The potential of induced pluripotent stem cell derived hepatocytes

Abstract

Orthotopic liver transplantation remains the only curative treatment for liver disease. However, the number of patients who die while on the waiting list (15%) has increased in recent years as a result of severe organ shortages; furthermore the incidence of liver disease is increasing worldwide. Clinical trials involving hepatocyte transplantation have provided encouraging results. However, transplanted cell function appears to often decline after several months, necessitating liver transplantation. The precise aetiology of the loss of cell function is not clear, but poor engraftment and immune-mediated loss appear to be important factors. Also, primary human hepatocytes (PHH) are not readily available, de-differentiate, and die rapidly in culture. Hepatocytes are available from other sources, such as tumour-derived human hepatocyte cell lines and immortalised human hepatocyte cell lines or porcine hepatocytes. However, all these cells suffer from various limitations such as reduced or differences in functions or risk of zoonotic infections. Due to their significant potential, one possible inexhaustible source of hepatocytes is through the directed differentiation of human induced pluripotent stem cells (hiPSCs). This review will discuss the potential applications and existing limitations of hiPSC-derived hepatocytes in regenerative medicine, drug screening, in vitro disease modelling and bioartificial livers.

In vivo reprogramming of hepatic myofibroblasts into hepatocytes attenuates liver fibrosis: back to the future?

“…engraftment potential of transplanted iPSC-derived hepatocytes and their functionality at both short and long term (9)(10)(11)(12). Whether cell therapy approach is specifically concerned, iPSC-derived hepatocytes have been used in a number of experimental models, but best results in terms of engraftment and repopulation have been reported in studies employing a protocol of acute liver failure performed in rather specific mouse models (for example fumarylacetoacetate hydrolase Fah…”

“…−/− and urokinase (alb-uPA) severe combined immunodeficient transgenic mice), in which transplanted HLCs efficiently repopulated damaged livers because of the proliferative advantage over resident hepatocytes granted by the model itself (3,(9)(10)(11). This need for a procedure offering a growth advantage/ proliferation to transplanted HLCs, already outlined also by previous studies employing cells obtained from non-iPSC sources (3)(4)(5)(6), is still a relevant problem for translation to humans.…”

“…A potentially more promising strategy, based on the development of the original studies of Yamanaka's group on the generation of induced pluripotent stem cells (iPSC) from adult cells (7,8), has led, using protocols involving either integrative or non-integrative strategies, to successful reprogramming of either murine or human fibroblasts into HLCs (9)(10)(11)(12). Whatever the protocol, HLCs derived from iPSC usually has the ability to: (I) express hepatocyterelated markers (albumin, α1-anti-trypsin and CYP3A4); (II) secrete albumin; (III) express CYP3A4 activity; (IV) store glycogen; and (V) take up cholesterol and indocyanine green.…”

“…Whatever the protocol, HLCs derived from iPSC usually has the ability to: (I) express hepatocyterelated markers (albumin, α1-anti-trypsin and CYP3A4); (II) secrete albumin; (III) express CYP3A4 activity; (IV) store glycogen; and (V) take up cholesterol and indocyanine green. Moreover, in most cases HLCs have been shown to have the potential to engraft murine liver and to be used as tools for disease modelling (9)(10)(11)(12). Human induced, PSC-derived hepatocytes (hiHeps) can indeed represent a multi-purpose and potentially inexhaustible source of viable and functional HLCs.…”

“…hiHeps from a healthy donor can be used for drug screening and toxicology, for allogenic therapy as well as a source of cells to be used in bioengineered livers. hiHeps from a patient donor can be used in specific disease modelling (i.e., modelling of HCV infection or malaria to investigate disease progression) or drug screening/toxicology but reprogrammed and corrected iPSC, than differentiated into iPSC-derived hepatocytes, may be in principle also used for autologous cell therapy (9)(10)(11). However, for any of these applications limitations have been described, ranging from the general problems still represented by the incomplete efficiency of either reprogramming or differentiation step to limitations related to the more specific application of choice, including cell function and viability of these iPSC-derived hepatocytes as well as homogeneity of the cell population obtained [see ref.…”