Co-encapsulation of HNF4α Overexpressing UMSCs and Human Primary Hepatocytes Ameliorates Mouse Acute Liver Failure

Abstract

Background: Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4α-overexpressing human umbilical cord MSCs (HNF4α-UMSCs) promoted the expression of hepatic-specific genes. In addition, microencapsulation allows exchange of nutrients, forming a protective barrier to the transplanted cells. Moreover, encapsulation of hepatocytes improves the viability and synthetic ability of hepatocytes and circumvents immune rejection. This study aimed to investigate the therapeutic effect of microencapsulation of hepatocytes and HNF4α-UMSCs in ALF mice.Methods: Human hepatocytes and UMSCs were obtained separately from liver and umbilical cord, followed by co-encapsulation and transplantation into mice by intraperitoneal injection. LPS/D-gal was used to induce ALF by intraperitoneal injection 24 h after transplantation. In addition, Raw 264.7cells (a macrophage cell line) were used to elucidate the effect of HNF4α-UMSCs-hepatocyte microcapsules on polarization of macrophages. The protein chip was used to define the important paracrine factors in the conditioned mediums (CMs) of UMSCs and HNF4α-UMSCs and investigate the possible mechanism of HNF4α-UMSCs for the treatment of ALF in mice.Results: HNF4α-UMSCs can enhance the function of primary hepatocytes in alginate–poly-L-lysine–alginate (APA) microcapsules. The co-encapsulation of both HNF4α-UMSCs and hepatocytes achieved better therapeutic effects in ALF mice by promoting M2 macrophage polarization and reducing inflammatory response mainly mediated by the paracrine factor HB-EGF secreted by HNF4α-UMSCs.Conclusions: The present study confirms that the co-encapsulation of HNF4α-UMSC and hepatocytes could exert therapeutic effect on ALF mainly by HB-EGF secreted by HNF4α-UMSCs and provides a novel strategy for the treatment of ALF.