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 crest stem cells, which give rise to the peripheral nervous system, are among the best characterized stem cells.† However, we are just beginning to understand how their functions are regulated. It has long been hypothesized that stem cells from different tissues may be regulated by conserved mechanisms. But testing this requires interdisciplinary approaches. 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, stem cell aging, and the role of stem cells in organogenesis.
The regulation of stem cell self-renewal
The ability to maintain mammalian tissues throughout adult life is dependent 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.† We and our 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, and peripheral and central nervous systems.† In each case, stem cells are formed in normal numbers during fetal development, but exhibit impaired self-renewal potential, and become depleted postnatally.† Bmi-1 promotes stem cell self-renewal partly by repressing p16Ink4a, a cyclin-dependent kinase inhibitor, and p19Arf, 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, we are studying additional pathways that we hypothesize will also regulate stem cell self-renewal, and which together will contribute to understanding the molecular basis for self-renewal.
Stem cell aging
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. We have found that stem cells from the hematopoietic and nervous systems undergo strikingly conserved changes in their properties as they age.† We are currently testing the hypothesis that there are conserved changes in gene expression within stem cells that regulate these age-related changes in function.† We 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.
Organogenesis from stem cells
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 ëneural diversityí, we have 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. We are currently studying how these differences are encoded, so as to understand the molecular basis for the regional patterning of neural stem cell function.
By understanding the mechanisms that regulate organogenesis from stem cells, it is also possible to identify molecular links between stem cell function and disease. We have 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 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 by-pass these defects.
1986-1991 B.Sc. with First Class Honors in Biology and Chemistry, Dalhousie University ( Halifax, Canada)
1991- 1996 Ph.D. in Immunology, Stanford University ( Stanford, CA), Supervisor, Dr. Irving L. Weissman
July 1996 - August 1999: Postdoctoral Scholar in the laboratory of Dr. David J. Anderson, California Institute of Technology ( Pasadena, CA)
Honors and Awards
1986 - Young Canadians Award for Excellence in Science
1986 - Waverly Award, Dalhousie University
1987 - Dalhousie University McKenzie Trust Scholarship
1988 - Dalhousie University Ross S. Smith and Alan Pollok Scholarships
1990 - Dalhousie University Ross S. Smith Scholarship
1991 - Natural Sciences and Engineering Research Council of Canada Research Award
1991 - Dalhousie University Medal in Biology
1991 to 1996 - Howard Huges Medical Institute Predoctoral Fellowship in Biological Sciences
1996 - Guenther Foundation Postdoctoral Fellowship
1996 to 1998 - Natural Sciences and Engineering Research Council Postdoctoral Fellowship
1997 to 1999 - American Cancer Society, California Division Junior Postdoctoral Fellowship
1999 - American Cancer Society, California Division Senior Postdoctoral Fellowship
2000 to 2003 - Searle Scholar
2000 - Mental Illness Research Association Milestone Award
2002 - Named to TR100 list: MIT Technology Review Magazine's list of 100 innovators
2003 - Wired Magazine Rave Award for Science
2003 - Presidential Early Career Award for Scientists and Engineers, White House Office of Science and Technology Policy
2004 - Dean's Award for Basic Science, University of Michigan Medical School
Bixby, S., G.M.. Kruger, J.T. Mosher, N. Joseph, and S.J. Morrison. 2002. Cell-intrinsic differences between neural stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity. Neuron 35:643-656.
Kruger, G.M., J. Mosher, S. Bixby, N. Joseph, T. Iwashita, and S.J. Morrison. 2002. Neural crest stem cells persist in the adult gut but undergo perinatal changes in self-renewal potential, neuronal subtype potential, and responsiveness to lineage determination factors. Neuron 35:657-669.
Kruger, G.M. and S.J. Morrison. 2002 Brain repair by endogenous progenitors. Cell 110:399-402.
Park, I-K, Q. Dalong, M. Kiel, M.W. Becker, M. Pihalja, I.L. Weissman, S.J. Morrison, and M.F. Clarke. 2003. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302-305.
Iwashita, T., G.M. Kruger, R. Pardal, M.J. Kiel, and S.J. Morrison. 2003. Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301:972-976.
Alvarez-Dolado, M., R. Pardal, J.M. Garcia-Verdugo, J.R. Fike, H.O. Lee, K. Pfeffer, C. Lois, S.J. Morrison and A. Alvarez-Buylla. 2003. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968-973.
Molofsky, A.V., R. Pardal, T. Iwashita, I-K. Park, M.F. Clarke, and S.J. Morrison. 2003. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962-967.
Pardal, R., M.F. Clarke, and S. J. Morrison. 2003. Applying the principles of stem cell biology to cancer. Nature Reviews Cancer 3:895-902.
Kruger G.M., Mosher, J.T., Y.H. Tsai, K.J. Yeater, T. Iwashita, C. E. Gariepy and S.J. Morrison. 2003. Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells. Neuron 40:917-929.
Morrison, S.J. and A. Spradling. 2008. Stem Cells and Niches: Mechanisms that promote stem cell maintenance throughout life. Cell 132: 598-611.
Kiel, M.J. and S.J. Morrison. 2008. Uncertainty in the niches that maintain haematopoietic stem cells. Nature Reviews Immunology 8: 290-301.
Kiel MJ, Yilmaz OH, Morrison SJ. CD150?-cells are transiently reconstituting multipotent progenitors with little or no stem cell activity. Blood. 2008 Apr 15;111(8):4413-4.
Please contact Dr. Morrison for information regarding current research projects.
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