Stem Cell Self-Renewal
Stem cells are critical for tissue maintenance and replenish themselves through a process known as self-renewal. Understanding the cellular and molecular mechanism of self-renewal would allow for stem cells to be expanded in culture. We found that two key signaling pathways, PI3K/Akt and Wnt/β-catenin, cooperatively stimulate self-renewal by promoting survival and proliferation while preventing differentiation of stem cells. Using pharmacologic agents to stimulate these pathways, we’ve achieved greater than 100-fold expansion of a subpopulation of hematopoietic (blood-forming) stem cells with the greatest functional capacity (Perry et al., Genes & Dev. 2011). Current efforts include the clinical translation of these results.
The Wnt/β-catenin and PTEN/PI3k/Akt pathways interact to drive hematopoietic stem cells (HSC) self-renewal and expansion. Shown here are wild-type, primitive mouse HSCs that have been pharmacologically manipulated in culture to reversibly activate both the Wnt/β-catenin and PI3K/Akt pathways. Cooperative activation of both pathways promotes the in vitro expansion of HSCs (smaller cells), which are growing among other bone marrow cells, including megakaryocytes (larger cells).
Image by John Perry