Inside CRI Newsletter
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Stem cells persist throughout life in our tissues by undergoing self-renewing divisions in which stem cells divide to form more stem cells. Research from our laboratory and others suggests that many cancers arise from the inappropriate activation of these self-renewal mechanisms, causing cells to proliferate out of control.
Our goal is to better understand the mechanisms that maintain adult tissues and how cancer cells hijack these mechanisms to enable the formation of tumors. To do this, we compare the processes by which stem cells and cancer cells replicate themselves. A better understanding of these mechanisms offers the potential for new regenerative medicine and cancer therapies. By promoting these mechanisms in the context of tissue injury, we can stimulate regeneration. By inhibiting these mechanisms in the context of cancer, we hope to develop anticancer therapies.
We study the cell-intrinsic and cell-extrinsic mechanisms that regulate stem cell self-renewal and the roles these mechanisms play in tissue homeostasis and cancer. The maintenance of many adult tissues depends on 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 identified a series of mechanisms that distinguish stem cell self-renewal from restricted progenitor proliferation as well as self-renewal mechanisms that are conserved among stem cells in different tissues. We are currently focused on areas of cellular physiology that are understudied in stem cells, including metabolism and proteostasis.
We focus on hematopoietic stem cells (HSCs) and the specialized microenvironments, or niches, in which they reside. We identified the location and cellular composition of the HSC niche in bone marrow, including the Leptin Receptor-expressing (LepR+) stromal cells that are the major source of factors for HSC maintenance. These LepR+ cells also include the skeletal stem cells that are the main source of new osteoblasts and adipocytes in adult bone marrow. We discovered a new bone-forming growth factor, Osteolecin, that is produced by the LepR+ cells and that promotes the maintenance and repair of the adult skeleton. LepR+ cells also give rise to osteogenic and adipogenic progenitors that create niches for hematopoietic stem and progenitor cells. We also identified the HSC niche for extramedullary hematopoiesis in the spleen that is activated when the bone marrow is damaged by chemotherapy, radiation, or cancer. This is an exciting time in niche biology as we now have the possibility of going beyond growth factors to ask what other mechanisms niches use to regulate stem and progenitor cell function. Recent studies from our lab have identified metabolic and mechanical regulation.
Kara, N., Xue, Y., Zhao, Z., Murphy, M.M., Comazzetto, S., Lesser, A., Du, L., and S.J. Morrison. (2023). Endothelial and Leptin Receptor+ cells promote the maintenance of stem cells and hematopoiesis in early postnatal murine bone marrow. Developmental Cell 58, 348-360. (PubMed)
Jeffery, E.C., Mann, T.L.A, Pool, J.A,. Zhao, Z., and S.J. Morrison. (2022). Bone marrow and periosteal skeletal stem/progenitor cells make distinct contributions to bone maintenance and repair. Cell Stem Cell 29, 1547-1561. (PubMed)
Shen, B., Tasdogan, A., Ubellacker, J.M., Zhang, J., Nosyreva, E.D., Du, L., Murphy, M.M., Hu, S., Yi, Y., Kara, N., Liu, X., Guela, S., Jia, Y., Ramesh, V., Embree, C., Mitchell, E.C., Zhao, Y.C., Ju, L.A., Zhao, H., Crane, G.M., Zhao, Z., Syeda, R., and S.J. Morrison. (2021). A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438-444. (PubMed)
Ubellacker, J.M., Tasdogan, A., Ramesh, V., Shen, B., Mitchell, E.C., Martin, M.S., McCormick, M.L., Durham, A.B., Spitz, D.R., Zhao, Z., Mathews, T.P., and S.J. Morrison. (2020). Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113-118. (PubMed)
Tasdogan, A., Faubert, B., Ramesh, V., Ubellacker, J.M., Shen, B., Solmonson, A., Murphy, M.M., Gu, Z., Gu, W., Martin, M., Kasitinon, S.Y., Vandergriff, T., Mathews, T.P., Zhao, Z., Schadendorf, D., DeBerardinis, R.J., and S.J. Morrison. (2020). Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115-120. (PubMed)
Shen, B., Vardy, K., Hughes, P., Tasdogan, A., Zhao, Z., Yue, R., Crane, G.M., and S.J. Morrison. (2019). Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass. eLife pii: e42274. (PubMed)
Comazzetto, S., Murphy, M.M., Berto, S., Jeffery, E., Zhao, Z., and S.J. Morrison. (2018). Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow. Cell Stem Cell 24, 477-486. (PubMed)
Agathocleous, M., Meecham, C.E., Burgess, R.J., Piskounova, E., Zhao, Z., Crane, G.M., Cowin, B.L., Bruner, E., Murphy, M.M., Chen, W., Spangrude, G.J., Hu, Z., DeBerardinis, R.J., and S.J. Morrison. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476-481. (PubMed)
Yue, R., Zhou, B.O., and S.J. Morrison. (2016). Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. eLife pii:e18782. (PubMed)
Acar, M., Kocherlakota, K.S., Murphy, M.M., Peyer, J.G., Oguro, H., Inra, C.N., Jaiyeola, C.J., Zhao, Z., Luby-Phelps, K., and S.J. Morrison. (2015). Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126-130. (PubMed)
Piskounova, E., Agathocleous, M., Murphy, M.M., Hu, Z., Mann, S., Zhao, Z., Leitch, A.M., Johnson, T.M., DeBerardinis, R.J., and S.J. Morrison.(2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191. (PubMed)
Inra, C., Zhou, B.O., Acar, M., Murphy, M.M., Zhao, Z., and S.J. Morrison. (2015). A perisinusoidal niche for extramedullary hematopoiesis in the spleen. Nature 527, 466-471. (PubMed)
Zhou, B.O., Yue, R., Murphy, M.M., Peyer, J.G., and S.J. Morrison. (2014). Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154-168. (PubMed)
Signer, R.A.J., Magee, J.A., Salic, A., and S.J. Morrison. (2014). Haematopoietic stem cells require a highly regulate protein synthesis rate. Nature 509, 49-54. (PubMed)
Nakada, D., Oguro, H., Levi, B., Ryan, N., Kitano, A., Saitoh, Y., Takeichi, M., Wendt, G., and S.J. Morrison. (2014). Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505, 555-558. (PubMed)
Morrison, S.J., and D.T. Scadden. (2014). The bone marrow niche for haematopoietic stem cells. Nature 505, 327-334. (PubMed)
Li, Q., Bohin, N., Wen, T., Ng, V., Magee, J., Chen, S.C., Shannon, K., and S.J. Morrison. (2013). Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143-147. (PubMed)
Meacham, C.E., and S.J. Morrison. (2013). Tumor heterogeneity and cancer cell plasticity. Nature 501, 328-337. (PubMed)
Ding, L., and S.J. Morrison. (2013). Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231-235. (PubMed)
Ding, L., Saunders, T.L., Enikolopov, G., and S.J. Morrison. (2012). Endothelial and perivascular cells maintain hematopoietic stem cells. Nature 481, 457-462. (PubMed)
Nakada, D., Saunders, T.L., and S.J. Morrison. (2010). Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653-658. (PubMed)
Chuikov, S., Levi, B.P., Smith, M.L., and S.J. Morrison. (2010). Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nature Cell Biology 12, 999-1006. (PubMed)
Shackleton, M., Quintana, E., Fearon, E., and S.J. Morrison. (2009). Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822-829. (PubMed)
Quintana, E., Shackleton, M., Sabel, M., Fullen, D., Johnson, T.M., and S.J. Morrison. (2008). Efficient tumor formation by single human melanoma cells. Nature 456, 593-598. (PubMed)
Nishino, J., Kim, I., Chada, K., and S.J. Morrison. (2008). Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16 Ink4a and p19Arf expression. Cell 135, 227-239. (PubMed)
Morrison, S.J., and A. Spradling. (2008). Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598-611. (PubMed)
Kiel, M.J., He, S., Ashkenazi, R., Gentry, S.N., Teta, M., Kushner, J.A., Jackson, T.L., and S.J. Morrison. (2007). Hematopoietic stem cells do not asymmetrically segregate chromosomes or retain bromodeoxyuridine. Nature 449, 238-242. (PubMed)
Kim, I., Saunders, T.L., and S.J. Morrison. (2007). Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470-483. (PubMed)
Molofsky, A.V., Slutsky, S.G., Joseph, N.M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N., and S.J. Morrison. (2006). Increasing p16 Ink4a expression decreases forebrain progenitor function and neurogenesis during ageing. Nature 443, 448-452. (PubMed)
Morrison, S.J., and J. Kimble. (2006). Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068-1074. (PubMed)
Yilmaz, O.H., Valdez, R., Theisen, B., Guo, W., Ferguson, D., Wu, H., and S.J. Morrison. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475-482. (PubMed)
Kiel, M.J., Yilmaz, O.H., Iwashita, T., Terhorst, C., 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. (PubMed)
Molofsky, A.V., Pardal, R., Iwashita, T., Park, I.K., Clarke, M.F., and S.J. Morrison. (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967. (PubMed)
Michalis Agathocleous, Ph.D.
Kati Ahlqvist, Ph.D.
Arin Aurora, Ph.D.
Johanna Buchstaller, Ph.D.
Rebecca Burgess, Ph.D.
Genevieve Crane, M.D., Ph.D.
Lei Ding, Ph.D.
Ugur Eskiocak, Ph.D.
Shay Geula, Ph.D.
Jennifer Gill, M.D., Ph.D.
Shenghui He, Ph.D.
Christopher Inra, M.D., Ph.D.
Toshihide Iwashita, Ph.D.
Nancy Joseph, M.D., Ph.D.
Nergis Kara-Takar, Ph.D.
Mark Kiel, M.D., Ph.D.
Injune Kim, Ph.D.
Jae Lee, M.D., Ph.D.
Boaz Levi, Ph.D.
Qing Li, M.D., Ph.D.
Jeffrey Magee, M.D., Ph.D.
Corbin Meacham, Ph.D.
John Mich, Ph.D.
Anna Molofsky, M.D., Ph.D.
Jack Mosher, Ph.D.
Malea Murphy, Ph.D.
Daisuke Nakada, M.D., Ph.D.
Hideyuki Oguro, Ph.D.
Ricardo Pardal, Ph.D.
Michel Perron, Ph.D.
James Peyer, Ph.D.
Elena Piskounova, Ph.D
Le Qi , Ph.D.
Elsa Quintana, Ph.D.
Mick Savona, Ph.D.
Mark Shackleton, Ph.D.
Issei Shimada, Ph.D.
Robert Signer, Ph.D.
Bo Shen, Ph.D.
Shalom Guy Slutsky, Ph.D.
Alpaslan Tasdogan, M.D., Ph.D.
Merritt Taylor, Ph.D.
Jessalyn Ubellacker, Ph.D.
Omer Yilmaz, M.D., Ph.D.
Stacy Yuan, M.D., Ph.D.
Rui Yue, Ph.D.
Bo Zhou, Ph.D.
Stay up-to-date with our latest discoveries and news by subscribing to our quarterly email newsletter.