Characterization of human derived liver progenitor cells and mesenchymal stem cells for their risk of malignant transformation

The last decade, stem cell therapy has raised much hope to treat patients presenting a variety of end-stage diseases. These promising results are sustained by the physiologic role of stem cells in tissue development and repair. Despite the enthusiasm, essential stability questions may not be overlooked and need to be assessed on the route to clinic. In the present study, we analyzed, both in vitro and in vivo, the phenotype and genotype stability of stem/progenitor cells issued from human bone marrow, Wharton jelly and liver during long-term culture. We observed that the proliferation potential of stem/progenitor cells was variable between donors; and decreased with time in culture. Cells progressively displayed senescent features, which were however acquired earlier in progenitor cells compared to bone marrow and umbilical cord derived mesenchymal stem cells. Differential sensitivity to oxidative stress, related to hyperoxic culture conditions and overexposure to mitogens, may explain these differences. The phenotype characteristics of stem cells remained stable over time. UCMSC, BMMSC and ADHLPC were able to differentiate in hepatocyte-like cells; which was demonstrated by enhanced mature hepatic functionality features. Nevertheless, the hepatocyte-like differentiation potential was incomplete for all cell types as their phenotype remains chimerical for mesenchymal and hepatic epithelial markers. Furthermore, the ability to differentiate into multilineage seems to decrease with time. Umbilical cord and bone marrow derived mesenchymal stem cells had normal karyotypes and cell cycle regulation genes were appropriately upregulated according to senescence. Some ADHLPC cultures displayed random cytogenetic instability at later passages. Aneuploidy was most likely driven by culture stress. These findings were correlated to an early decrease in growth potential, upregulation of cell cycle regulation genes and premature senescence. Moreover, karyotypic changes do not confer selective growth advantage in vitro to cells that carry them. Instead, cells seem to undergo apoptosis. All these characteristics suggest that ADHLPC carrying cytogenetic instability demonstrate the capacity to regulate their cell cycle and induce premature senescence as a potent mechanism against transformation.(MED 3) -- UCL, 201