Radio-resistant mesenchymal stem cells: mechanisms of resistance and potential implications for the clinic

Abstract

Mesenchymal stem cells (MSCs) comprise a heterogeneous population of multipotent stromal cells and can be isolated from various tissues and organs. Due to their regenerative potential, they have been subject to intense research efforts, and they may provide an efficient means for treating radiation-induced tissue damage. MSCs are relatively resistant to ionizing radiation and retain their stem cell characteristics even after high radiation doses. The underlying mechanisms for the observed MSC radioresistance have been extensively studied and may involve efficient DNA damage recognition, double strand break repair and evasion of apoptosis. Here, we present a concise review of the published scientific data on the radiobiological features of MSCs. The involvement of different DNA damage recognition and repair pathways in the creation of a radioresistant MSC phenotype is outlined, and the roles of apoptosis, senescence and autophagy regarding the reported radioresistance are summarized. Finally, potential influences of the radioresistant MSCs for the clinic are discussed with respect to the repair and radioprotection of irradiated tissues.

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…Chk1 and Chk2 are main inhibitors of Cdc25A and Cdc25C resulting in Cdk/cyclin-mediated cell cycle arrest [71]. It has been suggested that DSB in MSCs are repaired by activation of both the homologous recombination (HR, during S and G2 phases) and the non-homologous end-joining (NHEJ, during all cell cycle phases) DNA repair pathways [95,104,106]. Our recent study showed the activation of HR and NHEJ repair pathways in irradiated aMSCs [159].…”

“…These mechanisms were also shown to be responsible for the IR resistance of cancer stem cells (CSC), also known as cancer initiating cells, which have been linked to cancer disease recurrence and aggression [100][101][102][103]. These mechanisms were tested in bmMSCs in earlier studies showing that these bmMSCs are relatively radio-resistant [95,96,[104][105][106]. Do MSCs from different tissue origins behave similarly?…”

“…The exposure of MSCs to ionizing radiation (IR) induces direct and indirect double stranded DNA breaks (DSB) which are detected by Poly (ADP-ribose) polymerase (PARP) and heterodimeric Ku protein complex (Ku70/80) sensor proteins [104,106].…”

“…P-ATM enhances the phosphorylation of histone H2X (to γ-H2AX) and DNA-PK (to p-DNA-PK), phosphorylates P53 (a tumor suppressor regulatory protein), activate the cell cycle checkpoint effector protein kinases (Chk-1 and Chk-2), and prepares for cell cycle arrest (G2/M). In addition to that, the Chk1 activation is augmented by the replication stress-mediated ATR pathway (through replication protein A, RPA), while the Chk2 activation is enhanced directly through Ku70/80-mediated p-DNA-PK signaling [104,106]. Cell division cycle phosphatase (Cdc25) is crucial for removing the inhibitory phosphorylation on specific residues on the cyclin-dependent kinase (Cdk).…”

“…Also, MSCs have some agiogenic properties evident by increased secretion of (platelets derived growth factor) PDGF, VEGF and TGF-β at the tumor perivascular area and parenchyma in low dose irradiated mice owing to MSCs infiltration at the tumor site [53]. MSCs angiogenic properties might counteract the anti-angiogenic cancer therapies, a question that needs to be answered with solid in-vitro and in-vivo studies [71,104].…”