Analyses to clarify rich fractions in hepatic progenitor cells from human umbilical cord blood and cell fusion

Abstract

Umbilical cord blood (UCB) is a source of hematopoietic stem cells and other stem cells, and human UCB cells have been reported to contain transplantable hepatic progenitor cells. However, the fractions of UCB cells in which hepatic progenitor cells are rich remain to be clarified. In the present study, first, the fractionated cells by CD34, CD38, and c-kit were transplanted via portal vein of NOD/SCID mice, and albumin mRNA expression was examined in livers at 1 and 3 months posttransplantation. At 1 and 3 months, albumin mRNA expression in CD34+UCB cells-transplanted livers was higher than that in CD34- cells-transplanted livers. Albumin mRNA expression in CD34+CD38+ cells-transplanted livers was higher than that in CD34+CD38- cells-transplanted [corrected] liver at 1 month. However, it was much higher [corrected] in CD34+CD38- cell-transplanted livers at 3 months. Similar expression of albumin mRNA was obtained between CD34+CD38+c-kit+ cells- and CD34+CD38-c-kit- cells-transplanted livers, and between CD34+CD38-c-kit+ cells- and CD34+CD38-c-kit- cells-transplanted livers, respectively. Second, fluorescence in situ hybridization and immunohistochemistry were performed to examine whether UCB cells really transdifferentiated into hepatocytes or they only fused with mouse hepatocytes. In mouse liver sections, of 1.2% cells which had human chromosomes, 0.9% cells were due to cell fusion, whereas 0.3% cells were transdifferentiated into human hepatocytes. These results suggest that CD34+UCB cells are rich fractions in hepatic progenitor cells, and that transdifferentiation from UCB cells into hepatocytes as well as cell fusion simultaneously occur in this situation.

Comparison of hepatic properties and transplantation of Thy-1+and Thy-1−cells isolated from embryonic day 14 rat fetal liver

“…48 Various studies have reported fusion of BM stem cells to hepatocytes in liver repopulation models in which there is extensive liver injury and strong selection for survival of transplanted cells, 49,50 including a study in a mouse retrorsine model in which both fusion and nonfusion events were reported. 51 Fusion appears to be a specific property of myeloid cells and myeloid progenitor cells 52,53 but has not been reported with fetal liver progenitor cells or adult hepatocytes. In other studies with BMderived hematopoietic stem cells or mesenchymal stem cells, generally low levels of plasticity or transdifferentiation into an hepatocytic phenotype have been reported.…”

Dimethylnitrosamine-Induced Liver Fibrosis and Recovery in NOD/SCID Mice

“…Iron deposition is an important pathological change in chronic liver diseases like viral hepatitis B [5] and C [16], and alcoholic and nonalcoholic hepatitis [17]. This pathological change has been demonstrated to occur in CCl 4 -induced liver damage or fibrosis [8].…”

“…Additionally much research has been performed about extracellular matrix (ECM) synthesis by hepatic stellate cells (HSCs) [7,10]. Recently, large numbers of research groups have studied the efficacy of human stem cells on liver diseases [2,17]. To evaluate the efficacy and safety of cell therapies in preclinical studies, adequate animal models for human diseases are absolutely necessary for research [12].…”

“…NOD/SCID mice are defective in innate and adaptive immunity and lack B and T lymphocytes and complements [6]. In the case of NOD/SCID mice, liver fibrosis models have been induced by allyl alcohol [4], retrorsine with CCl 4 [17] or hepatectomy [1]. However, there is no report concerning a DMN-induced fibrosis model from intoxication to recovery in NOD/SCID mice.…”

Advances in cell lineage reprogramming

“…It has been established that myelomonocytic cells are the major source of hepatocyte fusion partners. However, Tanabe et al [33] detected hepatocyte-like cells with mouse and human chromosomes, and cells with only human chromosomes in receipt mice transplanted with human cord blood cells. These studies demonstrate that both cell fusion and transdetermination may be the mechanisms for human cord blood cell-derived hepatocyte-like cells in transplanted mouse models.…”