Principal Investigator Harvey Lodish
Hematopoietic stem cell environments or niches are very important in determination of HSC self-renewal and differentiation. Fibroblasts, endothelial cells, and osteoblasts have been postulated as important constituents and regulators of HSC niches in the bone marrow. We are interested in characterizing additional cell types that contribute to regulation of HSC microenvironments and as noted we uncovered one such population from fetal liver. Megan Kaba and Alec Babic are studying different subpopulations of fetal liver immature T lymphocytes and their potential to interact with and regulate stem cell self renewal and expansion during fetal and adult hematopoiesis. Specifically, Megan and Alec are performing coculture experiments to further characterize which populations of fetal liver cells are able to enhance the ex vivo expansion of long-term repopulating adult bone marrow HSCs. Of interest are the embryonic day 15 fetal liver CD3+ Ter119- cells that express the T cell b or gd receptors. Characterization of a specific type of supportive cell will aid in the identification of yet other new growth factors that stimulate HSC expansion.
Song Chou, together with Yachao Liu, are also trying to identify the stromal cells that support HSC expansion in fetal liver. By using real-time PCR, Song discovered that fetal liver CD3+ cells not only are highly enriched for Angptl3 and IGF2 mRNAs, but also for stem cell factor (SCF), The membrane- anchored ligand for the c-kit tyrosine kinase receptor, and TPO mRNAs. Song also sorted E15.5 fetal liver cells according to surface expression of SCF and found SCF+ cells are enriched for the mRNAs encoding Angptl3, TPO and IGF2, in comparison to SCF- cells. Since these four hormones form a complete set of growth factors that are able to significantly expand HSCs ex vivo, it is likely that subpopulation(s) of fetal liver CD3+ cells are able to secrete all four crucial growth factors and are able to support HSC expansion in fetal liver in the absence of other added cytokines. Plasma membrane SCF binds to its receptor, c-Kit, in adjacent cells. Since all HSCs in fetal liver express c-Kit, these stromal cells may be located in close proximity to HSCs and interact with HSCs through SCF. Song and Yachao are developing methods to further purify these potential HSCs stromal cells and to identify additional signal molecules emanating from these cells for HSC expansion.