Abstract
Background: Accumulating evidence indicates that mesenchymal stem cells (MSCs) are precursors of myofibroblasts, which play a vital role in renal fibrosis. The close interaction between MSCs and other immune cells regulates the development of multiple fibrosis-related diseases. However, the effect of myeloid-derived suppressor cells (MDSCs) on MSCs remains unexplored. Here, we investigated the effect of MDSCs on the myofibroblastic differentiation of MSCs. Methods: MSCs were induced to undergo myofibroblastic differentiation with transforming growth factor beta 1 (TGF-β1). M-MDSCs and G-MDSCs were sorted by flow cytometry. Supernatants derived from MDSCs were administered to cultured bone marrow MSCs (BM-MSCs) undergoing TGF-β1-induced myofibroblastic differentiation. Myofibroblastic differentiation was evaluated by immunostaining. The expression of fibrosis-related genes was determined by quantitative PCR and western blot analysis. In vitro, M-MDSC supernatant or M-MDSC supernatant with interleukin (IL)-15 mAbs was administered following unilateral renal ischemia-reperfusion injury (IRI) to observe the myofibroblast differentiation of renal resident MSCs (RRMSCs) in a murine model. Results: Myofibroblastic differentiation of MSCs was hindered when the cells were treated with MDSC-derived supernatants, especially that from M-MDSCs. The inhibitory effect of M-MDSC supernatant on the myofibroblastic differentiation of MSCs was partially mediated by IL-15-Ras-Erk1/2-Smad2/3 signaling. Treatment with M-MDSC supernatant ameliorated renal fibrosis and myofibroblastic differentiation in RRMSCs through IL-15. Additionally, M-MDSC supernatant increased M-MDSC infiltration in the kidney in a mouse IRI model. M-MDSC supernatant downregulated the adhesion and migration marker CD44 on the cell membrane of MSCs via IL-15. Conclusion: M-MDSC-derived supernatant inhibited the TGF-β1-induced myofibroblastic differentiation of MSCs through IL-15. Our findings shed new light on the effect of MDSCs on myofibroblastic differentiation and adhesion of MSCs, which might provide a new perspective in the development of treatment strategies for renal fibrosis.
Highlights
Mesenchymal stem cells (MSCs) are a type of multipotent stem cell of mesodermal origin that is derived from practically all tissue adventitial progenitor cells and pericytes (Ma et al, 2020)
We found that TGF-β1 (5 ng/mL) triggered a myofibroblastic differentiation process that was characterized by an alteration in cell morphology from the characteristic organized spindle-shaped appearance to a disorganized elongated fibroblast-like phenotype, and this effect was attenuated by treatment with high-dose myeloid-derived suppressor cells (MDSCs) supernatant (Figure 1A)
MSCs induced by TGF-β1 that were treated with high-dose MDSC supernatant displayed dramatically decreased levels of ACTA2, COL1A1 and COL1A3 (Figures 1B,C)
Summary
Mesenchymal stem cells (MSCs) are a type of multipotent stem cell of mesodermal origin that is derived from practically all tissue adventitial progenitor cells and pericytes (Ma et al, 2020). LeBleu et al (2013) found that circulating BM-MSCs contributes to renal myofibroblasts. Kramann et al (2015) reported that renal myofibroblasts were derived from kidneyresident MSC-like cells. Circulating BM-MSCs, resident perivascular MSC-like kidney cells or pericytes have recently been regarded as major sources of myofibroblasts that drive kidney fibrosis. It is critical to study how to inhibit TGF-β1-induced differentiation of MSCs into myofibroblasts to attenuate renal fibrosis. Accumulating evidence indicates that mesenchymal stem cells (MSCs) are precursors of myofibroblasts, which play a vital role in renal fibrosis. The effect of myeloid-derived suppressor cells (MDSCs) on MSCs remains unexplored. We investigated the effect of MDSCs on the myofibroblastic differentiation of MSCs
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