We study the mechanisms that regulate stem cell self-renewal in the hematopoietic and nervous systems and the role these mechanisms play in cancer. Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating stem cells throughout life to regenerate adult tissues. We discovered a series of key regulators of stem cell self-renewal that distinguish it from the proliferation of restricted progenitors in the same tissues. We also identified ways in which self-renewal mechanisms change with age, conferring temporal changes in stem cell properties that match the changing growth and regeneration demands of tissues. Our studies suggest that cancers arise from the inappropriate or ectopic activation of these self-renewal mechanisms, and therefore, that the mechanisms that are competent to cause cancer also change with age. Thus, we study the self-renewal of normal stem cells and the self-replication of developmentally related cancers to understand both the physiological function of self-renewal and the ways in which ectopic activation can promote tumorigenesis.
We have recently extended our studies of self-renewal mechanisms to include the extrinsic mechanisms by which the niche regulates hematopoietic stem cell (HSC) maintenance. We discovered that bone marrow HSCs are maintained in a perivascular niche in which endothelial cells and leptin receptor–expressing stromal cells secrete the factors that promote stem cell maintenance. The identification of cell-intrinsic and cell-extrinsic mechanisms that regulate self-renewal have set the stage for us to characterize novel growth factors that regulate stem cell function in the niche, as well as aspects of cellular physiology that have not previously been studied in stem cells.
Stem Cell Self-Renewal
The maintenance of many adult tissues depends upon 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.
We have historically taken forward and reverse genetic approaches to identify new genes that are required for stem cell self-renewal without being generically required for restricted progenitor proliferation. Each time we identify a self-renewal regulator we learn something new about how self-renewal occurs by examining the downstream mechanisms. For example, we have identified a network of heterochronic gene products that regulates stem cell maintenance throughout life, while also regulating the temporal changes in stem cell properties that are required to match the changing growth and regeneration demands of fetal and adult tissues.
To go beyond traditional studies of individual gene products we are now developing new methods to study aspects of cellular physiology, such as the regulation of proteostasis and metabolism, that have not previously been studied 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 may be necessary for the maintenance of tissue homeostasis. These studies may also provide general insights into the extent to which these mechanisms differ in extensively self-replicating cells as compared to other cells.
We have also expanded the scope of our studies of stem cell self-renewal to include the extrinsic mechanisms by which the niche regulates stem cell maintenance. Our studies of the niche focus on the hematopoietic system, where we have discovered that quiescent hematopoietic stem cells (HSCs) reside in a perisinusoidal niche in which endothelial cells and leptin receptor–expressing perivascular stromal cells secrete the factors that promote HSC maintenance. The discovery and characterization of this niche has allowed us to study novel 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.
Stem Cell Aging
Until recently there has been little insight into why aging tissues exhibit reduced regenerative capacity. Aging is also associated with increased cancer incidence in tissues that contain stem cells. These observations suggest a link between aging and stem cell function because stem cells drive the regeneration of most tissues, and because many cancers either arise from the transformation of stem cells or at least require hyperactivation of stem cell self-renewal mechanisms. Much of age-related morbidity in mammals may be determined by the influence of aging on stem cell function. We have found that stem cells from the hematopoietic and nervous systems undergo strikingly conserved changes in their properties as they age, including declining self-renewal capacity.
We discovered that the networks of heterochronic gene products that regulate temporal changes in stem cell properties between fetal and adult stages (see above) also regulate stem cell aging. For example, Hmga2 expression declines while let-7 expression and Ink4a expression increase with age, reducing stem cell frequency and function in multiple tissues. By deleting Ink4a from mice, we partially rescued the decline in stem cell function with age and enhanced the regenerative capacity of aging tissues. Networks of proto-oncogenes and tumor suppressors thus change throughout life to balance tissue regeneration with tumor suppression: proto-oncogenic signals dominate during fetal development when tissue growth is rapid but cancer risk is low, and tumor-suppressor mechanisms are amplified during aging when there is little tissue growth but cancer risk is high. By developing the ability to study aspects of cellular physiology that have not been studied before in stem cells, we expect to gain insights into the aging of regenerative tissues. For example, do proteostasis mechanisms differ between extensively self-renewing stem cells, versus cells with limited replicative potential and postmitotic cells, and to what extent is tissue regeneration during aging limited by failures of proteostasis in stem cells?
The Self-Replication of Cancer Cells
Cancer cells hijack stem cell self-renewal mechanisms by acquiring mutations that overactivate these pathways. What does this mean for aspects of cellular physiology that differ between stem cells and other cells? Does the extensive replicative capacity of cancer cells depend upon the same differences? Or do the cancer cells acquire independence from some of the constraints on normal stem cells as they mutate tumor-suppressor mechanisms? As we develop tools to study aspects of cellular physiology that have not previously been studied in normal stem cells, we also study how these mechanisms change in cancer cells, particularly in leukemia and melanoma. These studies sometimes reveal new vulnerabilities in cancer cells that could be exploited in anticancer therapies. For example, ion gradients are rarely studied in cancer cells. However, we have discovered that the ability of cancer cells to maintain subcellular ion gradients appears to be persistently stressed and that inhibitors of ion transporters can have synthetic lethal effects when combined with targeted agents that inhibit oncogenic signaling pathways. Our data suggest that a new class of anticancer agents can be developed to disrupt ion gradient homeostasis in cancer cells.
This research has been supported in part by grants from the National Institute on Aging; the National Institute of Neurological Disorders and Stroke; the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; and the Cancer Prevention and Research Institute of Texas.
As of March 17, 2015