The isolation and characterization of human embryonic stem (ES) cells permits an exciting new approach to reach the goals of regenerative medicine. ES cells can be maintained virtually indefinitely as undifferentiated cells in culture, yet retain the ability to differentiate to form any cell type in the body. Therefore, human ES cells will provide an excellent source of cells to replace damaged or degenerated cells and tissues to treat a host of diseases. In the area of hematology, derivation of hematopoietic stem cells (HSCs) from human ES cells may be used for hematopoietic cell transplantation therapies for patients with hematologic malignancies such as leukemia or myeloma. Production of mature blood cells may provide an unlimited supply of red blood cells, platelets and other blood products from this well-defined source that is free of viral or other contaminants. Already, in vitro studies with human ES cells have produced hematopoietic, neural, cardiomyocyte, and other cell types. Hematopoietic cells of myeloid (white blood cells), erythroid (red blood cells), and megakaryocyte (platelet precursors) lineages can all be produced by co-culture of human ES cells with irradiated bone marrow stromal cells. To reach their full potential, it is crucial to now demonstrate in vivo function of human ES cell-derived cells. This proposal aims to define the in vivo potential of hematopoietic cells derived from human ES cells by transplantation of undifferentiated human ES cells, and human ES cells induced to form hematopoietic precursors in vitro, into immunodeficient (NOD/SCID) mice. Use of this xenotransplant model to demonstrate human SCID-repopulating cells (SRCs) is an effective measure of hematopoietic stem cells with long-term regenerative potential. Genetically modified (GFP-labeled) hematopoietic cells derived from human ES cells will also be used to demonstrate the stability of foreign gene expression, and the potential use of this model as a vector for gene replacement therapies. Serial transplantation experiments into secondary and tertiary hosts will be done to demonstrate the ability of HSCs derived from human ES cells to sustain long-term self-renewal. Since rhesus monkey ES cell are also available, successful completion of the aims of this proposal will lead to a non-human primate model of ES cell-derived hematopoietic cell transplantation. Eventually, clinical trials to define human ES cells as a novel source of cells for hematopoietic cell transplantation therapies will open new avenues to treat hematopoletic malignancies, immunodeficiencies, autoimmunity, and many other diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL072000-03
Application #
6794691
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Thomas, John
Project Start
2002-09-30
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$222,750
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cameron, C M; Harding, Frances; Hu, Wei-Shou et al. (2008) Activation of hypoxic response in human embryonic stem cell-derived embryoid bodies. Exp Biol Med (Maywood) 233:1044-57
Tian, Xinghui; Woll, Petter S; Morris, Julie K et al. (2006) Hematopoietic engraftment of human embryonic stem cell-derived cells is regulated by recipient innate immunity. Stem Cells 24:1370-80
Cameron, C M; Hu, Wei-Shou; Kaufman, Dan S (2006) Improved development of human embryonic stem cell-derived embryoid bodies by stirred vessel cultivation. Biotechnol Bioeng 94:938-48
Anderson, Joseph S; Bandi, Sriram; Kaufman, Dan S et al. (2006) Derivation of normal macrophages from human embryonic stem (hES) cells for applications in HIV gene therapy. Retrovirology 3:24
Schwartz, Robert E; Linehan, Jonathan L; Painschab, Matthew S et al. (2005) Defined conditions for development of functional hepatic cells from human embryonic stem cells. Stem Cells Dev 14:643-55
Woll, Petter S; Martin, Colin H; Miller, Jeffrey S et al. (2005) Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity. J Immunol 175:5095-103
Lakshmipathy, Uma; Pelacho, Beatriz; Sudo, Kazuhiro et al. (2004) Efficient transfection of embryonic and adult stem cells. Stem Cells 22:531-43
Tian, Xinghui; Morris, Julie K; Linehan, Jon L et al. (2004) Cytokine requirements differ for stroma and embryoid body-mediated hematopoiesis from human embryonic stem cells. Exp Hematol 32:1000-9