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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL056416-17
Application #
8694868
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Thomas, John
Project Start
1996-04-01
Project End
2018-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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O'Leary, H A; Capitano, M; Cooper, S et al. (2017) DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. Leukemia 31:2468-2478
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Lee, Man Ryul; Mantel, Charlie; Lee, Sang A et al. (2016) MiR-31/SDHA Axis Regulates Reprogramming Efficiency through Mitochondrial Metabolism. Stem Cell Reports 7:1-10
Broxmeyer, Hal E (2016) Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation. Transfus Apher Sci 54:364-72
Huang, X; Lee, M-R; Cooper, S et al. (2016) Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression. Leukemia 30:144-53
Broxmeyer, Hal E; Capitano, Maegan; Campbell, Timothy B et al. (2016) Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26. Stem Cells Dev 25:575-85
Dong, Lei; Yu, Wen-Mei; Zheng, Hong et al. (2016) Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539:304-308
Messina-Graham, Steven; Broxmeyer, Hal (2016) SDF-1/CXCL12 modulates mitochondrial respiration of immature blood cells in a bi-phasic manner. Blood Cells Mol Dis 58:13-8

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