Hematopoietic stem cells (HSCs) are a rare population of cells that can self-renew and differentiate into all blood cell types. They form the basis of bone marrow transplantation for treatment of leukemia and other cancers. However, the clinical applications of HSCs are severely hampered by our limited understanding of the extracellular and intracellular signals that govern HSC cell fates and by the difficulty in ex vivo expansion of these cells. Recently I identified day 15 mouse fetal liver CD3+Ter119- cells as a novel cell population that supports HSC expansion. From these cells I identified insulin-like growth factor 2 (IGF-2) and Angiopoietin-like protein 2 (Angptl2) as the factors that stimulate the ex vivo expansion of HSCs. In combination with other growth factors, Angptl2 stimulates a greater than 20-fold expansion of HSCs in 10 days of culture. Angptl2 is largely unstudied and its receptor(s) and signal transduction are unknown. I hypothesize that Angptl2 interacts with a currently unknown receptor on the surface of HSCs, and this results in activation of specific intracellular signaling pathway(s) and induction of transcription of targets gene(s) that are required for self-renewal or survival of HSCs. To this end, will test the hypotheses that Angptl2, IGF-2, and other growth factors stimulate HSC expansion by inducing their self-renewal and/or survival, and dissect the specific intracellular signal transduction pathway(s) and transcriptional activation induced by Angptl2, in both cell lines and in HSCs. Moreover, I will use expression cloning to isolate the Angptl2 cell surface receptor(s). This work will provide new insights into a novel link between Angptl2, its membrane receptor(s), and the regulation of HSC expansion. Through this proposed research, the applicant will receive training in advanced molecular biology, stem cell biology, protein biochemistry, and system biology in order to gain the requisite skills and knowledge to become an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01CA120099-01
Application #
7076781
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2006-07-01
Project End
2006-12-31
Budget Start
2006-07-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$68,581
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Zheng, Junke; Umikawa, Masato; Cui, Changhao et al. (2012) Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485:656-60
Kocabas, Fatih; Zheng, Junke; Thet, Suwannee et al. (2012) Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120:4963-72
Zheng, Junke; Huynh, HoangDinh; Umikawa, Masato et al. (2011) Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood 117:470-9
Zheng, Junke; Umikawa, Masato; Zhang, Shichuan et al. (2011) Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9:119-30
Zhang, Shichuan; Yajima, Hirohiko; Huynh, Hoangdinh et al. (2011) Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J Cell Biol 193:295-305
Huynh, Hoangdinh; Zheng, Junke; Umikawa, Masato et al. (2011) IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood 118:3236-43
Huynh, HoangDinh; Zheng, Junke; Umikawa, Masato et al. (2011) Components of the hematopoietic compartments in tumor stroma and tumor-bearing mice. PLoS One 6:e18054
Zhang, Cheng Cheng; Kaba, Megan; Iizuka, Satoru et al. (2008) Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 111:3415-23
Huynh, Hoangdinh; Iizuka, Satoru; Kaba, Megan et al. (2008) Insulin-like growth factor-binding protein 2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells 26:1628-35
Zhang, Cheng C; Lodish, Harvey F (2008) Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol 15:307-11

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