An understanding of the biology of human stem cells is of primary importance in attempting to address diseases of hemopoietic tissues. In order to study the properties, regulation, and differentiation decisions of human stem cells, we propose a multiparameter approach using both in vitro and in vivo models. The first part of the application, (SA#l) is aiming at the characterization of the functional features of integrin expressing subsets of human fetal stem cells that we have recently isolated (including the hierarchical order in the expression of integrins in relation to stem cell CD34 antigen expression, and their cytoadhesive interactions with stromal cells). In the second part of the application (SA#2), we will use a newly developed immunodeficient mouse model (bg/SCID) and several experimental innovations (implantation of human stroma, supply of unique cytokines) for studying the in vivo behavior of human stem cells. Parameters necessary for multilineage reconstitution by donor human cells, their """"""""homing' ability, or the consequences of abrogation of their adhesive properties will be explored. The third and fourth parts of the application (SA#3 and SA#4) concern fundamental questions on the molecular control of early stages of hemopoiesis. Unique cell lines which differentiate in response to physiologic growth factors, as well as isolated populations of normal progenitors, will be employed. We will test whether multipotent single progenitors express a combination of lineage specific RNAs or whether the two daughter cells are phenotypically identical; in regards to erythroid cell differentiation we will examine whether late lineage specific RNA (globin mRNA) is present onprimitive BFUe and, if not, whether erythropoietin, a lineage specific regulator can induce directly the expression of this RNA (globin mRNA) and whether cell division is required for this purpose.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046557-02
Application #
3365703
Study Section
Special Emphasis Panel (SRC (JD))
Project Start
1991-05-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chang, Kai-Hsin; Huang, Andy; Han, Hemei et al. (2013) Transcriptional environment and chromatin architecture interplay dictates globin expression patterns of heterospecific hybrids derived from undifferentiated human embryonic stem cells or from their erythroid progeny. Exp Hematol 41:967-979.e6
Chang, Kai-Hsin; Fang, Xiangdong; Wang, Hao et al. (2013) Epigenetic modifications and chromosome conformations of the beta globin locus throughout development. Stem Cell Rev 9:397-407
Li, Li B; Chang, Kai-Hsin; Wang, Pei-Rong et al. (2012) Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell 11:615-9
Byon, John C H; Papayannopoulou, Thalia (2012) MicroRNAs: Allies or foes in erythropoiesis? J Cell Physiol 227:7-13
Ulyanova, Tatiana; Jiang, Yi; Padilla, Steven et al. (2011) Combinatorial and distinct roles of ?? and ?? integrins in stress erythropoiesis in mice. Blood 117:975-85
Garmy-Susini, Barbara; Avraamides, Christie J; Schmid, Michael C et al. (2010) Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 70:3042-51
Chang, Kai-Hsin; Huang, Andy; Hirata, Roli K et al. (2010) Globin phenotype of erythroid cells derived from human induced pluripotent stem cells. Blood 115:2553-4
Banerjee, Ena Ray; Jiang, Yi; Henderson Jr, William R et al. (2009) Absence of alpha 4 but not beta 2 integrins restrains development of chronic allergic asthma using mouse genetic models. Exp Hematol 37:715-727.e3
Jiang, Yi; Bonig, Halvard; Ulyanova, Tatiana et al. (2009) On the adaptation of endosteal stem cell niche function in response to stress. Blood 114:3773-82
Bonig, Halvard; Chudziak, Doreen; Priestley, Greg et al. (2009) Insights into the biology of mobilized hematopoietic stem/progenitor cells through innovative treatment schedules of the CXCR4 antagonist AMD3100. Exp Hematol 37:402-15.e1

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