Abstract
Umbilical cord matrix stem cells (UCMSC) have generated great interest in various therapeutic approaches, including liver regeneration. This article aims to analyze the specific characteristics and the potential occurrence of premalignant alterations of UCMSC during long-term expansion, which are important issues for clinical applications. UCMSC were isolated from the umbilical cord of 14 full-term newborns and expanded in vitro until senescence. We examined the long-term growth potential, senescence characteristics, immunophenotype and multilineage differentiation capacity of these cells. In addition, their genetic stability was assessed through karyotyping, telomerase maintenance mechanisms and analysis of expression and functionality of cell cycle regulation genes. The tumorigenic potential was also studied in immunocompromised mice. In vitro, UCMSC reached up to 33.7±2.1 cumulative population doublings before entering replicative senescence. Their immunophenotype and differentiation potential, notably into hepatocyte-like cells, remained stable over time. Cytogenetic analyses did not reveal any chromosomal abnormality and the expression of oncogenes was not induced. Telomere maintenance mechanisms were not activated. Just as UCMSC lacked transformed features in vitro, they could not give rise to tumors in vivo. UCMSC could be expanded in long-term cultures while maintaining stable genetic features and endodermal differentiation potential. UCMSC therefore represent safe candidates for liver regenerative medicine.
Highlights
Stem cell transplantation has recently emerged as a promising alternative approach to orthotopic liver transplantation for the treatment of metabolic liver diseases [1,2]
The cumulative population doubling (CPD) was calculated by adding the Population doubling (PD) obtained at each successive passage
umbilical cord matrix stem cells (UCMSC) growth potential was quite homogeneous between the 14 donors we tested and cells were able to undergo an average of 33.762.1 population doublings before reaching senescence, consistent with previous reports [42,43]
Summary
Stem cell transplantation has recently emerged as a promising alternative approach to orthotopic liver transplantation for the treatment of metabolic liver diseases [1,2]. Umbilical cord matrix stem cells (UCMSC) have received a great deal of interest owing to their multipotency, proliferation potential and low immunologic profile. UCMSC stand as a non-controversial and accessible cell source for clinical-based therapies. The multipotency of UCMSC has been widely demonstrated in vitro and in vivo in animal models. Among others, they have shown the ability to differentiate into osteoblasts [3], adipocytes [4] and even neurons [5]. We have further reported their ability to acquire specific hepatocyte-like functions [6] making them suitable for liver-based cell therapies [7]. UCMSC present interesting tolerogenic properties for allogenic cell transplantation [8]
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