Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine

Abstract

Human hepatocyte transplantation has been actively perused as an alternative to liver replacement for acute liver failure and liver-based metabolic defects. Current challenges in this field include a limited cell source, reduced cell viability following cryopreservation and poor engraftment of cells into the recipient liver with consequent limited life span. As a result, alternative stem cell sources such as pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells and mesenchymal stem/stromal cells (MSCs) can be used to generate induced hepatocyte like cells (HLC) with each technique exhibiting advantages and disadvantages. HLCs may have comparable function to primary human hepatocytes and could offer patient-specific treatment. However, long-term functionality of transplanted HLCs and the potential oncogenic risks of using stem cells have yet to be established. The immunomodulatory effects of MSCs are promising, and multiple clinical trials are investigating their effect in cirrhosis and acute liver failure. Here, we review the current status of hepatocyte transplantation, alternative cell sources to primary human hepatocytes and their potential in liver regeneration. We also describe recent clinical trials using hepatocytes derived from stem cells and their role in improving the phenotype of several liver diseases.

Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

“…Our study demonstrated cGMP‐derived hepatic constructs remained viable, and more importantly, functional within the peritoneal cavity of fully immune competent C57BL/6 and CD‐1 mice for a time period long enough to result in recovery from ALF if used in patients. This in turn strongly advocates for further development of hPSC‐hepatocytes as a clinical therapeutic .…”

Acute Liver Failure

“…Specifically, one of the main indications for human hepatocyte transplantation therapy is ALF 125,126 ; human hepatocyte transplantation has been actively perused as an alternative to liver replacement for ALF. 127 In this regard, 37 patients with ALF have been treated with human hepatocytes for drug-induced, viral, and obscure ALF. Ten of these patients received intraportal hepatocyte infusions, with 2 making a full recovery without the requirement of OLT, and 3 were successfully bridged to transplantation.…”

“…However, present challenges include a reduced cell source, decreased cell viability following cryopreservation, and poor engraftment of cells into the recipient liver with consequently a limited lifespan. 127,133,134 Therefore, alternative stem cell sources including pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells, and mesenchymal stem/stromal cells can be introduced to generate induced hepatocyte-like cells, with each technique exhibiting advantages and disadvantages. Mesenchymal stem/stromal cells transplantation had beneficial effects, especially in ACLF patients.…”

“…1 However, long-term functionality of transplanted hepatocyte-like cells and the potential carcinogenic risks of administering stem cells have yet to be proven. 127 Research has focused also on HE potential novel therapies, as a substantial body of evidence has signified that inflammation acts in concert with ammonia in HE pathogenesis, and inflammatory mediators have a significant role in modulating the cerebral effect of ammonia. Relative novel and potential therapeutic strategies include hypothermia, minocycline, nonsteroidal anti-inflammatory drugs, tumor necrosis factor-alpha antagonists, and p38 inhibitors, which seem to ameliorate systemic inflammation-neuroinflammation, improve or reverse neuropsychiatric manifestations, and prevent the onset and progression of HE in patients and/or animal models of ACLF.…”

Intrahepatic Administration of Human Liver Stem Cells in Infants with Inherited Neonatal-Onset Hyperammonemia: A Phase I Study

“…However, several issues complicated the feasibility and safety of liver transplantation in the clinical practice, including shortage of donor livers, the quality of cryopreserved cells, the need for invasive procedures to perform portal infusions, limited space in the native liver, the risk of extra-hepatic spread of transplanted hepatocytes (mostly to the lung), limited engraftment of transplanted cells and the need of immunosuppression to prevent rejection. These limitations led to an increased interest in the potential use of stem cells with hepatic differentiation capability [10].…”