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

Abstract

Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01-11, EudraCT-No. 2012-002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.

Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

“…When seeded in acellular liver scaffold, HLSC were shown to differentiate into mature functional hepatocytes [ 9 ]. More recently, a phase 1 study demonstrated the safety of HLSC administration in infants with neonatal hyperammonemia [ 10 ]. Growing evidence supports the hypothesis that the biological effects of stem cells on neighboring cells are mediated by paracrine mechanisms related to the release of soluble factors and extracellular vesicles (EV) [ 11 , 12 ].…”

Differentiation of Cells Isolated from Afterbirth Tissues into Hepatocyte-Like Cells and Their Potential Clinical Application in Liver Regeneration

“…It should be noted, that there are discrepancies in the data presented by authors in the literature concerning the pattern of markers expressed by epithelial and mesenchymal afterbirth cells [109,181]. Native human afterbirth cells share some phenotypic features comparable with human hepatic multipotent stem cells (hHpSC) and bipotent hepatoblasts: EpCAM, CK19, CD133 [17,27,35,181], adult multipotent stem cells expressing mesenchymal markers: CD44, CD73, CD90, CD105, CK19, SSEA-4, NANOG, OCT-4 [15,52,66,67,181,[53][54][55][56][57][58][59][60] and adult bipotent hepatic progenitor cells (HPC): DLK-1 [78,184]. EpCAM expression, characteristic of hepatoblasts, but not of mesenchymal liver cells, has been confirmed in afterbirth cells only in few studies [181,[183][184][185].…”

“…In vitro liver mesenchymal stem cells divide intensively reaching the confluence required for passage after about 3-5 days of culture. They are able to differentiate in vitro not only towards the hepatocytic lineage [ 52 , 59 , 60 , 64 , 65 ], but also osteocytic [ 52 , 59 , 65 ], chondrocytic [ 61 ], endothelial [ 52 , 53 ] lineages, and insulin-producing islet cells of the pancreas [ 52 , 56 ], but not to the adipocytic lineage [ 52 , 59 , 61 ]. On the other hand, one study demonstrated that liver mesenchymal stem cells are able the differentiate into adipocyte-like cells [ 65 ].…”

“…The results confirmed the safety of HLSC administration to humans. No significant negative side effects were observed, and no need for immunosuppression was demonstrated [ 59 ]. Several human clinical trials using HLSC are currently ongoing.…”

“…On the other hand, in some studies the cells expressing Dlk-1 and AFP have not been observed in the healthy, uninjured liver, what argues against the relationship between fetal hepatoblast and adult HPC [ 78 ]. Furthermore, HPC differ phenotypically and functionally from human liver multipotent stem cells expressing mesenchymal markers [ 52 , 59 ]. These contradictory findings regarding the origin of HPC may also suggest their multiple maturational stages [ 38 , 78 ].…”