title: In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells.
abstract: Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone. Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Rodman
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Almeida-Porada
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: George
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Moon
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Soker
authors.affiliation: Department of Hematology/Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: T
authors.initials: T
authors.lastname: Pardee
authors.affiliation: Department of Hematology/Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Beaty
authors.affiliation: Biological, Environmental, and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guida
authors.affiliation: Center for Public Health Genomics, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Sajuthi
authors.affiliation: Center for Public Health Genomics, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Walker
authors.affiliation: Biological, Environmental, and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.|Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Wilson
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Porada
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D018480:Astronauts; D001822:Body Burden; D049109:Cell Proliferation; D003359:Cosmic Radiation / Q000009:adverse effects*; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology* / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D014407:Tumor Cells, Cultured