Spaceflight/microgravity Inhibits the Proliferation of Hematopoietic Stem Cells by Decreasing Kit-Ras/cAMP-CREB Pathway Networks As Evidenced by RNA-Seq Assays

Exposure to spaceflight and microgravity causes physiologic and psychologic changes including bone loss, cardiovascular dysfunction, and immune dysfunction. Anemia and hematopoietic disorders are observed in astronauts after spaceflight. Hematopoietic stem and progenitor cells (HSPCs), which can self-renew and give rise to all blood cells, play vital roles in hematopoiesis and homeostasis; however, the molecular mechanisms responsible for the impacts of microgravity on the proliferation of HSPCs remain unclear. We maintained mouse bone marrow HSPCs in the presence of stem cell factor for 12 d under spaceflight and simulated microgravity conditions, respectively, and analyzed cell proliferation and gene expression. Both spaceflight and simulated microgravity significantly decreased the number of HSPCs, mainly by blocking cell cycle at G/S transition, but did not affect their differentiation abilities. RNA-sequencing data indicated that genes related to cell proliferation were down-regulated, whereas the genes related to cell death were up-regulated under microgravity. Among the gene signatures, we identified that the Kit-Ras/cAMP-cAMP response element-binding protein pathway might be one of the major microgravity-regulated pathways during HSPC proliferation. Furthermore, the quantification of notable genes was validated at the mRNA levels under simulated microgravity condition. Overall, these results would help us to understand the intracellular molecular mechanisms regulating microgravity-inhibited proliferation of HSPCs.-Wang, P., Tian, H., Zhang, J., Qian, J., Li, L., Shi, L., Zhao, Y. Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit-Ras/cAMP-CREB pathway networks as evidenced by RNA-Seq assays.