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Human embryonic stem cells exhibit altruistic behavior in the microenvironment of oxidative stress

      Altruism is a cytoprotective mechanism having deep evolutionary root. It implies a defense mechanism of cytoprotection, where a few cells sacrifice their own fitness to increase the fitness of the population. We considered the potential altruistic behavior of stem cells when exposed to extreme microenvironment prevalent in the area of injury/inflammation. We considered this possibility based on several clinical reports that although stem cells including human embryonic stem cells (hESCs) exert cytoprotective activity in the area of tissue injury, the engrafting of viable donor stem cells at the site of injury is very minimal. This is expected, because, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of donor stem cells. Therefore, stem cells might have evolved cytoprotective mechanism without engrafting. Using the hESCs as a model, we indeed discovered an altruistic mechanism that allow a small subset of hESCs to protect the rest of the population from DNA-damage, differentiation and death in the microenvironment of oxidative stress. We found that within the hESCs, the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high HIF-2α state of transcriptional activity in the microenvironment of extreme hypoxia (<0.01% Oxygen)/re-oxygenation. This state can be sustained for a period of two-weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, and high secretion of glutathione. Conditioned medium (CM) obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection of SSEA3+/ABCG2- cells from oxidative-stress-induced p53 activation. siRNA inhibition of ABCG2 reduced glutathione in the CM, and also diminished the cytoprotective activity. We then demonstrated that the underlying molecular mechanism of this transient phenotype of “enhanced stemness” involved an altered state of the p53/MDM2 oscillation system. Our study indicates the potential presence of an altruistic mechanism of stem cell cytoprotection.
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