Our aim is to define developmental pathways that govern the genesis of hematopoietic stem cells (HSC). The main goal of this proposal is to investigate the role of placenta in hematopoietic stem cell development. Our hypothesis is that placenta contributes to the formation, maturation and/or expansion of hematopoietic stem cells during fetal life, and thus may represent an important, previously unrecognized site for HSC development. Our temporal transplantation studies have shown a development of a major HSC niche in placenta during midgestation. 1) We will now define the immunophenotype of HSCs in placenta by transplantation of sorted cell populations from placenta and fetal hematopoietic organs into irradiated adult recipients. 2) Subsequently, we will define the spatial localization of placenta HSCs and their putative precursors in placenta sections by immunohistochemistry and confocal microscopy by using markers that will be defined by transplantation and by analyzing mouse strains where genes for critical hematopoietic transcription factors SCL or runxl/AML1 have been targeted. 3) By establishing placenta explant cultures we will address whether HSCs are generated de novo in placenta or seeded from elsewhere and investigate whether placenta microenvironment can support HSC maturation and expansion. If we can identify precursors for HSCs by functional assessment in explant cultures, we will ultimately compare these developmentally related but functionally distinct hematopoietic cell populations by expression profiling. Our goal is to identify molecular programs that are associated with the ability to reconstitute adult bone marrow and define stemness in the hematopoietic compartment. We believe that our studies will not only clarify the controversy of HSC origin during embryogenesis but also help to identify cell autonomous and microenvironmental factors supporting the genesis, maturation, and expansion of HSCs. If microenvironmental factors promoting """"""""stemness"""""""" of HSCs during embryonic development can be harnessed to induce HSC maturation and expansion in vitro on placenta explant cultures, this culture system might potentially be used to generate or expand human HSCs for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK069659-03
Application #
7026483
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Wright, Daniel G
Project Start
2005-03-15
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$150,869
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Rhodes, Katrin E; Gekas, Christos; Wang, Yanling et al. (2008) The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell 2:252-63
Martinez-Agosto, Julian A; Mikkola, Hanna K A; Hartenstein, Volker et al. (2007) The hematopoietic stem cell and its niche: a comparative view. Genes Dev 21:3044-60
Schenke-Layland, Katja; Angelis, Ekaterini; Rhodes, Katrin E et al. (2007) Collagen IV induces trophoectoderm differentiation of mouse embryonic stem cells. Stem Cells 25:1529-38
Teitell, Michael A; Mikkola, Hanna K A (2006) Transcriptional activators, repressors, and epigenetic modifiers controlling hematopoietic stem cell development. Pediatr Res 59:33R-9R