Current status of hepatocyte xenotransplantation

Abstract

The treatment of acute liver failure, a condition with high mortality, comprises optimal clinical care, and in severe cases liver transplantation. However, there are limitations in availability of organ donors. Hepatocyte transplantation is a promising alternative that could fill the medical need, in particular as the bridge to liver transplantation. Encapsulated porcine hepatocytes represent an unlimited source that could function as a bioreactor requiring minimal immunosuppression. Besides patients with acute liver failure, patients with alcoholic hepatitis who are unresponsive to a short course of corticosteroids are a target for hepatocyte transplantation. In this review we present an overview of the innate immune barriers in hepatocyte xenotransplantation, including the role of complement and natural antibodies; the role of phagocytic cells and ligands like CD47 in the regulation of phagocytic cells; and the role of Natural Killer cells. We present also some illustrations of physiological species incompatibilities in hepatocyte xenotransplantation, such as incompatibilities in the coagulation system. An overview of the methodology for cell microencapsulation is presented, followed by proof-of-concept studies in rodent and nonhuman primate models of fulminant liver failure: these studies document the efficacy of microencapsulated porcine hepatocytes which warrants progress towards clinical application. Lastly, we present an outline of a provisional clinical trial, that upon completion of preclinical work could start within the upcoming 2-3 years

Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model

“…The pig is considered a promising candidate as a potential source animal (1,2). Despite the progress in recent years (3)(4)(5)(6), robust immunological rejection remains a major obstacle to xenotransplantation (7). An attractive approach to preventing xenograft rejection is tolerance induction so that the human immune system is specifically unresponsive to the pig xenografts (1,2,8), thus avoiding the use of long-term immunosuppression while preserving the ability of the immune system to respond to pathogens.…”

Isolations and Cultures of Primary Hepatocytes

“…Whole liver organs or resected liver tissues are both available to isolate hepatocytes, as long as they fulfill the criteria regarding the absence of infectious agents or high level of hepatic lesions. Various routes can be exploited to administer hepatocytes in whole liver organs: intrasplenic, directly into the hepatic parenchyma, or in the peritoneal cavity, but more often intraportal [16]. Left lateral sector segments are usually suitable to obtain normal resected tissues, with proportionate volumes, after which the lobular blood vessels can be easily exposed for catheterization.…”

Transplantation of hepatocytes from genetically engineered pigs into baboons

“…2 Progress in the field of both hepatocyte allotransplantation and xenotransplantation has recently been reviewed. [3][4][5][6][7][8] Hepatocytes from wild-type pigs have been reported to be resistant to complement-mediated injury, 9 and capable of producing pig proteins when transplanted into immunosuppressed monkeys. The genetic engineering of these pigs renders their cells no more immunogenic than their human counterparts.…”