The continuous and life-long production of all mature blood cells in the circulation and hematopoietic tissues is contingent upon hematopoietic stem cells (HSCs). These rare cells, at the base of the hematopoietic differentiation hierarchy, reside in the bone marrow of adult mammals. In human medicine, HSCs are clinically important cells in transplantation therapies for blood-related diseases and leukemias. The ability to manipulate adult HSCs, particularly to expand the limiting numbers of these cells in vitro, has been difficult. Despite the isolation and characterization of many hematopoietic growth factors, HSC numbers can only (at best) be maintained in culture. Taking a developmental approach, we have been investigating the origins and growth of HSCs in the mouse embryo. We conjectured that at some early stage the embryo must induce the production of HSCs, generate a supportive microenvironment, and expand HSC numbers. With insight into these processes, novel factors to promote HSC induction/expansion may be discovered. We have shown that the aorta-gonads-mesonephros (AGM) region autonomously generates the first fully potent adult HSCs and that HSC activity is localized to the major vascular regions of the embryo body; the dorsal aorta, vitelline and umbilical arteries. Presently, the direct precursor cells to HSCs are unknown but are speculated to be hemangioblasts, hemogenic endothelial cells or mesenchymal cells in these vascular regions. Additionally, the lineage relationships of the first intraembryonic HSCs to those in the adult have not yet been established. Thus, we propose to examine cellular source of HSCs in the mouse embryo and to follow the migration of HSCs and the colonization of fetal and adult hematopoietic tissues by HSCs. Cultured whole mouse embryos will be injected with dye to fate map putative HSC precursors. Also, sorted putative HSC precursors will be injected into cultured whole mouse embryos to follow their migration and functional potential. Finally, cre-lox recombination will be used to specifically mark putative pre-HSCs so as to follow their functional potential and fate in fetal and adult hematopoietic tissues. These results should give insight into the source and complexity of adult HSC production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054077-08
Application #
6851703
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Bishop, Terry Rogers
Project Start
1998-06-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
8
Fiscal Year
2005
Total Cost
$148,729
Indirect Cost
Name
Erasmus University of Rotterdam
Department
Type
DUNS #
410450258
City
Rotterdam
State
Country
Netherlands
Zip Code
Kaimakis, Polynikis; de Pater, Emma; Eich, Christina et al. (2016) Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors. Blood 127:1426-37
Crisan, Mihaela; Solaimani Kartalaei, Parham; Neagu, Alex et al. (2016) BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo. Stem Cell Reports 6:383-95
Crisan, Mihaela; Kartalaei, Parham Solaimani; Vink, Chris S et al. (2015) BMP signalling differentially regulates distinct haematopoietic stem cell types. Nat Commun 6:8040
Imanirad, Parisa; Solaimani Kartalaei, Parham; Crisan, Mihaela et al. (2014) HIF1? is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo. Stem Cell Res 12:24-35
Imanirad, Parisa; Dzierzak, Elaine (2013) Hypoxia and HIFs in regulating the development of the hematopoietic system. Blood Cells Mol Dis 51:256-63
Buckley, Shannon M; Ulloa-Montoya, Fernando; Abts, David et al. (2011) Maintenance of HSC by Wnt5a secreting AGM-derived stromal cell line. Exp Hematol 39:114-123.e1-5
Chen, Michael J; Yokomizo, Tomomasa; Zeigler, Brandon M et al. (2009) Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457:887-91
Dzierzak, Elaine; Medvinsky, Alexander (2008) The discovery of a source of adult hematopoietic cells in the embryo. Development 135:2343-6
Dzierzak, Elaine; Speck, Nancy A (2008) Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9:129-36
Yokomizo, Tomomasa; Dzierzak, Elaine (2008) Fine-tuning of hematopoietic stem cell homeostasis: novel role for ubiquitin ligase. Genes Dev 22:960-3

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