Characterization of adipose tissue-derived stromal cells of mice with nonalcoholic fatty liver disease and their use for liver repair

Abstract

Introduction Freshly isolated uncultured adipose tissue-derived stromal cells (u-ADSCs), containing miscellaneous cells like the relatively abundant mesenchymal stem cells, are attractive for repair and regenerative therapy. However, the detailed characteristics and therapeutic efficacy of u-ADSCs obtained from disease-affected hosts are unknown. We compared the properties of u-ADSCs obtained from wild-type mice and from a mouse model of non-alcoholic steatohepatitis (NASH). Methods The NASH model was established by feeding C57BL/6J mice an atherogenic high-fat diet for 4 (NASH (4w)) or 12 weeks (NASH (12w)), followed by the isolation and characterization of u-ADSCs. Wild-type u-ADSCs or NASH-derived u-ADSCs were administered to mice with NASH cirrhosis, followed by analyses of hepatic inflammatory cells, antigen profiles, fibrosis, and gene expression. Results Wild-type u-ADSCs and NASH-derived u-ADSCs did not show marked differences in surface antigen profiles. In NASH (4w) u-ADSCs, but not NASH (12w) u-ADSCs, the frequencies of the leukocyte markers CD11b, CD45, and CD44 were elevated; furthermore, we observed an increase in the M1/M2 macrophage ratio only in NASH (12w) u-ADSCs. Only in NASH-4w u-ADSCs, the expression levels cell cycle-related genes were higher than those in u-ADSCs. Wild-type u-ADSCs administered to mice with NASH-related cirrhosis decreased the infiltration of CD11b+, F4/80+, and Gr-1+ inflammatory cells, ameliorated fibrosis, and had a restorative effect on liver tissues, as determined by gene expression profiles and the NAFLD activity score. The therapeutic effects of NASH (4w) u-ADSCs and NASH (12w) u-ADSCs on NASH-related cirrhosis were highly similar to the effect of wild-type u-ADSCs, including reductions in inflammation and fibrosis. Conclusions NASH-derived u-ADSCs, similar to wild-type u-ADSCs, are applicable for reparative and regenerative therapy in mice with NASH.

Mechanisms of Action of Mesenchymal Stem Cells in Metabolic-Associated Fatty Liver Disease

“…This is mediated by triggering Notch signaling [71]. Based on the above study, Yano et al [72] transplanted ADSCs into NASH-related cirrhotic mice and observed decreased infiltration of inflammatory cytokines (CD11b+, Gr-1+, etc. ), improved liver fibrogenesis, and repaired damaged liver tissue.…”

Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease

“…Another discovery was that MSC transplantation inhibited NASH progression by reducing hepatic inflammation, as demonstrated by the decreased expression of the acute-phase protein serum amyloid A, inflammation-associated markers such as lipocalin 2, and the proinflammatory cytokine TNF-α[ 54 , 55 ]. The ability of ADSCs to hinder NASH progression by mitigating IL-17-mediated and other inflammatory effects underscores their therapeutic potential, showing outcomes comparable to those of both NASH-specific uncultured adipose tissue-derived stromal cells (u-ADSCs) and wild-type u-ADSCs[ 56 , 57 ]. An integrated approach, employing either a combination of MSCs and MSC-EVs or solely MSC-EVs led to a noticeable increase in the number of anti-inflammatory macrophages in the liver, showing their robust immunomodulatory potency in NASH[ 45 , 49 , 58 ].…”

“…In certain studies, ADSC treatments have been shown to effectively inhibit the progression of NASH fibrosis by targeting IL-17-mediated inflammation, a key factor in the activation of hepatic stellate cells (HSCs)[ 57 ]. Interestingly, both NASH-derived u-ADSCs and wild-type u-ADSCs show promise in preventing and reducing fibrosis in NASH[ 56 ].…”

Translation of Adipose-Derived Stem Cells Into Clinical Use to Treat Chronic Wounds

“…Based on these advantages, ASCs are being investigated as a therapeutic strategy for various pathological conditions, including hard-to-heal wounds. Currently, ASCs are employed in many early clinical trials for inflammatory and autoimmune diseases, ischemic heart disease, limb ischemia, fistulas, liver disease, and orthopedics, where their safety and efficiency have been verified and revealed great promise [28][29][30][31][32][33][34][35]. Cutaneous wounds treated with ASCs have exhibited great therapeutic potential [36][37][38].…”