Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

Charlie R. Mantel, Heather A. O'Leary, Brahmananda R. Chitteti, Xinxin Huang, Scott Cooper, Giao Hangoc, Nickolay Brustovetsky, Edward F. Srour, Man Ryul Lee, Steven Messina-Graham, David M. Haas, Nadia Falah, Reuben Kapur, Louis M. Pelus, Nabeel Bardeesy, Julien Fitamant, Mircea Ivan, Kye Seong Kim, Hal E. Broxmeyer

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117 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1553-1565
Number of pages13
JournalCell
Volume161
Issue number7
DOIs
StatePublished - Jun 18 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mantel, C. R., O'Leary, H. A., Chitteti, B. R., Huang, X., Cooper, S., Hangoc, G., Brustovetsky, N., Srour, E. F., Lee, M. R., Messina-Graham, S., Haas, D. M., Falah, N., Kapur, R., Pelus, L. M., Bardeesy, N., Fitamant, J., Ivan, M., Kim, K. S., & Broxmeyer, H. E. (2015). Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell, 161(7), 1553-1565. https://doi.org/10.1016/j.cell.2015.04.054