Early Passage Mesenchymal Stem Cells Display Decreased Radiosensitivity and Increased DNA Repair Activity

Abstract

Cell therapies using human mesenchymal stem cells (MSCs) have received much attention in the past decade. In pursuit of the therapeutic potential of MSCs, cell expansion is required to generate a great number of cells with desired phenotype and functionality. Long‐term expansion in vitro, however, can lead to altered functions. To explore the changes in DNA damage responses (DDR) in MSCs expanded, DDR pathways following irradiation were characterized in early‐ and late‐passage bone marrow MSCs. Seventy‐two hours after irradiation, the percentage of sub‐G1 cells in early‐passage MSCs did not change significantly. Reduced TUNEL staining was observed in early‐passage MSCs compared to late‐passage MSCs 4 h after irradiation. Comet assay also revealed that early‐passage MSCs were more resistant to irradiation or DNA damages induced by genotoxic agents than late‐passage MSCs. ATM phosphorylation and γ‐H2AX and phospho‐p53 increased in early‐passage MSCs while decreased in late‐passage MSCs. Through inhibition by KU55933, DDR pathway in early‐passage MSCs was shown to be ATM‐dependent. Higher levels of poly (ADP‐ribose) polymerase‐1 (PARP‐1) and PAR synthesis were observed in early‐passage MSCs than in late‐passage MSCs. Knockdown of PARP‐1 in early‐passage MSCs resulted in sensitization to irradiation‐induced apoptosis. Overexpression of PARP‐1 in late passage MSCs could render irradiation resistance. Lower activity of DDR in late‐passage MSCs was associated with rapid proteasomal degradation of PARP‐1. In conclusion, early‐passage MSCs are more irradiation‐resistant and have increased DDR activity involving PARP‐1, ATM and their downstream signals. Stem Cells Translational Medicine 2017;6:1504–1514

Rescuing mesenchymal stem cell regenerative properties on hydrogel substrates post serial expansion

“…Previous studies have shown reduced proliferation, differentiation capacity and the onset of replicative senescence for hMSCs expanded on TCPS . As these cell types are further investigated, their mechanosensing and secretory properties have become of interest for their use in tissue engineering and cellular therapies.…”

“…Previous studies have shown reduced proliferation, differentiation capacity and the onset of replicative senescence for hMSCs expanded on TCPS. [24][25][26][27] As these cell types are further investigated, their mechanosensing and secretory properties have become of interest for their use in tissue engineering and cellular therapies. Loss in mechanosensing with expansion could have widespread implications for the design of biomaterials and scaffolds for hMSC therapeutics.…”

Growth factors profile in conditioned medium human adipose tissue-derived mesenchymal stem cells (CM-hATMSCs)

“…VCAM-1 mediates leukocyteendothelium adhesion, and elevated levels of circulating soluble form has been related to systemic inflammation disease [45]. Older passage of MSCs has lower angiogenesis activity compared to early passage, whereas early-passage of MSCs (P2-3) exhibited a significantly higher DNA damage response (DDR) capacity than late-passage cells [46], the cellular senescence can be regarded as a permanent DNA damage response activation [45]. Shortening telomeres produces a persistent DDR, which activates and sustains the senescence growth arrest [45,47,48], in the early passage, MSCs secreted higher VCAM-1 than late passage.…”

Intrinsically 32P‐Labeled Diamond Nanoparticles for In Vivo Imaging and Quantification of Their Biodistribution in Chicken Embryos

“…This cell type is highly proliferative and bears multipotent differentiation capacities. Additionally, MSCs represent a very suitable model for risk assessment as their response to radiation has been widely studied . Nanodiamond concentrations of 0.02, 0.2, 1, or 2 mg mL −1 were added to proliferating cells and incubated for either 24 or 72 h to assess cell viability (Figure a,b) .…”