A single cell, the pluripotential hematopoietic stem cell (PHSC), is capable of repopulating all of the hematopoietic lineages including those of the immune system. These stem cells are present throughout life and in mice, those isolated from aged individuals appear to have an undiminished capacity to act as progenitors and are therefore, at least, partially exempt from the life-span restrictions imposed on most cells. The object of this proposal is to isolate and characterize these stem cells and to understand the cellular and molecular events which govern their differentiation. An understanding of these cells is crucial to developing new strategies for bone marrow transplantation and gene therapy. The first specific aim of this proposal is to: develop the BU/CY SClD human-mouse chimeric system as an assay for human PHSC and use this assay to identify these cells and characterize those properties which will permit the isolation of a highly enriched population of human stem cells. The second specific aim is to use these enriched populations to examine the events leading to, and the mechanism(s) involved in, the generation of lineage restriction. The investigators will examine the influence of treatment of the chimeric mice in vivo with IL-1, IL-3, IL-4, IL-6 and IL-7 as well as GM-, G- and M-CSF, SC-CF and LIF. These workers will determine if the developmental fate of isolated multipotential hematopoietic cells can be altered by exposure to these growth factors in vivo or in vitro. Dr. Basch and corkers hope to establish the timing of the lineage restrictions imposed on myeloid progenitors as they mature and determine if these are associated with alterations in cytokine responsiveness or receptor expression. The third specific aim is to establish when the separation between the myeloid and lymphoid lineages occurs and to determine if there are separate precursors for the T- and B- lineages. The investigators expect to be able to determine if the CD5+ subset of human B cells can develop from bone marrow PHSC and what conditions are required for its development.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Immunobiology Study Section (IMB)
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New York University
Schools of Medicine
New York
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Zhang, Xin-Min; Chang, Qing; Zeng, Lin et al. (2006) TBLR1 regulates the expression of nuclear hormone receptor co-repressors. BMC Cell Biol 7:31
Dormady, S P; Bashayan, O; Dougherty, R et al. (2001) Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment. J Hematother Stem Cell Res 10:125-40
Zhang, X; Dormady, S P; Basch, R S (2000) Identification of four human cDNAs that are differentially expressed by early hematopoietic progenitors. Exp Hematol 28:1286-96
Dormady, S P; Zhang, X M; Basch, R S (2000) Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6). Proc Natl Acad Sci U S A 97:12260-5
Basch, R S; Zhang, X M; Dolzhanskiy, A et al. (1999) Expression of CD41 and c-mpl does not indicate commitment to the megakaryocyte lineage during haemopoietic development. Br J Haematol 105:1044-54
Dolzhanskiy, A; Hirst, J; Basch, R S et al. (1998) Complementary and antagonistic effects of IL-3 in the early development of human megakaryocytes in culture. Br J Haematol 100:415-26
Dolzhanskiy, A; Basch, R S; Karpatkin, S (1997) The development of human megakaryocytes: III. Development of mature megakaryocytes from highly purified committed progenitors in synthetic culture media and inhibition of thrombopoietin-induced polyploidization by interleukin-3. Blood 89:426-34
Basch, R S; Quito, F L; Beh, J et al. (1997) Growth of human hematopoietic cells in immunodeficient mice conditioned with cyclophosphamide and busulfan. Stem Cells 15:314-23
Basch, R S; Dolzhanskiy, A; Zhang, X M et al. (1996) The development of human megakaryocytes. II. CD4 expression occurs during haemopoietic differentiation and is an early step in megakaryocyte maturation. Br J Haematol 94:433-42
Dolzhanskiy, A; Basch, R S; Karpatkin, S (1996) Development of human megakaryocytes: I. Hematopoietic progenitors (CD34+ bone marrow cells) are enriched with megakaryocytes expressing CD4. Blood 87:1353-60

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