Malignant Transformation Potentials of Human Umbilical Cord Mesenchymal Stem Cells Both Spontaneously and via 3-Methycholanthrene Induction

Abstract

Human umbilical cord mesenchymal stem cells (HUMSCs) are highly proliferative and can be induced to differentiate into advanced derivatives of all three germ layers. Thus, HUMSCs are considered to be a promising source for cell-targeted therapies and tissue engineering. However there are reports on spontaneous transformation of mesenchymal stem cells (MSCs) derived from human bone marrows. The capacity for HUMSCs to undergo malignant transform spontaneously or via induction by chemical carcinogens is presently unknown. Therefore, we isolated HUMSCs from 10 donors and assessed their transformation potential either spontaneously or by treating them with 3-methycholanthrene (3-MCA), a DNA-damaging carcinogen. The malignant transformation of HUMSCs in vitro was evaluated by morphological changes, proliferation rates, ability to enter cell senescence, the telomerase activity, chromosomal abnormality, and the ability to form tumors in vivo. Our studies showed that HUMSCs from all 10 donors ultimately entered senescence and did not undergo spontaneous malignant transformation. However, HUMSCs from two of the 10 donors treated with 3-MCA displayed an increased proliferation rate, failed to enter senescence, and exhibited an altered cell morphology. When these cells (tHUMSCs) were injected into immunodeficient mice, they gave rise to sarcoma-like or poorly differentiated tumors. Moreover, in contrast to HUMSCs, tHUMSCs showed a positive expression of human telomerase reverse transcriptase (hTERT) and did not exhibit a shortening of the relative telomere length during the long-term culture in vitro. Our studies demonstrate that HUMSCs are not susceptible to spontaneous malignant transformation. However, the malignant transformation could be induced by chemical carcinogen 3-MCA.

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

“…Therefore, they can be cellular vectors for delivering MMkilling agents. In fact, beyond their intrinsic tumor tropism [57], these cells possess further advantages for cytotherapies such as their virtually unlimited availability, low immunogenicity [58], anti-inflammatory potential [59], absence of spontaneous malignant transformation [60], and suitability to genetic manipulation [61]. However, further studies are needed to optimize their therapeutic use in preclinical models of MM as well as to define their efficacy and safety profiles for future cell-based gene therapies for the clinical setting.…”

The influence of fibroblast growth factor 2 on the senescence of human adipose-derived mesenchymal stem cells during long-term culture

“…Several studies have demonstrated the stability of human ASCs during prolonged cultivation with a low risk of tumorigenicity up to passage 20 . Although rare, spontaneous tumorigenic transformation of MSCs that are expanded in vitro has been reported, particularly when they were treated with certain carcinogens . For example, supplementing FGF2 in the culture medium of human bone marrow‐derived MSCs transfected with TERT (telomerase reverse transcriptase) resulted in an increased potential for neoplastic transformation .…”

“…10,20 Although rare, spontaneous tumorigenic transformation of MSCs that are expanded in vitro has been reported, particularly when they were treated with certain carcinogens. 21,22 For example, supplementing FGF2 in the culture medium of human bone marrow-derived MSCs transfected with TERT (telomerase reverse transcriptase) resulted in an increased potential for neoplastic transformation. 23 Thus, cell therapy with FGF2-treated ASCs may harbor a risk of tumorigenicity, especially after long-term stimulation.…”

Platelet poor plasma gel combined with amnion improves the therapeutic effects of human umbilical cord-derived mesenchymal stem cells on wound healing in rats

“…As HUMSCs are obtained from discarded umbilical cord tissue during caesarean sections, there are fewer ethical issues involved compared with ESCs. Compared with MSCs derived from adipose and bone marrow, HUMSCs represent a source of more primitive stromal cells that do not undergo spontaneous malignant transformation (9). Together with their relative ease of accessibility, cost-effectiveness, and efficacy, it is predicted that HUMSCs will have increasing application in tissue engineering and cellular-based therapies (10).…”