Our long term research goals are to understand the mechanisms controlling cellular proliferation and differentiation in embryonic blood forming vessels. During embryogenesis, hematopoietic and endothelial cells require common growth factors for formation and may share a common precursor, the hemangioblast. Murine blood cells reportedly arise directly from yolk sac endothelial cells in vitro, however, no in vivo tests of blood cell derivation from endothelium have been performed. We have identified a visceral yolk sac cell population that possesses HSC activity upon transplantation into conditioned newborn mice and we have determined in preliminary studies that this population is comprised of both hematopoietic and endothelial cells. We will use our unique newborn mouse transplantation model to test the hypothesis that endothelial cells formed within the embryonic yolk sac give rise to HSC in vivo, facilitate HSC engraftment upon transplantation into hematologically compromised hosts, and augment HSC expansion ex vivo.
Our specific aims are: 1. To determine the potential of endothelial cells to give rise to HSC in vivo. We will use a retroviral marking strategy and reagents that provide isolation of a homogenous population of endothelial cells to determine the clonal relationship of endothelium and blood cells. 2. To determine the capacity of yolk sac endothelial cells to facilitate HSC engraftment upon transplantation into myeloablated hosts. Donor endothelial cells from hematopoietic deficient mice will be injected in varying concentrations with the HSC and repopulating activity measured. 3. To determine if endothelial cells and/or endothelial mitogens alone or in combination with selected hematopoietic growth factors stimulate visceral yolk sac-derived HSC expansion ex vivo. The results of these experiments will provide novel insight into hematopoietic and endothelial cell development during embryogenesis, clarify the role of endothelial-HSC interactions during HSC transplantation, and provide new approaches to modulate HSC proliferative behavior.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063169-03
Application #
6390451
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Thomas, John
Project Start
1999-07-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$318,504
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Zou, Gang-Ming; Chan, Rebecca J; Shelley, W Christopher et al. (2006) Reduction of Shp-2 expression by small interfering RNA reduces murine embryonic stem cell-derived in vitro hematopoietic differentiation. Stem Cells 24:587-94

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