Concise Review: Cell Therapies for Hereditary Metabolic Liver Diseases—Concepts, Clinical Results, and Future Developments

Abstract

The concept of cell-based therapies for inherited metabolic liver diseases has been introduced for now more than 40 years in animal experiments, but controlled clinical data in humans are still not available. In the era of dynamic developments in stem cell science, the "right" cell for transplantation is considered as an important key for successful treatment. Do we aim to transplant mature hepatocytes or do we consider the liver as a stem/progenitor-driven organ and replenish the diseased liver with genetically normal stem/progenitor cells? Although conflicting results from cell tracing and transplantation experiments have recently emerged about the existence and role of stem/progenitor cells in the liver, their overall contribution to parenchymal cell homeostasis and tissue repair is limited. Accordingly, engraftment and repopulation efficacies of extrahepatic and liver-derived stem/progenitor cell types are considered to be lower compared to mature hepatocytes. On the basis of these results, we will discuss the current clinical cell transplantation programs for inherited metabolic liver diseases and future developments in liver cell therapy. STEM CELLS 2015;33:1055-1062 HEPATOCYTES OR STEM CELLS: WHICH CELL DRIVES PARENCHYMAL LIVER MAINTENANCE AND REGENERATION OF THE LIVER?The long prevailing view in liver physiology and pathophysiology has localized a hepatic stem/progenitor cell compartment at or near the canals of Hering, in periductular glands and in extrahepatic bile duct structures [1][2][3]. Some researchers found proof that biliary tree-associated stem/progenitor cells countinuously generate hepatocytes and bile duct cells and maintain the normal turnover of parenchymal liver cells [4]. According to the "streaming theory," stem/progenitor cellderived hepatocytes continuously migrate from the periportal areas toward central vein structures, mature and express differential metabolic activities. Cell fate tracing experiments have attributed Sox9 expressing cells with stem/progenitor properties in the liver as well as in several other epithelial organs [5][6][7]. More recent data challenge this view and provide evidence for a more complex situation in the liver.Following acute injury small cells, which express the WNT ligand receptor Lgr5, emerge in the liver and generate hepatocytes [8]. These cells were identified randomly throughout the liver and could not be traced in the noninjured liver. Although the Lgr5 1 cells, which coexpress Krt19 and Sox9, could still be derived from a (not identified) biliary lineagederived stem/progenitor cell in the liver, other studies indicate that mature hepatocytes can dedifferentiate and acquire properties of a liver stem/progenitor cell including the expression of progenitor and biliary lineageassociated cell surface markers. "Knockdown" of the Hippo/Yes-associated protein (YAP) signalling pathway in hepatocytes resulted in emergence of cells with liver stem/progenitor characteristics. Upon restauration of YAP expression, at least some progenitor cells turned ...

Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

“…Importantly, we also noticed that the engrafted iHeps could be maintained in LRG mouse liver, and were functional, for at least 3 months. Overall, these results highlight the potential relevance of transplanting iPSC-derived iHeps for the treatment of hereditary metabolic liver disorders (Cantz et al., 2015), and the use of chimeric animals humanized with disease-specific iHeps for preclinical evaluation of novel therapies. However, the long-term therapeutic efficacy of iPSC-based approaches remains unclear, and future studies are necessary to address this as well as safety concerns.…”

Transdifferentiation of human male germline stem cells to hepatocytesin vivovia the transplantation under renal capsules

“…Hepatocytes transplantation has emerged as a promising treatment for a variety of liver diseases [1–3]. However, there is severe shortage of primary human hepatocytes, which precludes their wider clinical applications [9, 10].…”

“…Human hepatocyte transplantation has been regarded as an alternative and effective treatment for acute- and end-stage liver failure and metabolic liver diseases [1–3]. Notably, hepatocyte transplantation has several advantages over orthotopic liver transplantation [4–9]: i) hepatocytes from one donor can be used for more patients; ii) hepatocytes could be transplanted into patients with liver diseases multiple times; iii) the transplanted hepatocytes are able to restore the liver parenchyma of patients directly or promote the native liver regeneration by secreting appropriate factors indirectly; and iv) transplantation of human hepatocytes is technically simple and reversible since the native liver doesn't need to be removed.…”

Stem Cell Therapies for Treatment of Liver Disease

“…Notwithstanding, both in vitro and in vivo signal patterns, mechanisms of differentiation, and optimum proliferation conditions must be studied in more depth before clinical applications can be considered, especially since the data suggest that engraftment and repopulation capacity is higher in mature hepatocytes than stem cells [73]. …”