Immunomodulation by systemic administration of exosomes derived from induced pluripotent stem cell mesenchymal stem cells to alleviate liver inflammation and fibrosis in Wilson's disease.

Abstract

BACKGROUND AND AIMS: Exosomes derived from mesenchymal stem cells (MSCs) are proposed to have anti-inflammatory and immunomodulatory effects. We sought to determine the therapeutic effects of human induced pluripotent stem cell-MSC derived exosomes (iPSC-MSC-Ex) on liver inflammation and fibrosis in Wilson's disease (WD). METHODS AND RESULTS: Exosomes derived from MSCs differentiated from iPSCs were administered intravenously into an ATPase Copper Transporting Beta (ATP7B) knockout mouse in-vivo model of WD. Hepatic function was then evaluated. iPSC-MSC-Ex treated mice showed attenuated liver injury, evidenced by enhanced liver functionality, decreased collagen accumulation, and reduced inflammation. Our results also revealed that treatment with iPSC-MSC-Ex regulated the immune response with reduced splenic inflammatory monocytes and NK cells and increased splenic Treg cells. Altered macrophage polarization was observed in mice that received iPSC-MSC-derived exosomes, accompanied by down-regulation of hepatic proinflammatory cytokines and up-regulation of hepatic anti-inflammatory cytokines. CONCLUSION: Our findings demonstrated that iPSC-MSC-derived exosomes could ameliorate hepatic fibrosis in a mouse model of WD via immunomodulation and macrophage polarization. These results support the development of iPSC-MSC-derived exosomes as a cell-free therapy for WD as well as other chronic liver diseases.