The Regulation of Stem Cell Self-Renewal | Stem Cell Aging | Organogenesis from Stem Cells
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 (stem cells dividing to make more stem cells), raising the question of whether this process is regulated by mechanisms that are conserved between tissues.
Dr. Morrison and his colleagues have found that the polycomb family transcriptional repressor Bmi-1 is required for the self-renewal but not for the differentiation of stem cells in the hematopoietic system and peripheral and central nervous systems. In each case, stem cells are formed in normal numbers during fetal development but exhibit impaired self-renewal and become depleted postnatally. Bmi-1 promotes stem cell self-renewal partly by repressing p16 Ink4a , a cyclin-dependent kinase inhibitor, and p19 Arf , a p53 agonist. Both of these checkpoint proteins negatively regulate cell proliferation, and their increased expression has been associated with cellular senescence. This demonstrates that stem cells require mechanisms to prevent premature senescence in order to self-renew throughout adult life. In contrast, restricted neural progenitors from the enteric nervous system and forebrain proliferate normally in the absence of Bmi-1. Thus Bmi-1 dependence is conserved between stem cells and distinguishes the cell cycle regulation of stem cells from the cell cycle regulation of at least some types of restricted progenitors. Using similar approaches, the Morrison lab is studying additional pathways that he hypothesizes will also regulate stem cell self-renewal, and that will contribute to understanding the molecular basis for self-renewal.
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Aging involves a slow deterioration of tissue function, including an elimination of new growth and decreased capacity for repair. Aging is also associated with increased cancer incidence in all 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. Dr. Morrison's lab has found that stem cells from the hematopoietic and nervous systems undergo strikingly conserved changes in their properties as they age. They are testing the hypothesis that there are conserved changes in gene expression within stem cells that regulate these age-related changes in function. Dr. Morrison and his colleagues hypothesize that stem cell aging is influenced by genes that regulate the proliferative activity of stem cells during development, as well as by genes that protect stem cells from the wear and tear of adult life. If we can identify these genes we might better understand the aging process.
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How do a small number of stem cells give rise to a complex three dimensional tissue with different types of mature cells in different locations? This is the most fundamental question in organogenesis. The hematopoietic and nervous systems employ very different strategies for generating diversity from stem cells. The hematopoietic system assiduously avoids regional specialization by stem cells. Hematopoietic stem cells are distributed in different hematopoietic compartments throughout the body during fetal and adult life, and yet these spatially distinct stem cells do not exhibit intrinsic differences in the types of cells they generate. This contrasts with the nervous system, where even small differences in position are associated with the acquisition of different fates by stem cells. While local environmental differences play an important role in this generation of "neural diversity," it has been found that intrinsic differences between stem cells are also critical. Part of the reason why different types of cells are generated in different regions of the nervous system is that intrinsically different types of stem cells are present in different regions of the nervous system. To understand the molecular basis for the regional patterning of neural stem cell function, the Morrison lab is studying how these differences are encoded.
An understanding of the mechanisms that regulate organogenesis from stem cells will make it possible to identify molecular links between stem cell function and disease. The Morrison lab has combined gene expression profiling with reverse genetics and analyses of stem cell function in the hematopoietic and nervous systems to identify mechanisms that regulate organogenesis from stem cells and that lead to congenital disease when defective. Hirschsprung disease is a relatively common birth defect characterized by a failure to form enteric ganglia in the hindgut. We have found that it is caused by mutations in two pathways (the GDNF [glial cell derived neurotrophic factor] and endothelin signaling pathways) that interact to regulate the generation and migration of neural crest stem cells in the gut. Mutations in these pathways lead to a failure to form the nervous system in the hindgut by preventing neural crest stem cells from migrating into the hindgut. These insights raise the possibility of treating this disease with stem cell therapies that would bypass these defects.
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