Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit‐Ras/cAMP‐CREB pathway networks as evidenced by RNA‐Seq assays

Abstract

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 G1/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. FASEB J. 33, 5903–5913 (2019). http://www.fasebj.org

Expression Profile of Cell Cycle-Related Genes in Human Fibroblasts Exposed Simultaneously to Radiation and Simulated Microgravity

“…The results revealed the distinct expression patterns of genes related to cell cycle regulation, DNA damage response, and other stress-responding mechanisms that were specific to the radiation quality [64]. In space experiments involving simultaneous exposure to space radiation and μ G , several different sets of results have been reported, with suppression of the cell cycle through activated p21 [65] and cell proliferation [66], but also no change in the amount of p21 protein [67,68]. The reason for this difference may be the short stay in space and the lack of a sufficient dose to induce radiation effects.…”

Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways

“…Flight information: programs and spaceflight This study was conducted during two flight programs, the Tianzhou-1 cargo ship program 57 and the SJ-10 space program of microgravity research. [57][58][59][60][61] All spaceflights took place in circular orbit at an altitude of~252 km and a flight path angle of 43 degrees. The daily average dose of radiation did not exceed 1 × 10 −2 Gy (100 mrad).…”

“…For simulated microgravity experiments, the sorted mouse HPCs were cultured as previously described. 21,61 Specifically, the HPCs were inoculated into 10 ml culture vessels in RCCS and cultured for 12 days in a humidified 37°C incubator with 5% CO 2 . The HPCs were also cultured in 6-well culture plates for 12 days in a humidified 37°C incubator with 5% CO 2 for the normal gravity condition (control group, 0 rpm).…”

“…All cell culture devices for spaceflight were designed and prepared by Shanghai Institute of Technical Physics, Chinese Academy of Sciences as reported previously. 60,61,63 The details are as follows. The device contained four parts: cell culture units, liquid storage units, an automatic liquid change system, and an electronic control system.…”

A Protective Strategy to Counteract the Oxidative Stress Induced by Simulated Microgravity on H9C2 Cardiomyocytes

“…The microgravity-induced decrease in cell proliferation was also seen in other cell phenotypes [22,32,48,49]. However, there are controversial evidences about the effects of microgravity on cell growth in stem cells and cardiomyocytes differentiating from pluripotent stem cells [50][51][52][53][54]. These introduce the hypothesis that the effects induced by microgravity are not only phenotype-dependent but also dependent on the functional and metabolic status of the cells tested.…”