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Mechanisms That Regulate Stem Cell Function in Diverse Tissues
Summary: Sean Morrison is investigating the mechanisms that regulate stem cell function in the nervous and hematopoietic systems, particularly the mechanisms that regulate stem cell self-renewal and aging. Parallel studies of these mechanisms in stem cells from two different tissues will reveal the extent to which different types of stem cells employ similar or different mechanisms to regulate these critical functions.
We are investigating the mechanisms that regulate stem cell function in the nervous and hematopoietic systems. Hematopoietic stem cells, which give rise to all blood and immune system cells, and neural stem cells, which give rise to the central and peripheral nervous systems, are among the best-characterized stem cells. Many fundamental questions remain, however, regarding the mechanisms that regulate their functions. Parallel studies of these mechanisms in stem cells from two different tissues will reveal the extent to which different types of stem cells employ similar or different mechanisms to regulate these critical functions. Our goal is to integrate what we know about stem cells in different tissues to understand the extent to which they employ similar or different mechanisms to regulate critical functions. We have focused on the mechanisms that regulate stem cell self-renewal and stem cell aging. Since cancer cells hijack these self-renewal mechanisms, we also evaluate the role that these mechanisms play in cancer.
Stem Cell Self-Renewal
The ability to maintain mammalian tissues throughout adult life depends on the persistence of stem cells. Stem cells are maintained in numerous adult tissues by self-renewal—the process by which stem cells divide to make more stem cells. By better understanding these mechanisms we gain insights into how tissues maintain their regenerative capacity, 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. Proto-oncogenes promote regenerative capacity by promoting stem cell function but must be balanced with tumor-suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerative capacity by promoting cell death or senescence in stem cells, but also protect against cancer. For example, the polycomb family proto-oncogene, Bmi-1, is required for the self-renewal of diverse adult stem cells, as well as for the proliferation of cancer cells in the same tissues. Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressors that are commonly deleted in cancer. Imbalances within these networks of proto-oncogenes and tumor suppressors cause cancer or premature declines in stem cell activity that resemble degenerative disease.
Stem Cell Aging
Aging tissues invariably exhibit reduced regenerative capacity, but until recently there have been few mechanistic insights into why this is. 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 growth and regeneration in most tissues, and because many cancers are thought to arise from the transformation of stem cells. One possibility is that much of age-related morbidity in mammals is 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.
While studying the mechanisms that are responsible for the decline in stem cell function with age, we discovered that the networks of proto-oncogenes and tumor suppressors that regulate stem cell self-renewal and cancer cell proliferation (see above) also regulate stem cell aging. For example, Ink4a expression increases with age, reducing stem cell frequency and function. By deleting Ink4a from mice, we have partially rescued the decline in stem cell function with age and enhanced the regenerative capacity of aging tissues. Increased tumor-suppressor activity during aging therefore partly accounts for declining stem cell function with age. Thus networks of proto-oncogenes and tumor suppressors have evolved to coordinately regulate stem cell function throughout life.
Stem Cell Self-Renewal Versus Cancer Cell Proliferation
Not all cancer cells have the same capacity to proliferate. In a variety of cancers it appears that most cancer cells have a limited ability to proliferate, while in the same tumors, minority populations of "cancer stem cells" retain the capacity to proliferate indefinitely and to form new tumors. These tumorigenic cancer cells are called cancer stem cells because, like normal stem cells, they can self-renew and give rise to phenotypically diverse nontumorigenic progeny. Cancer stem cells are often phenotypically and functionally similar to normal stem cells from the same tissue. Although at least some cancers are hierarchically organized, with tumorigenic cancer stem cells that give rise to phenotypically diverse nontumorigenic progeny, it is likely that not all cancers follow a cancer stem cell model. Most cells may have a similar ability to proliferate in some cancers. Additional work is required to detect tumorigenic human cancer cells, to assess the frequency of such cells, and to better define the cancers that are hierarchically organized. Precise identification of the spectrum of cells capable of driving the growth and progression of human cancers may make it possible to develop more effective new treatments.
The similarities between normal stem cells and cancer stem cells have raised the question of whether it will be possible to develop therapies that eliminate cancer stem cells without eliminating normal stem cells. By understanding the mechanisms that regulate normal stem cell self-renewal, we have discovered that it is possible to identify rare mechanistic differences relative to cancer stem cell proliferation. For example, deletion of the Pten tumor suppressor has different effects on the self-renewal of normal hematopoietic stem cells and the proliferation of leukemic stem cells. Conditional deletion of Pten in adult hematopoietic cells rapidly leads to the development of leukemias, marked by the expansion of leukemic stem cells. In contrast, Pten deletion leads to the depletion of hematopoietic stem cells. These effects of Pten deficiency can be inhibited by the drug rapamycin, which inhibits mTor activation (a kinase that is activated after Pten deletion). Rapamycin treatment of Pten-deficient mice not only depletes leukemic stem cells but also restores normal hematopoietic stem cell function. Mechanistic differences between the maintenance of normal stem cells and cancer stem cells can thus be targeted to eliminate cancer stem cells without damaging normal stem cells. Identification of additional such drugs will reduce the toxicity of chemotherapy and facilitate regeneration of normal tissue after cancer treatment.
Last updated: May 6, 2008
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