title: Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock.
abstract: Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Charlie R
authors.initials: CR
authors.lastname: Mantel
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Leary
authors.affiliation: Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: XinXin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Giao
authors.initials: G
authors.lastname: Hangoc
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Soonchunhyang Institute of Medi-bio Science, Chungcheongnam-do 336-745, Korea.
authors.forename: Man Ryul
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Messina-Graham
authors.affiliation: Division of Clinical Pharmacology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Haas
authors.affiliation: Division of Clinical Pharmacology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Falah
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Pelus
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea.
authors.forename: Kye-Seong
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: hbroxmey@iupui.edu.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001853:Bone Marrow; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D018380:Hematopoietic Stem Cell Transplantation / Q000295:instrumentation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D016159:Tumor Suppressor Protein p53; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D021983:Cyclophilins; D010100:Oxygen