Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-li...Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-like cells(HLCs)derived from mesenchymal stromal/stem cells(MSCs)offer a promising alternative cell source for hepatocyte therapy,their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy.To this end,MSCs are bioengineered into multicellular spheroids in the present study.The proteomic analyses and experimental results reveal that extracellular vesicles(EVs)derived from these MSC spheroids(SpEV)contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells,resulting in enhanced pro-angiogenic and antioxidative effects.In addition,MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs,particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement.Following orthotopic implantation in the mouse model,the enhanced paracrine effects of SpEV,combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules(ALL),synergically contribute to the effective amelioration of ALF,highlighting the substantial potential for clinical translation.展开更多
基金supported by the National Key Research and Devel-opment Program of China(2019YFA0111300)the National Natural Science Foundation of China(52422318,32471423,22277155,52373166)+5 种基金Guangdong Basic and Applied Basic Research Foundation(2022A1515110685,2023A1515011067)the Natural Science Foun-dation of Guangdong Province for Distinguished Young Scholar(2024B1515020025)the Science and Technology Program of Guangz-hou(2025A04J7161,2024A04J6572)the Talent Introduction Program of Postdoctoral International Exchange Program(YJ20200313)the China Primary Health Care Foundation(2022-003)the Thousand Tal-ents Plan,and the Guangdong Provincial Pearl River Talents Program(2019QN01Y131).
文摘Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-like cells(HLCs)derived from mesenchymal stromal/stem cells(MSCs)offer a promising alternative cell source for hepatocyte therapy,their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy.To this end,MSCs are bioengineered into multicellular spheroids in the present study.The proteomic analyses and experimental results reveal that extracellular vesicles(EVs)derived from these MSC spheroids(SpEV)contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells,resulting in enhanced pro-angiogenic and antioxidative effects.In addition,MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs,particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement.Following orthotopic implantation in the mouse model,the enhanced paracrine effects of SpEV,combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules(ALL),synergically contribute to the effective amelioration of ALF,highlighting the substantial potential for clinical translation.
