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    By Alpha|By Interest|Emeritus


Sean Morrison, PhD.
Research Professor, MBNI
Professor, Dept. of Internal Medicine
Professor, Department of Cell and Developmental Biology
Research Professor, Life Sciences Institute
Director, Center for Stem Cell Biology
Henry Sewall Professor in Medicine • Investigator, HHMI

5435 LSI, 210 Washtenaw Ave.
Ann Arbor, MI 48109-2216

 

seanjm@umich.edu

(734) 647-6261

 

 

Current Research Interests:

Mechanisms that regulate stem cell function

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.

The Regulation of 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, and the high mobility group transcription factor, Hmga2, promote the self-renewal of diverse adult stem cells, as well as the proliferation of cancer cells in the same tissues. Bmi-1 and Hmga2 promote stem cell self-renewal partly by repressing the expression of p16Ink4a and p19Arf, 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 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, Hmga2 expression decreases with age, increasing Ink4a expression, and 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

The similarities between normal stem cells and cancer cells have raised the question of whether it will be possible to develop therapies that eliminate cancer 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 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 leukemia initiating cells. Conditional deletion of Pten in adult hematopoietic cells rapidly leads to the development of leukemias, marked by the expansion of leukemia-initiating 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 leukemia-initiating cells but also restores normal hematopoietic stem cell function. Mechanistic differences between the maintenance of normal stem cells and cancer cells can thus be targeted to eliminate cancer 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.


Image 1: Wild-type neural crest stem cells engraft and form neurons
as efficiently in the aganglionic region of endothelin receptor B (Ednrb) deficient gut
as in wild-type gut
.



Image 2: Bmi1-deficient neural stem cells exhibit a reduced rate of proliferation.



Image 3: The identification of neural crest stem cells in the adult gut
(enteric nervous system).


Selected Publications:

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.

Kiel, M.J., O.H. Yilmaz, T. Iwashita, O.H. Yilmaz, C. Terhorst, and S.J. Morrison. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109-1121.

Yilmaz, O.H., R. Valdez, B. Theisen, W. Guo, D. Ferguson, H. Wu, S.J. Morrison. 2006. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initating cells. Nature 441:475-482.

Morrison, S. J., J. Kimble. 2006. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441:1068-1074.

Molofsky, A.V., S.G. Slutsky, N.M. Joseph, S. He, R. Pardal, J. Krishnamurthy, N. Sharpless and S.J. Morrison. 2006. Increasing Ink4a expression decreases forebrain progenitor function and neurogenesis during ageing. Nature 443:448-452.

Kim, I., T.L. Saunders, and S.J. Morrison. 2007. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130:470-483.

Kiel, M., S. He, R. Ashkenazi, S.N. Gentry, M. Teta, J.A. Kushner, T.L. Jackson and S. J. Morrison. 2007. Hematopoietic stem cells do not asymmetrically segregate chromosomes or retain bromodeoxyuridine. Nature 449:238-242.

Joseph, N.M., J.T. Mosher, J. Buchstaller, P. Snider, P.E. McKeever, M. Lim, S. J. Conway, L.F. Parada, Y. Zhu, and S. J. Morrison. 2008. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13: 129-140.

Morrison, S.J. and A. Spradling. 2008. Stem Cells and Niches: Mechanisms that promote stem cell maintenance throughout life. Cell 132: 598-611.

Nishino, J., I. Kim, K. Chada, and S.J. Morrison. 2008. Hmga2 promotes neural stem cell self-renewal in young, but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135:227-239

 

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