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 h… Show more
“…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].…”
“…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].…”
Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell-based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome-based pathway analysis of in vitro-expanded human bone marrow-derived mesenchymal stem cell (hBM-MSCs), supplemented with cellular assays focusing on DNA double-strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (c-H2AX + 53BP1 foci) and repair (pBRCA1 + c-H2AX foci) of X-ray-induced DNA DSBs in hBM-MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3-to fourfold reduction of their mRNA expression by qRT-PCR. We conclude that the in vitro expansion of hMSCs can lead to aging-related impairment of the recognition and repair of DNA breaks.Mesenchymal stem or mesenchymal stromal cells (MSCs) are adult stem cells that reside in bone marrow stroma and other connective tissues. Their lifelong potential to generate committed precursor cells for various lineages is essential for both the continuous replacement of cellular losses and the recovery of connective tissue damage. In addition to their role as a stem cell pool, MSCs are also a source for immunomodulatory paracrine factors, thereby serving as a regulator of inflammation and immune response
Background
Tissue‐resident mesenchymal stem cells (MSCs) possess the ability to migrate to areas of inflammation and promote the regeneration of damaged tissue. However, it remains unclear how radiation influences this capacity of MSC in the head and neck region.
Methods
Two types of MSCs of the head and neck region (mucosa [mMSC] and parotid gland [pMSC]) were isolated, cultured and exposed to single radiation dosages of 2 Gy/day up to 10 days. Effects on morphology, colony forming ability, apoptosis, chemokine receptor expression, cytokine secretion, and cell migration were analyzed.
Results
Although MSC preserved MSC‐specific regenerative abilities and immunomodulatory properties following irradiation in our in vitro model, we found a deleterious impact on colony forming ability, especially in pMSC.
Conclusions
MSC exhibited robustness and activation upon radiation for the support of tissue regeneration, but lost their potential to replicate, thus possibly leading to depletion of the local MSC‐pool after irradiation
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