Jessica Pham, Shuvro P. Nandi, Larisa Balaian, Claire Engstrom, Patrick Chang, Karla Mack, Inge van der Werf, Emma Klacking, Jenna Sneifer, Neha Katragadda, Kendale Wirtjes, Antonio Sánchez‐Ruiz, Daisy Chilin-Fuentes, Elsa Molina, Pinar Mesci, Jana Stoudemire, Sheldon Morris, Thomas Whisenant, Ludmil B. Alexandrov, Catriona Jamieson
Previous reports revealed immune dysfunction, chromosomal abnormalities, cytokine deregulation, and telomere alterations after prolonged spaceflight. However, the stress of space on hematopoietic stem and progenitor cells (HSPCs) and the resilience properties maintaining lifelong hematopoiesis and immunity were not studied. We performed HSPC functionally organized multi-omics aging and resilience (HSPC-FOMA-R) analyses in 9 astronauts before, during, and after three short-duration International Space Station (ISS) missions. Whole-genome sequencing (with telomere length analysis and mitochondrial and clonal mutational profiling), whole-transcriptome sequencing (with RNA editing and retrotransposon analyses), single-cell RNA sequencing, cytokine arrays, and fluorescence-activated cell sorting (FACS) analyses assessed HSPC and immune subpopulation survival dynamics. We show that spaceflight is associated with partially reversible changes in HSPC survival and self-renewal, adenosine deaminase associated with RNA1 (ADAR1), telomere maintenance, mobilization, cell cycle, and "fight or flight" gene expression. Combined with clonal hematopoietic mutations, apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3C) activation, and retrotransposon deregulation, HSPC-FOMA-R analyses are needed before extended missions.