Stem Cell Self-Renewal
The maintenance of many adult tissues depends on the persistence of stem cells throughout life. Stem cells are maintained in adult tissues by self-renewal, the process by which stem cells divide to make more stem cells. By better understanding this process, we gain insights into how tissues develop and regenerate, how reduced self-renewal can lead to degenerative disease and how increased self-renewal can lead to tumorigenesis. We have discovered that networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewal but that these networks do not generically regulate the proliferation of all cells. Restricted progenitor proliferation does not require many of the mechanisms that regulate stem cell self-renewal.
To go beyond traditional studies of individual gene products, we are developing new methods to study aspects of cellular physiology, such as the regulation of proteostasis and metabolism, that have been studied only to a limited extent in somatic stem cells. Studies of these mechanisms in stem cells have the potential to reveal ways in which they are used differently by different kinds of dividing somatic cells and how these differences regulate tissue homeostasis.
We also study the extrinsic mechanisms by which the niche regulates stem cell maintenance. Our studies focus on the hematopoietic system, where we have discovered that quiescent hematopoietic stem cells (HSCs) reside in a perivascular niche in which endothelial cells and leptin receptor-expressing perivascular stromal cells secrete factors that promote HSC maintenance. The discovery and characterization of this niche has allowed us to identify new mechanisms by which HSCs and the niche regulate each other, including the identification of new growth factors and the ways in which the niche changes in response to injury.