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
Capitano, Maegan; Zhao, Liang; Cooper, Scott et al. (2018) Phosphatidylinositol transfer proteins regulate megakaryocyte TGF-?1 secretion and hematopoiesis in mice. Blood 132:1027-1038
Huang, Xinxin; Guo, Bin; Liu, Sheng et al. (2018) Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment. Nat Commun 9:2741
Cai, Qingchun; Capitano, Maegan; Huang, Xinxin et al. (2018) Combinations of antioxidants and/or of epigenetic enzyme inhibitors allow for enhanced collection of mouse bone marrow hematopoietic stem cells in ambient air. Blood Cells Mol Dis 71:23-28
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Ha, Tae Won; Kang, Hyun Soo; Kim, Tae-Hee et al. (2018) MiR-9 Controls Chemotactic Activity of Cord Blood CD34? Cells by Repressing CXCR4 Expression. Int J Stem Cells 11:187-195
Broxmeyer, Hal E (2018) Enhancement of stem cell engraftment on a WHIM. J Clin Invest 128:3240-3242
Guo, Bin; Huang, Xinxin; Lee, Man Ryul et al. (2018) Antagonism of PPAR-? signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med 24:360-367
Capitano, Maegan L; Broxmeyer, Hal E (2017) A role for intracellular and extracellular DEK in regulating hematopoiesis. Curr Opin Hematol 24:300-306
Guo, Bin; Huang, Xinxin; Cooper, Scott et al. (2017) Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment. Nat Med 23:424-428
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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