Transplantation of Encapsulated Hepatocytes during Acute Liver Failure Improves Survival without Stimulating Native Liver Regeneration

Abstract

The aim of this study was to evaluate the effects of intraperitoneal transplantation of encapsulated human hepatocytes on liver metabolism and regeneration of mice with acute liver failure. Primary human hepatocytes were immortalized using lentiviral vectors coding for antiapoptotic genes and microencapsulated using alginate-polylysine polymers. In vitro, immortalized human hepatocytes showed low, but stable, synthetic and catabolitic functions over time, when compared to primary hepatocytes. In vivo, mice with acute liver failure and transplanted with encapsulated immortalized human hepatocytes had a significantly improved survival and biochemical profile, compared to mice transplanted with empty capsules. Serum levels of cytokines implicated in liver regeneration were lower in mice transplanted with hepatocytes compared to mice receiving empty capsules. This decrease was significant for IL-6 and HGF at 3 h. Measurement of liver regeneration showed no significant difference between mice transplanted with hepatocytes compared to control groups. Intraperitoneal transplantation of encapsulated immortalized hepatocytes significantly improved survival of mice with acute liver failure by providing metabolic support and without modifying liver regeneration. The lower levels of cytokines implicated in liver regeneration suggest that the metabolic support provided by the encapsulated hepatocytes reduced the inflammatory stress on the liver and herein decreased the regenerative trigger on residual hepatocytes. These data emphasize that metabolic function and regeneration of hepatocytes are two distinct aspects that need to be studied and approached separately during acute liver failure.

Beneficial Effects of Human Mesenchymal Stromal Cells on Porcine Hepatocyte Viability and Albumin Secretion

“…Micropores permit exchanges of nutrients, oxygen, and small-sized molecules. The promising first transplants with encapsulated hepatocytes in pig-to-rodent animal models showed that such transplanted encapsulated hepatocytes were still functional over several weeks [4][5][6]. In a pig-to-baboon model, 75% of baboons after induction of fulminant liver failure and subsequent transplantation with encapsulated hepatocytes recovered from liver injury [7], demonstrating further the therapeutic potential of such a treatment.…”

“…Porcine hepatocyte cell transplantation might present an alternative solution to overcome acute liver failure damages by replacing the metabolic function of the liver until its recovery. Earlier studies in mice with acetaminophen-and hepatectomy-induced fulminant liver failure showed that transplantation of microencapsulated human or porcine hepatocytes increased survival rates of mice [5,6] and the first protocols for porcine hepatocyte isolation and encapsulation with Alg-PLL capsules were applied [5,6]. Here, we developed an optimized high-yield porcine hepatocyte isolation protocol from 10-kilogram pigs.…”

Translational Regenerative Medicine—Hepatic Systems

“…This deficiency may be attributed to the use of synthetic material on which the cells are seeded in the apparatus. Functional efficiency can be improved by providing a more natural substrate in the extracorporeal device to allow cells to function more closely to an in vivo state [131,132]. Natural ECM should enable cells to maintain higher functionality and ultimately lead to greater levels of protein secretion and waste metabolism.…”

Current status of hepatocyte xenotransplantation

“…In this study cells were microencapsulated in alginate-poly(L-lysine)-alginate microspheres. Porcine hepatocytes microencapsulated in alginatepoly(L-lysine)-alginate microspheres manifested in vitro production of albumin and urea, and degraded ammonium, diazepam and lidocaine; in vivo a 55% increase in survival of mice with fulminant liver failure was shown [29,64]. Recently, porcine hepatocytes microencapsulated in alginate-poly(L-lysine)-alginate microspheres (Fig.…”