Hepatoprotective Effects of Intra-Splenic Injection of Extracellular Vesicles Generated from Human ES-MSCs onChronic Liver Injury

Hepato-protective effects of somatic tissue derived mesenchymalstromal cells (MSCs) against liver injuries have beenwidely observed in both experimental models and clinical trials.MSCs promote liver regeneration mostly through their paracrineeffect following the secretion of extracellular vesicles(EVs). Human embryonic stem cell-derived MSCs (ES-MSCs)as an alternative source can overcome most challenges facingclinical application of somatic tissue derived-MSCs. The aim ofthis study is to illustrate biological properties of ES-MSCs andtheir generated EVs both in vitro and in vivo in Thioacetamideinducedchronic liver injury (CLI). We shows that ES-MSC canmarkedly inhibit the proliferation of peripheral blood mononuclearcells (PBMCs) in comparison to somatic tissue derivedbonemarrow (BM)-MSCs and adipose (AD)-MSCs. Higherlevels of anti-inflammatory cytokines (i.e. TGF-β and IL-۱۰)and decreased IFN-γ were observed in the supernatant of ESMSCscompared to other MSCs following MLR assay. Moreover,ES-MSC EVs also possess significant immunosuppressionfeature compared to other counterparts in vitro.ES-MSC EVs exerted functional properties comparable to theirparental cells and reversed fibrosis in TAA-induced chronicliver injury. ES-MSC EVs exhibited reduction of collagen density,necrosis, caspase density, portal vein diameter (PVD) andresolution of fibrosis. In addition, the results indicated downregulationof major contributors to fibrosis (Col۱α, αSMAand TIMP۱), pro-apoptotic gene (BAX) and pro-inflammatorycytokines (TNFα and IL-۲) and uplregulation of collagenase(MMP۹ and MMP۱۳), anti-apoptotic gene (BCL۲) and antiinflammatorycytokines (TGF-β۱ and IL-۱۰) following intrasplenicinjection of both ES-MSC and ES-MSC EVs in Thioacetamide-induced CLI.In conclusion, these finding suggest that ES-MSCs and ESMSCEVs as the next generation cell-free product can promotethe recovery of liver injuries. Administration of allogeneic ESMSCEVs as the next generation cell-free product may representa novel therapeutic strategy for liver regeneration and itmay considered as an alternative approach for stem cell basedtherapy for chronic liver injuries.

کلیدواژه ها:

Dlk۱-Dio۳ Locus ، Ground State Pluripotency ، Micro RNA ، Small RNA Sequencing ، Differentiation