Oncotarget

Research Papers:

Resistance to neoplastic transformation of ex-vivo expanded human mesenchymal stromal cells after exposure to supramaximal physical and chemical stress

Antonella Conforti, Nadia Starc, Simone Biagini, Luigi Tomao, Angela Pitisci, Mattia Algeri, Pietro Sirleto, Antonio Novelli, Giulia Grisendi, Olivia Candini, Cintia Carella, Massimo Dominici, Franco Locatelli _ and Maria Ester Bernardo

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Oncotarget. 2016; 7:77416-77429. https://doi.org/10.18632/oncotarget.12678

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Abstract

Antonella Conforti1, Nadia Starc1,2, Simone Biagini1, Luigi Tomao1, Angela Pitisci1, Mattia Algeri1, Pietro Sirleto3, Antonio Novelli3, Giulia Grisendi4, Olivia Candini4, Cintia Carella5, Massimo Dominici4, Franco Locatelli1,6, Maria Ester Bernardo1,7

1Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

2Department of System Medicine, University of Rome “Tor Vergata”, Rome, Italy

3Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

4Department of Medical and Surgical Sciences for Children & Adults, Division of Oncology, University-Hospital of Modena and Reggio Emilia, Modena, Italy

5Istituto Superiore di Sanità, Rome, Italy

6Department of Pediatrics, University of Pavia, Pavia, Italy

7Current address: San Raffaele-Telethon Institute for Gene Therapy, SR-TIGET, Pediatric Immunohematology, San Raffaele Scientific Institute, Milan, Italy

Correspondence to:

Franco Locatelli, email: [email protected]

Keywords: mesenchymal stromal cells, ionizing radiation, starvation, malignant transformation, biosafety

Received: May 17, 2016    Accepted: September 24, 2016    Published: October 15, 2016

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.


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