Long-Term Fate of Human Fetal Liver Progenitor Cells Transplanted in Injured Mouse Livers

Abstract

Liver progenitor cells have the potential to repair and regenerate a diseased liver. The success of any translational efforts, however, hinges on thorough understanding of the fate of these cells after transplant, especially in terms of long-term safety and efficacy. Here, we report transplantation of a liver progenitor population isolated from human fetal livers into immunepermissive mice with follow-up up to 36 weeks after transplant. We found that human progenitor cells engraft and differentiate into functional human hepatocytes in the mouse, producing albumin, alpha-1-antitrypsin, and glycogen. They create tight junctions with mouse hepatocytes, with no evidence of cell fusion. Interestingly, they also differentiate into functional endothelial cell and bile duct cells. Transplantation of progenitor cells abrogated carbon tetrachlorideinduced fibrosis in recipient mice, with downregulation of procollagen and anti-smooth muscle actin. Paradoxically, the degree of engraftment of human hepatocytes correlated negatively with the anti-fibrotic effect. Progenitor cell expansion was most prominent in cirrhotic animals, and correlated with transcript levels of pro-fibrotic genes. Animals that had resolution of fibrosis had quiescent native progenitor cells in their livers. No evidence of neoplasia was observed, even up to 9 months after transplantation. Human fetal liver progenitor cells successfully attenuate liver fibrosis in mice. They are activated in the setting of liver injury, but become quiescent when injury resolves, mimicking the behavior of de novo progenitor cells. Our data suggest that liver progenitor cells transplanted into injured livers maintain a functional role in the repair and regeneration of the liver. STEM CELLS 2018;36:103-113 SIGNIFICANCE STATEMENTLiver stem cells hold tremendous potential as cell therapy for liver injury. However, engraftment efficiency, efficacy, long-term cell fate, and safety issues remain unresolved. Transplantation of human fetal liver stem cells in a mouse liver injury model shows low engraftment efficiency. Under injury stimulus, they can integrate, proliferate, differentiate, and repair the injured liver, returning to a quiescent state as injury abates. They can differentiate into a variety of cell types, including hepatocyte, cholangiocyte, and endothelial-like cells. Metaplasia occurs in an extreme fibrotic milieu and underscores the need to test candidate stem cells for prolonged period in a cirrhotic environment.

Cell therapy for advanced liver diseases: Repair or rebuild

“…Epithelial cells isolated from foetal human livers have been transplanted into injured murine livers, promoting fibrosis resolution and functionally regenerating parenchyma. 64,65 Comparisons between the matched repopulation capacity of foetal and adult hepatocytes in immune-deficient liver repopulation mouse models have demonstrated superior repopulation capacity of adult over foetal hepatocytes, 66,67 which may be a result of the adult liver providing inadequate signals to retain or promote proliferation of immature cell types. Compared to injecting cells in suspension, which lowers engraftment efficacy (as cells migrate to ectopic sites), direct intrahepatic injection of cells within a hyaluronan matrix significantly improves liver engraftment.…”

Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?

“…Although less mature cells are believed to engraft and repopulate a host liver less efficiently than mature hepatocytes [16,42,44,45], progenitors have been proven to be useful for transplantations. This has been demonstrated not only in animal models (both single [16,42,45,51] and serial transplantations [44] in transgene-induced liver damage mouse models; in general also treated with Futhan, anti-asialo GM1 or oncostatin M (OSM) to increase efficiency), but also clinically. Sokal et al transplanted 9 × 10 8 adult mesenchymal-like liver progenitor cells (0.75% of total body mass) in a 3-year-old female patient with ornithine carbamoyltransferase (OTC) deficiency, via a percutaneous intraportal catheter.…”

Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration

“…Moreover, it has been suggested that FLPs can also transdifferentiate into functional human endothelial cells with no evidence of neoplasia observed within nine months after transplantation. However, the contamination by endothelial cells in the transplanted LFP cell population was not formally excluded [88]. Being less apoptotic and immunogenic than adult hepatocytes, their smaller size allows for an easier intraportal injection and dispersion compared with primary cells [89].…”