Abstract

The overall objective of the proposed study is to delineate the parameters that permit the long-term engraftment and expression of fetal and adult hematopoietic stem cells (HSC) transplanted in utero without cytoablation and without graft-vs-host disease (GVHD). Specifically, we will the sheep as the large animal experimental model to achieve more efficient HSC engraftment by a) determining the optimal concentrations of fetal and adult sheep cells that will result in the most efficient HSC engraftment, b) the effect of upmodulation of HSC homing receptor activity on donor cell engraftment, and c) the role of donor T cell subsets in grafting efficiency and GVHD. Modulation of homing receptor activity and in vitro transduction of autologous HSC will be used to study a) the mechanism(s) underlying the naturally occurring switches in primary sites of hematopoiesis from yolk sac to liver and bone marrow during ontogeny, and b) the role of bone marrow (and liver) in blood cell production during the early prenatal periods. It is hoped that the in utero HSc transplantation procedures developed here will permit the treatment of some lymphohematopoietic disorders in utero before the disease has had a chance to clinically compromise the patient.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049042-02
Application #
3368155
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1992-09-01
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Sierra Biomedical Research Corporation
Department
Type
DUNS #
783285752
City
Reno
State
NV
Country
United States
Zip Code
89502

  Publications

Goodrich, A Daisy; Ersek, Adel; Varain, Nicole M et al. (2010) In vivo generation of beta-cell-like cells from CD34(+) cells differentiated from human embryonic stem cells. Exp Hematol 38:516-525.e4
Ersek, Adel; Pixley, John S; Goodrich, A Daisy et al. (2010) Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells. Exp Hematol 38:311-20
Skopal-Chase, Jessica L; Pixley, John S; Torabi, Alireza et al. (2009) Immune ontogeny and engraftment receptivity in the sheep fetus. Fetal Diagn Ther 25:102-10
Porada, Christopher D; Zanjani, Esmail D; Almeida-Porad, Graca (2006) Adult mesenchymal stem cells: a pluripotent population with multiple applications. Curr Stem Cell Res Ther 1:365-9
Narayan, A Daisy; Chase, Jessica L; Lewis, Rachel L et al. (2006) Human embryonic stem cell-derived hematopoietic cells are capable of engrafting primary as well as secondary fetal sheep recipients. Blood 107:2180-3
Porada, Christopher D; Park, Paul J; Tellez, Joe et al. (2005) Male germ-line cells are at risk following direct-injection retroviral-mediated gene transfer in utero. Mol Ther 12:754-62
Porada, Christopher D; Park, Paul J; Almeida-Porada, Graca et al. (2005) Gestational age of recipient determines pattern and level of transgene expression following in utero retroviral gene transfer. Mol Ther 11:284-93
Lucas, M Lee; Seidel, Nancy E; Porada, Christopher D et al. (2005) Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes. Blood 106:51-8
Airey, Judith A; Almeida-Porada, Graca; Colletti, Evan J et al. (2004) Human mesenchymal stem cells form Purkinje fibers in fetal sheep heart. Circulation 109:1401-7
Almeida-Porada, Graca; Porada, Christopher; Zanjani, Esmail D (2004) Plasticity of human stem cells in the fetal sheep model of human stem cell transplantation. Int J Hematol 79:1-6

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