Microgravity Impairs DNA Damage Repair in Human Hematopoietic Stem/Progenitor Cells and Inhibits Their Differentiation into Dendritic Cells

Astronauts on missions beyond low-Earth orbit are exposed to a hostile environment in which they are continually bombarded with unique high-energy species of radiation, while in conditions of microgravity (G), which can alter radiation response and immunity. In the present studies, we examined the impact exposing human hematopoietic stem/progenitor cells (HSC) to G had upon their capacity to repair DNA damage and their ability to generate immune cells critical for mounting an effective antitumor response. To this end, we first treated a human HSC-like cell line with an acute dose of the radiomimetic drug bleomycin, cultured them in normal gravity (1G) or simulated G, and quantitated double-strand breaks through -H2AX foci. Calculating the median fluorescence intensity ratio at 1-to-4h post-bleomycin revealed a 26% decrease in 1G, but a 20% increase in G, suggesting that G compromised HSC DNA damage repair and thus has the potential to enhance the genotoxic effects of space radiation. We next examined whether G negatively affected the development of dendritic cells (DC), critical regulators of both the innate and acquired arms of the immune system. Primary human HSC were cytokine induced in 1G or G and analyzed for generation of plasmacytoid (CD123(+)) and myeloid (CD11c(+)) DC. HSC cultured in 1G gave rise to significantly higher numbers of both myeloid and plasmacytoid DC than those cultured in G, suggesting G impairs production of these critical antigen-presenting cells. Our studies thus indicate that conditions of G present during spaceflight perturb multiple pathways that could potentially enhance astronaut risk from exposure to space radiation.