Mechanisms of Synergistic Regulation of Stem/Progenitors

$384,150R01FY2015HLNIH

Indiana University Indianapolis, Indianapolis IN

Investigators

Linked publications & trials

Paper 32127640 Paper 31350528 Paper 31275803 Paper 31107242 Paper 31089283 Paper 31045644 Paper 30843664 Paper 30343551 Paper 30042096 Paper 30013077 Paper 29939159 Paper 29608487 Paper 29422232 Paper 29377004 Paper 28344320 Paper 28306668 Paper 28263313 Paper 27783593 Paper 27760758 Paper 27346679 Paper 27211041 Paper 27067482 Paper 26943017 Paper 26799652 Paper 26375488 Paper 26202933 Paper 26073944 Paper 26049746 Paper 25976461 Paper 25928721 Paper 25753525 Paper 25586960 Paper 25329668 Paper 25306246 Paper 25155719 Paper 24914588 Paper 24892711 Paper 24740813 Paper 24723677 Paper 24602918 Paper 24449278 Paper 24307836 Paper 24304086 Paper 23953010 Paper 23733396 Paper 23637126 Paper 23594692 Paper 23401569 Paper 23255147 Paper 23160239 Paper 23088399 Paper 23082805 Paper 22901266 Paper 22665934 Paper 22132941 Paper 22076938 Paper 21983347 Paper 21943234 Paper 21936707 Paper 21795591 Paper 21628410 Paper 21537169 Paper 21505191 Paper 21447833 Paper 21411351 Paper 21393480 Paper 21216274 Paper 21083429 Paper 20966168 Paper 20727784 Paper 20516368 Paper 20495374 Paper 20132051 Paper 20109617 Paper 19917679 Paper 19690340 Paper 19633199 Paper 18953349 Paper 18788999 Paper 18640494 Paper 18536570 Paper 18371449 Paper 18235235 Paper 18024793 Paper 17932422 Paper 17784832 Paper 17709522 Paper 17610364 Paper 17585053 Paper 17526724 Paper 17507482 Paper 17379092 Paper 17379091 Paper 17360804 Paper 17289813 Paper 17179222 Paper 17138958 Paper 17038523 Paper 16863914 Paper 16863913

Abstract

DESCRIPTION (provided by applicant): 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.

View original record on NIH RePORTER →