Abstract
Mesenchymal stem cells (MSCs) are regarded as unique cells which play an imperative role in the field of regenerative medicine. They are characterized by the self-renewal capacity, multi-lineage differentiation abilities and immunomodulation properties which render them perfectly ideal cell type for treating a wide range of chronic diseases. Despite these enchanted features, there are many hurdles that need to be circumvented to ensure their long-term survival and viability after transplantation. Recently, hypoxia has been indicated as one of the most baffling stress conditions that can affect the survival rate of MSCs either positively or negatively depending on the level of hypoxia. MSCs can survive well under moderate hypoxia, but die shortly if they were exposed to severe hypoxia without clearly convincing explanation for this enigma. The current study reveals a novel mechanism of 26S proteasome in controlling the ability of BM-MSCs to withstand hypoxic stress by maintaining proper mitochondrial function. The results indicated that 26S proteasome remains functioning once BM- MSCs are exposed to moderate hypoxia (2.5%O2) and preserves their survival and proliferation mediated by intact mitochondrial performance, whereas 26S proteasome becomes inactive when BM-MSCs faces severe hypoxia that lead to poor mitochondrial function and less chance to survive longer. The outcomes of this study demonstrated the importance of 26S proteasome machinery in enhancing the resistance of BM-MSCs to hypoxic stress condition which may help in better planning future studies that target this system. Schematic representation summarizing the findings of the current study. 26S proteasome function preservation in normoxia and moderate hypoxia leads to maintain appropriate proliferation and mitochondrial activity in human BM-MSCs and promote their survival. On the opposite side, severe hypoxia disrupts the 26S proteasome function leading to significant reduction in the proliferation, survival and mitochondrial dynamics in human BM-MSCs causing their death.