- Molecular regulation of human hematopoietic stem cells
M.M.S. van Lohuizen
- Award date
- 20 March 2014
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Peter van Galen focuses on understanding the determinants that maintain the stem cell state. Using human hematopoietic stem cells (HSCs) as a model, processes that govern self-renewal and tissue regeneration were investigated. Specifically, a role for microRNAs in balancing the human HSC quiescence/proliferation equilibrium was uncovered. By attenuating PI3K/AKT signaling, miR-126 restrains HSC proliferation. Second, it was shown that ID proteins restrain expression of differentiation-associated genes in HSCs (lineage priming), thereby enhancing self-renewal of HSCs. Exploiting the link between lineage priming and the stem cell state can be used to successfully expand human HSCs in vivo. As well, a new role for stress signaling in the maintenance of HSC pool integrity was uncovered. Through differential activation of the Unfolded Protein Response pathway in HSCs compared to progenitors, damaged HSCs are purged from the blood system. This process is thought to limit damage accumulation in the stem cell pool and enable tissue regeneration throughout life. Overall, mechanisms are uncovered that balance human HSC quiescence/proliferation, self-renewal/differentiation and apoptosis/survival.
- Research conducted at: Ontario Cancer Institute, Toronto, Canada
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