Abstract
The risk of malignant transformation of ex-vivo expanded human mesenchymal stromal cells (huMSCs) has been debated in the last years; however, the biosafety of these cells after exposure to supramaximal physical and chemical stress has never been systematically investigated.We established an experimental in vitro model to induce supramaximal physical (ionizing radiation, IR) and chemical (starvation) stress on ex-vivo expanded bone marrow (BM)-derived huMSCs and investigated their propensity to undergo malignant transformation. To this aim, we examined MSC morphology, proliferative capacity, immune-phenotype, differentiation potential, immunomodulatory properties and genetic profile before and after stressor exposure. Furthermore, we investigated the cellular mechanisms underlying MSC response to stress. MSCs were isolated from 20 healthy BM donors and expanded in culture medium supplemented with 5% platelet lysate (PL) up to passage 2 (P2). At this stage, MSCs were exposed first to escalating doses of IR (30, 100, 200 Gy) and then to starvation culture conditions (1% PL).With escalating doses of radiation, MSCs lost their typical spindle-shaped morphology, their growth rate markedly decreased and eventually stopped (at P4-P6) by reaching early senescence. Irradiated and starved MSCs maintained their typical immune-phenotype, ability to differentiate into adipocytes/osteoblasts and to inhibit mitogen-induced T-cell proliferation. The study of the genetic profile of irradiated/starved MSCs did not show any alteration. While the induction of supramaximal stress triggered production of ROS and activation of DNA damage response pathway via multiple mechanisms, our data indicate that irradiated/starved MSCs, although presenting altered morphology/growth rate, do not display increased propensity for malignant transformation.
Highlights
Human mesenchymal stromal cells (MSCs) are multipotent cells that can be found in a variety of adult tissues, including bone marrow (BM) and adipose tissue (AT), besides fetal tissues such as fetal lung and blood [1, 2]
MSCs were isolated from 20 healthy BM donors and expanded in culture medium supplemented with 5% platelet lysate (PL) up to passage 2 (P2)
Our results indicate that ex-vivo expanded human mesenchymal stromal cells (huMSCs) are resistant to these stressors and are not prone to undergo neoplastic transformation even after application of supramaximal doses of ionizing radiation (IR) and starvation culture
Summary
Human mesenchymal stromal cells (MSCs) are multipotent cells that can be found in a variety of adult tissues, including bone marrow (BM) and adipose tissue (AT), besides fetal tissues such as fetal lung and blood [1, 2]. MSCs have been shown to possess broad immune-regulatory properties through which they are able to influence both adaptive and innate immune responses [7, 8, 9]. Considering their fundamental role in immune regulation and in balancing tissue homeostasis, MSCs have been administered to patients, within experimental phase I-II clinical studies, with the aim of repairing tissues and blunting immune responses [10, 11, 12]. Based on these initial clinical findings, MSC anti-inflammatory therapy is being considered as a novel and potentially effective therapeutic option in the rapidly evolving field of Regenerative Medicine [13]
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