Construction of vascularized liver microtissues recapitulates angiocrine-mediated hepatocytes maturation and enhances therapeutic efficacy for acute liver failure

Abstract

Liver failure poses a significant challenge for millions of patients. The use of primary human hepatocytes and the engineering of liver organoids or liver tissue provide promising solutions to mitigate the shortage of donor organs. However, insufficient vascularization and functional immaturity remain major barriers impeding optimal functional recovery after transplantation. In this study, adult stem cells derived from human liver tissues were induced to form liver organoids, which were subsequently co-cultured with vascular organoids generated from human induced pluripotent stem cells in a defined ratio to create vascularized liver microtissues. This approach successfully established a complex vascular network analogous to that found in the liver, effectively recapitulating a more physiologically relevant liver architecture. Mechanistically, this configuration promoted the structural and secretory maturation of liver organoids through paracrine signaling from the vasculature. Following transplantation into the mesentery of mice, the vascularized liver microtissues rapidly established connections with the host vasculature and enhanced secretion of albumin into the bloodstream. Moreover, the transplantation of vascularized liver microtissues could effectively ameliorate liver injury and inflammatory responses, reduce apoptosis while promoting cell proliferation in CCl₄-induced acute liver failure mice. These findings provide a robust platform for investigating the interactions between vessels and liver, and have important implications for liver failure treatment in the field of regenerative medicine.