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

Abstract

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 (μG), which can alter radiation response and immunity. In the present studies, we examined the impact exposing human hematopoietic stem/progenitor cells (HSC) to μG 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 μG, and quantitated double-strand breaks through γ-H2AX foci. Calculating the median fluorescence intensity ratio at 1-to-4 h post-bleomycin revealed a 26% decrease in 1G, but a 20% increase in μG, suggesting that μG compromised HSC DNA damage repair and thus has the potential to enhance the genotoxic effects of space radiation. We next examined whether μG 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 μG 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 μG, suggesting μG impairs production of these critical antigen-presenting cells. Our studies thus indicate that conditions of μG present during spaceflight perturb multiple pathways that could potentially enhance astronaut risk from exposure to space radiation.