Hematopoiesis is a finely tuned process involving self-renewal or proliferation/differentiation of hematopoietic stem cells (HSC) to respectively produce more HSC, or hematopoietic progenitor cells (HPC). HSC and HPC functions are controlled by cytokines, chemokines, and interactions with the bone marrow (BM) microenvironment. During the past grant period where we assessed the role of SIRT1, a member of the sirtuin family of deacetylases, on regulation of HSC and HPC we fortuitously came upon a phenomenon that we termed: "extra physiologic oxygen shock/stress (EPHOSS)". It is known that HSC and HPC reside in the BM in a more hypoxic (? 5% oxygen) environment than that of ambient air (~18-20 oxygen;normoxia), yet most investigators still study hematopoiesis and HSC/HPC function under normoxia. However, our work, over the last 28 years, and that of others evaluating effects of lowered oxygen tension on growth of HSC and HPC were based on experiments in which cells removed from mice and man were subjected to normoxia, prior to placing the cells under hypoxia. We reasoned that even a relatively short interval of minutes to hours in normoxia might change the phenotypic characteristics and functional activities of HSC and HPC. We hypothesized that maintaining cells under hypoxic conditions during removal from mice and man, without the cells being subjected to normoxia at all, would greatly enhance numbers of phenotypically-defined HSC collected, and perhaps enhance their functional capabilities. We present preliminary data that suggests this is the case. Our goal is to substantiate and better define the EPHOSS phenomenon, and mechanisms inherent in it. Towards this goal, we propose two specific aims: (1) Evaluate our newly designated phenomenon of EPHOSS at a cell and molecular level for HSC and HPC. Use this information to obtain greater numbers of HSC/HPC with increased functional activity and enhanced engrafting activity and for their increased expansion ex-vivo and in-vivo. (2) Enhance generation capacity of fully vs. partially reprogrammed induced pluripotent stem (iPS) cells and their differentiation towards the hematopoietic lineage, by blocking or counteracting EPHOSS.

Public Health Relevance

Understanding the molecular mechanisms underlying blood cell development, specifically the self-renewal properties and fate decisions of hematopoietic stem cells, is crucial to improving treatment of many non-malignant and malignant disorders, through accelerated recovery from stresses, such as radiation or drugs, and in the context of hematopoietic cell transplantation. Here we propose to study a newly identified phenomenon termed extra physiologic oxygen shock/stress (EPHOSS) that is of importance to a full understanding of blood cell regulation in vivo and how best to isolate and utilize stem/progenitors for clinical applicability.

National Institute of Health (NIH)
Research Project (R01)
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Molecular and Cellular Hematology (MCH)
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Thomas, John
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Broxmeyer, Hal E; Pelus, Louis M (2014) Inhibition of DPP4/CD26 and dmPGE? treatment enhances engraftment of mouse bone marrow hematopoietic stem cells. Blood Cells Mol Dis 53:34-8
Ou, Xuan; Lee, Man Ryul; Huang, Xinxin et al. (2014) SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells 32:1183-94
Prasain, Nutan; Lee, Man Ryul; Vemula, Sasidhar et al. (2014) Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat Biotechnol 32:1151-7
Broxmeyer, Hal E (2014) Inhibiting HDAC for human hematopoietic stem cell expansion. J Clin Invest 124:2365-8
Broxmeyer, Hal E; Etienne-Julan, Maryse; Gotoh, Akihiko et al. (2013) Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function. Stem Cells Dev 22:998-1006
Liu, Ying; Timani, Khalid; Ou, Xuan et al. (2013) C-MYC controlled TIP110 protein expression regulates OCT4 mRNA splicing in human embryonic stem cells. Stem Cells Dev 22:689-94
Lee, Man Ryul; Prasain, Nutan; Chae, Hee-Don et al. (2013) Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem Cells 31:666-81
Broxmeyer, Hal E; Mor-Vaknin, Nirit; Kappes, Ferdinand et al. (2013) Concise review: role of DEK in stem/progenitor cell biology. Stem Cells 31:1447-53
Broxmeyer, Hal E (2013) Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration. J Exp Med 210:205-8
Ou, Xuan; O'Leary, Heather A; Broxmeyer, Hal E (2013) Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood 122:161-9

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