Cryopreserved cGMP-compliant human pluripotent stem cell-derived hepatic progenitors rescue mice from acute liver failure through rapid paracrine effects on liver cells

• Published in: Current stem cell research and therapy 2024-03, Vol.15 (1), p.71-71, Article 71
• Main Authors: Gantier, Malika, Rispal, Raphaël, Fourrier, Angélique, Ménoret, Séverine, Delbos, Frédéric, Anegon, Ignacio, Nguyen, Tuan Huy
• Format: Article
• Language: English
• Subjects: Acetaminophen; Acute liver failure; Albumin; Analysis; Animals; Blood coagulation factors; Cell Differentiation; Cell fate; Cell therapy; Cryopreservation; Ethylenediaminetetraacetic acid; Fibroblasts; Glycoproteins; Good Manufacturing Practice; Growth factors; Health aspects; Hepatic progenitor cells; Hepatocyte growth factor; Hepatocytes; Hepatocytes - metabolism; Humans; Immunodeficiency; Immunosuppression; Immunotherapy; Inflammation; Inflammation - metabolism; Life Sciences; Liver - metabolism; Liver diseases; Liver failure; Liver Failure, Acute - therapy; Liver transplantation; Liver transplants; Major histocompatibility complex; Manufacturers; Metabolism; Mice; Mortality; Organ donors; Paracrine signalling; Phenotypes; Pluripotency; Pluripotent Stem Cells; Progenitor cells; Proteomes; Proteomics; Recovery of function; Regenerative medicine; Stem cells; Surgery; Thioacetamide; Transplantation; α-Fetoprotein
• ISSN: 1757-6512; 1757-6512; 1574-888X
• DOI: 10.1186/s13287-024-03673-9

Liver transplantation remains the only curative treatment for end-stage liver diseases. Unfortunately, there is a drastic organ donor shortage. Hepatocyte transplantation emerged as a viable alternative to liver transplantation. Considering their unique expansion capabilities and their potency to be driven toward a chosen cell fate, pluripotent stem cells are extensively studied as an unlimited cell source of hepatocytes for cell therapy. It has been previously shown that freshly prepared hepatocyte-like cells can cure mice from acute and chronic liver failure and restore liver function. Human PSC-derived immature hepatic progenitors (GStemHep) were generated using a new protocol with current good manufacturing practice compliant conditions from PSC amplification and hepatic differentiation to cell cryopreservation. The therapeutic potential of these cryopreserved cells was assessed in two clinically relevant models of acute liver failure, and the mode of action was studied by several analytical methods, including unbiased proteomic analyses. GStemHep cells present an immature hepatic phenotype (alpha-fetoprotein positive, albumin negative), secrete hepatocyte growth factor and do not express major histocompatibility complex. A single dose of thawed GStemHep rescue mice from sudden death caused by acetaminophen and thioacetamide-induced acute liver failure, both in immunodeficient and immunocompetent animals in the absence of immunosuppression. Therapeutic biological effects were observed as soon as 3 h post-cell transplantation with a reduction in serum transaminases and in liver necrosis. The swiftness of the therapeutic effect suggests a paracrine mechanism of action of GStemHep leading to a rapid reduction of inflammation as well as a rapid cytoprotective effect with as a result a proteome reprograming of the host hepatocytes. The mode of action of GStemHep relie on the alleviation of inhibitory factors of liver regeneration, an increase in proliferation-promoting factors and a decrease in liver inflammation. We generated cryopreserved and current good manufacturing practice-compliant human pluripotent stem cell-derived immature hepatic progenitors that were highly effective in treating acute liver failure through rapid paracrine effects reprogramming endogenous hepatocytes. This is also the first report highlighting that human allogeneic cells could be used as cryopreserved cells and in the absence of immunosuppression for human PSC-based regenerative