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p53-NF-κB crosstalk in febrile temperature treated human umbilical cord-derived Mesenchymal Stem Cells.
Stem Cells and Development 2018 October 16
Mesenchymal Stem Cells (MSCs) are successful for their therapeutic application in immune and inflammatory contexts due to their anti-inflammatory, trophic and immunomodulatory roles. However, though MSCs have the potential to provide regenerative treatment towards a wide range of devastating diseases, massive cell death of transplanted MSCs remains an obstacle to overcome. The relation between MSCs and inflammation is multifactorial and challenging to comprehend. Fever is a critical component of the inflamed microenvironment. Also, the choice of MSC source could be critical in determining the fate of the transplanted cells under stress. Here we investigated the thermo sensitivity of Wharton's jelly MSCs (WJ-MSCs) from human umbilical cord to elevated temperature in the physiological fever range. We explored the effect of febrile range temperature on morphology, viability, proliferation kinetics and cell cycle status of WJ-MSCs. WJ-MSCs adopted a flattened morphology at 40◦C and our data from proliferation kinetics study, MTT and apoptosis assays showed that WJ-MSCs had reduced proliferation and viability at 40◦C as compared to control cultures. There was also a G0/G1 cell cycle arrest which was further confirmed by mRNA levels of genes specific for different stages of cell cycle. On evaluating p53 status, we observed an increase in p53 protein expression and its nuclear localization in WJ-MSCs exposed to 40˚C. Its' downstream effector gene p21 too was upregulated. Moreover, this temperature-induced p53 induction was inhibited on exposure to 40˚C in the presence of NF-kB pathway inhibitor, PDTC. Febrile temperature exposure did not affect the senescence status of WJ-MSCs. The MSC-specific surface antigen profile at 40˚C was similar to control WJ-MSCs. Our findings suggest that under febrile temperature stress condition, while retaining their basic characteristics, umbilical cord-derived MSCs exhibit G0/G1 cell cycle arrest and reduction in viable cell count with an underlying interplay of p53 and NF-kB pathway.
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