Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock.

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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.

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Journal

Journal ID (iso-abbrev): Cell

Title: Cell

ISSN (Electronic): 1097-4172

ISSN (Print): 0092-8674

Publication date (Electronic): Jun 18 2015

Volume: 161

Issue: 7

Affiliations

[1 ] Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

[2 ] Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, IN 46202, USA.

[3 ] Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

[4 ] 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.

[5 ] Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Soonchunhyang Institute of Medi-bio Science, Chungcheongnam-do 336-745, Korea.

[6 ] Division of Clinical Pharmacology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

[7 ] 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.

[8 ] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.

[9 ] 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.

[10 ] Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Korea.

[11 ] Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: hbroxmey@iupui.edu.

Article

Publisher Item ID: S0092-8674(15)00574-7 Mid ID: NIHMS699297

DOI: 10.1016/j.cell.2015.04.054

PubMed ID: 26073944

SO-VID: 11b1662b-0960-419d-ad63-f7520cb2a372

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