Open Access Adult-Derived Human Liver Progenitor Cells in Long-Term Culture Maintain Appropriate Gatekeeper Mechanisms Against Transformation

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Abstract:

The use of human liver progenitor cells in the development of clinical cell therapy depends on their constant availability and unaltered properties during culture. The present study investigates the effects of long-term in vitro culture on the specific characteristics of these cells and on their genetic stability. Adult-derived human liver progenitor cells (ADHLPCs) were isolated from 12 donors and cultured until senescence and cell death. Cells were analyzed at different time points for their phenotype stability and differentiation potential. In addition, growth characteristics, chromosomal karyotype, telomere maintenance mechanisms, and activity of cell cycle-related genes were studied. Finally, their in vivo tumorigenicity was investigated in a xenograft assay. The long-term culture of ADHLPCs revealed a variable proliferation capacity. Cells maintained their original phenotype and acquired hepatocyte-like metabolic functions after differentiation. Eight of the 12 cell populations grew fast (doubling time of 6.3 days) during a limited time period (mean, 116.2 days), and mainly presented normal cytogenetic features. The four other cell cultures presented an early decline in growth potential (doubling time of 28.6 days) and premature senescence. Chromosomal alterations were detected in three of four cultures at passage 6. Cytogenetic anomalies were not correlated with tumorigenic potential in vitro or in vivo, and expression of cell cycle-related genes was appropriately upregulated, inducing senescence. Although chromosomal anomalies may occur in long-term cell cultures, neither transformation nor alteration of their characteristics was noted during in vitro expansion. All ADHLPCs reached senescence and growth arrest. Presenescent ADHLPCs might therefore be considered as a suitable source for liver-based cell therapy.

Keywords: Cell senescence; Cytogenetic instability; Liver cell therapy; Progenitor cells

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368912X639026

Affiliations: Université Catholique de Louvain, Institut de Recherche Clinique et Expérimentale (IREC), Laboratory of Pediatric Hepatology and Cell Therapy, Brussels, Belgium

Publication date: October 1, 2012

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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