrophage co-culture system was constructed to further confirm the role of FSTL1 in the immunosuppressive capacity of MSCs. RNA sequencing was used to screen target genes of FSTL1. Results FSTL1low MSCs had comparable gene expression for surface markers to wildtype but limited differentiation and migration capacity. FSTL1low MSCs failed to alleviate CCl4-induced hepatic fibrosis in a mouse model. Our data indicated that FSTL1 is essential for the immunosuppressive action of MSCs on inflammatory macrophages during liver fibrotic therapy. FSTL1 silencing attenuated this capacity by inhibiting the downstream JAK/STAT1/IDO pathway. Conclusions Our data suggest that FSTL1 facilitates the immunosuppression of MSCs on macrophages and that guarantee the anti-fibrotic effect of MSCs in liver fibrosis.

From Phenomenon to Essence: A Newly Involved lncRNA Kcnq1ot1 Protective Mechanism of Bone Marrow Mesenchymal Stromal Cells in Liver Cirrhosis

“…also clarified that Fstl1 facilitates the immunosuppressive of MSCs on macrophages and guarantees the anti‐fibrotic effect of MSCs in liver fibrosis. [ 28 ] Fstl1 is highly expressed in activated HSCs, while Fstl1 knockdown effectively suppresses HSCs proliferation by the TGF‑ β 1/Smad3 signaling pathway. [ 29 ] In our study, Fstl1 was also highly expressed in cirrhosis and regulated by Kcnq1ot1 and miR‐374‐3p.…”

Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications

“…It has been reported that human bone marrow-derived MSCs (BM-MSCs) transplantation rescued fulminant hepatic failure mice, as demonstrated by robust proliferation and trans-differentiation of functional hepatocytes and multiple immune cell lineages, including B cells, T cells, NK cells, DCs and macrophages [ 55 ]. Zheng et al [ 56 ] reported that Follistatin-like 1 (FSTL1) is essential for the immunosuppressive action of MSCs on inflammatory macrophages in liver fibrotic therapy. Knockdown of FSTL1 in MSCs significantly attenuated this property through inhibiting the downstream Janus kinase/STAT1/IDO pathway.…”

Cell therapy in end-stage liver disease: replace and remodel

“…The transformed cells may be injected into the liver locally or intravenously to restore liver function or encourage liver regeneration [ 9 ]. The therapeutic effect of cell therapy has been extensively studied in animal models [ 10 , 11 ]. The first study on cell therapy was conducted in 1976 by Najarian, who transplanted allogeneic hepatocytes into a rat model of congenital enzyme deficiency disease via the portal vein [ 12 ].…”