In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject ...In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject to prolonged timelines for tissue architecture and functional restoration,remains poorly understood.In this study,we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin(GelTA)that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers(hiPSC-myofibers)and hiPSC-muscle precursor cells.This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix.Secreted EVs from the hiPSC-myofibers contain specific microRNAs,potentially improving myogenesis and angiogenesis.Herein,we demonstrate increased myogenic markers and fusion/differentiation indexes through the combina-tory effects of EVs and integrin-mediated adhesions in the 3D matrix.Furthermore,we observe a unique impact of EVs,which aid in maintaining the viability and phenotype of myofibers under harsh environments.The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains.Later,we confirmed a combinational effect,whereby muscle tissue regeneration and functional restoration were improved,via an in vivo murine volumetric muscle loss model.展开更多
基金funded by the National Institutes of Health(R01AR077132)AHA collaborative award(944227)+3 种基金the Gillian Reny Stepping Strong Center for Trauma Innovationpartially supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2021R1A6A3A14039720)supporting Jiseong Kim and Jieun Jeon by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Minstry of Health&Welfare,Republic of Korea(HI19C0757)partially funded by the Deanship of Scientific Research(DSR)at King Abdulaziz University,Jeddah,under Grant No.RG-22-135-39.
文摘In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject to prolonged timelines for tissue architecture and functional restoration,remains poorly understood.In this study,we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin(GelTA)that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers(hiPSC-myofibers)and hiPSC-muscle precursor cells.This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix.Secreted EVs from the hiPSC-myofibers contain specific microRNAs,potentially improving myogenesis and angiogenesis.Herein,we demonstrate increased myogenic markers and fusion/differentiation indexes through the combina-tory effects of EVs and integrin-mediated adhesions in the 3D matrix.Furthermore,we observe a unique impact of EVs,which aid in maintaining the viability and phenotype of myofibers under harsh environments.The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains.Later,we confirmed a combinational effect,whereby muscle tissue regeneration and functional restoration were improved,via an in vivo murine volumetric muscle loss model.
