Stem cells reside within fixed anatomical compartments — called niches — which provide a specialized environment to regulate the rate of stem cell proliferation, determine the fate of stem cell daughters, and protect stem cells from exhaustion or death. Many features of stem cell niches are conserved among diverse organisms and in multiple tissues, including signals from secreted factors and support cells, cell adhesion, mechanical inputs and spatial cues.
The formation and activity of niches are carefully regulated to ensure appropriate stem cell function. Niches form at discrete developmental times, and their appearance often enables the establishment or recruitment of stem cells at particular anatomic locations.
Because stem cells may function either homeostatically (continually replacing short-lived mature cells that are lost because of normal cell turnover) or facultatively (replacing differentiated cells only in response to injury or disease), stem cell niches must be dynamic enough to provide proper developmental and physiological cues to regulate stem cell behaviour normally and to mobilize stem cell activity in response to acute pathological conditions.
Deficient niche function may cause the loss or deregulation of tissue stem cells. Niche dysfunction contributes to age-associated deficiencies of stem cell function and, because niche cells normally control stem cell division, loss of input from the niche may permit overproliferation of stem cells, predisposing to malignant transformation.
An improved understanding of the relationship between stem cells and their niches will facilitate the recreation of niches in vitro, as well as in vivo manipulation of the niche to modulate endogenous stem cell function, yielding new and improved stem-cell-based therapies.
Stem cells are rare cells that are uniquely capable of both reproducing themselves (self-renewing) and generating the differentiated cell types that are needed to carry out specialized functions in the body. Stem cell behaviour, in particular the balance between self-renewal and differentiation, is ultimately controlled by the integration of intrinsic factors with extrinsic cues supplied by the surrounding microenvironment, known as the stem cell niche. The identification and characterization of niches within tissues has revealed an intriguing conservation of many components, although the mechanisms that regulate how niches are established, maintained and modified to support specific tissue stem cell functions are just beginning to be uncovered.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Regional gain and global loss of 5-hydroxymethylcytosine coexist in genitourinary cancers and regulate different oncogenic pathways
Clinical Epigenetics Open Access 20 September 2022
BMC Biology Open Access 20 January 2022
The mini player with diverse functions: extracellular vesicles in cell biology, disease, and therapeutics
Protein & Cell Open Access 10 August 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978). First proposal of the niche hypothesis. Suggests that niches have a defined anatomical location, regulate self-renewal, and that displacement from the niche results in stem cell differentiation.
Kimble, J. E. & White, J. G. On the control of germ cell development in Caenorhabditis elegans. Dev. Biol. 81, 208–219 (1981). Demonstrates the role of the distal tip cell in maintaining germline stem cell proliferation in the C. elegans gonad, and as such provides one of the first examples of support cells that directly contribute to a stem cell niche.
Henderson, S. T., Gao, D., Lambie, E. J. & Kimble, J. lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120, 2913–2924 (1994).
Xie, T. & Spradling, A. C. Decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94, 251–260 (1998). Together with references 6 and 7, provides evidence that localized signalling within the niche is necessary for maintaining GSCs in the D. melanogaster gonad.
Xie, T. & Spradling, A. C. A niche maintaining germ line stem cells in the Drosophila ovary. Science 290, 328–330 (2000).
Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK–STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001). Together with references 4 and 7, provides evidence that localized signalling within the niche is necessary for maintaining GSCs in the D. melanogaster gonad.
Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK–STAT signaling. Science 294, 2546–2549 (2001). Together with references 4 and 6, provides evidence that localized signalling within the niche is necessary for maintaining GSCs in the D. melanogaster gonad.
Kai, T. & Spradling, A. An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proc. Natl Acad. Sci. USA 100, 4633–4638 (2003). Shows that niches can remain functional in the absence of endogenous stem cells and stimulate the proliferation of incoming cells that are not normally found within that niche.
Crittenden, S. L., Leonhard, K. A., Byrd, D. T. & Kimble, J. Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol. Biol. Cell 17, 3051–3061 (2006).
Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).
Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).
Nilsson, S. K., Johnston, H. M. & Coverdale, J. A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97, 2293–2299 (2001).
Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).
Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).
Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).
Visnjic, D. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, 3258–3264 (2004).
Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005). Demonstrates the importance of the systemic environment as a component of the stem cell niche, particularly in the regulation of stem cells during ageing.
Ryu, B. Y., Orwig, K. E., Oatley, J. M., Avarbock, M. R. & Brinster, R. L. Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells 24, 1505–1511 (2006).
Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).
Boyle, M., Wong, C., Rocha, M. & Jones, D. L. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1, 470–478 (2007).
Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K. & Parada, L. F. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920–922 (2002). Indicates that genetic alterations in non-neoplastic cells of the tumour microenvironment are necessary for tumorigenesis.
Yang, F. C. et al. Nf1+/− mast cells induce neurofibroma like phenotypes through secreted TGF-β signaling. Hum. Mol. Genet. 15, 2421–2437 (2006).
Sneddon, J. B. et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842–14847 (2006).
Corre, J. et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia 21, 1079–1088 (2007).
Deng, W. & Lin, H. Spectrosomes and fusomes anchor mitotic spindles during asymmetric germ cell divisions and facilitate the formation of a polarized microtubule array for oocyte specification in Drosophila. Dev. Biol. 189, 79–94 (1997).
Yamashita, Y., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003). Reveals that mitotic spindle orientation is fixed within dividing male germline stem cells, providing one mechanism to ensure an asymmetric outcome to stem cell divisions.
Song, X. & Xie, T. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc. Natl Acad. Sci. USA 99, 14813–14818 (2002).
Song, X., Zhu, C. H., Doan, C. & Xie, T. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296, 1855–1857 (2002).
Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).
Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).
Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005).
Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005).
Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).
Watt, F. M. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919–3926. (2002).
Gordon, J. I., Schmidt, G. H. & Roth, K. A. Studies of intestinal stem cells using normal, chimeric, and transgenic mice. FASEB J. 6, 3039–3050 (1992).
Potten, C. S., Booth, C. & Pritchard, D. M. The intestinal epithelial stem cell: the mucosal governor. Int. J. Exp. Pathol. 78, 219–243 (1997).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1008 (2007).
Chiarini-Garcia, H., Raymer, A. M. & Russell, L. D. Non-random distribution of spermatogonia in rats: evidence of niches in the seminiferous tubules. Reproduction 126, 669–680 (2003).
Yoshida, S., Sukeno, M. & Nabeshima, Y. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317, 1722–1726 (2007).
Mauro, A. Satellite cells of muscle skeletal fibers. J. Biophys. Biochem. 9, 493–495 (1961).
Collins, C. A. et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122, 1–13 (2005).
Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007).
Winton, D. J. in Stem Cell Biology (eds Marshak, D. R., Gardner, R. L. & Gottlieb, D.) 515–536 (Cold Spring Harbor Press, New York, 2001).
van de Wetering, M. et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).
van Es, J. H. et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nature Cell Biol. 7, 381–386 (2005).
Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003).
Kim, I., Saunders, T. L. & Morrison, S. J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).
Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998).
Lowry, W. E. et al. Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells. Genes Dev. 19, 1596–1611 (2005).
Nguyen, H., Rendl, M. & Fuchs, E. Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127, 171–183 (2006).
Cotsarelis, G. Gene expression profiling gets to the root of human hair follicle stem cells. J. Clin. Invest. 116, 19–22 (2006).
Ohyama, M. et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J. Clin. Invest. 116, 249–260 (2006).
Van Mater, D., Kolligs, F. T., Dlugosz, A. A. & Fearon, E. R. Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev. 17, 1219–1224 (2003).
Rochat, A. et al. Insulin and Wnt1 pathways cooperate to induce reserve cell activation in differentiation and myotube hypertrophy. Mol. Biol. Cell 15, 4544–4555 (2004).
Taylor-Jones, J. M. et al. Activation of an adipogenic program in adult myoblasts with age. Mech. Ageing Dev. 123, 649–661 (2002).
Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006).
Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).
Irintchev, A., Zeschnigk, M., Starzinski-Powitz, A. & Wernig, A. Expression pattern of M-cadherin in normal, denervated, and regenerating mouse muscles. Dev. Dyn. 199, 326–337 (1994).
Hollnagel, A., Grund, C., Franke, W. W. & Arnold, H. H. The cell adhesion molecule M-cadherin is not essential for muscle development and regeneration. Mol. Cell. Biol. 22, 4760–4770 (2002).
Kiel, M. J., Radice, G. L. & Morrison, S. J. Lack of evidence that hematopoietic stem cells depend on N-cadherin mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1, 204–217 (2007).
Shinohara, T., Avarbock, M. R. & Brinster, R. L. β1- and α6-integrin are surface markers on mouse spermatogonial stem cells. Proc. Natl Acad. Sci. USA 96, 5504–5509 (1999).
Shinohara, T., Orwig, K. E., Avarbock, M. R. & Brinster, R. L. Spermatogonial stem cell enrichment by multiparameter selection of mouse testis cells. Proc. Natl Acad. Sci. USA 97, 8346–8351 (2000).
Brakebusch, C. et al. Skin and hair follicle integrity is crucially dependent on β1 integrin expression on keratinocytes. EMBO J. 19, 3990–4003 (2000).
Wagers, A. J., Allsopp, R. C. & Weissman, I. L. Changes in integrin expression are associated with altered homing properties of Lin(-/lo)Thy1.1(lo)Sca-1(+)c-kit(+) hematopoietic stem cells following mobilization by cyclophosphamide/granulocyte colony-stimulating factor. Exp. Hematol. 30, 176–185 (2002).
Sherwood, R. I. et al. Isolation of adult mouse myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 119, 543–554 (2004).
Bungartz, G. et al. Adult murine hematopoiesis can proceed without β1 and β7 integrins. Blood 108, 1857–1864 (2006).
Fleming, W. H., Alpern, E. J., Uchida, N., Ikuta, K. & Weissman, I. L. Steel factor influences the distribution and activity of murine hematopoietic stem cells in vivo. Proc. Natl Acad. Sci. USA 90, 3760–3764 (1993).
Gu, Y. et al. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302, 445–449 (2003).
Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12–CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006).
Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). Indicates that the relative elasticity of the stem cell niche influences the cell fate choice of differentiating mesenchymal stem cells.
Seery, J. P. & Watt, F. M. Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr. Biol. 10, 1447–1450 (2000).
Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).
Yu, F., Kuo, C. T. & Jan, Y. N. Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology. Neuron 51, 13–20 (2006).
Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006).
Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).
Ohlstein, B. & Spradling, A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315, 988–992 (2007).
Margolis, J. & Spradling, A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121, 3797–3807 (1995).
Gönczy, P. & DiNardo, S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. Development 122, 2437–2447 (1996).
De Franca, L. R. et al. Sertoli cells in testes containing or lacking germ cells: a comparative study of paracrine effects using the W (c-kit) gene mutant mouse model. Anat. Rec. 240, 225–232 (1994).
Ogawa, T., Dobrinski, I., Avarbock, M. R. & Brinster, R. L. Transplantation of male germ line stem cells restores fertility in infertile mice. Nature Med. 6, 29–34 (2000).
Kanatsu-Shinohara, M. et al. Germline niche transplantation restores fertility in infertile mice. Hum. Reprod. 20, 2376–2382 (2005). Demonstrates that transplantation of Sertoli cells can correct defects in the SSC microenvironment, providing evidence that niche transplantation may be a plausible approach to restoring stem cell activity in tissues where niche function is compromised by injury, disease or ageing.
Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004). Indicates that multipotent stem cells within the follicular bulge can self-renew in vitro and give rise to epidermis as well as new hair follicles on transplantation. The generation of new hair follicles indicated that epithelial stem cells are capable of generating their own niche.
Relaix, F., Rocancourt, D., Mansouri, A. & Buckingham, M. A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435, 948–953 (2005).
Gros, J., Manceau, M., Thome, V. & Marcelle, C. A common somitic origin for embryonic muscle progenitors and satellite cells. Nature 435, 954–958 (2005).
Schienda, J. et al. Somitic origin of limb muscle satellite and side population cells. Proc. Natl Acad. Sci. USA 103, 945–950 (2006).
Wagers, A. J. & Conboy, I. M. Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell 122, 659–667 (2005).
Mikkola, H. K. & Orkin, S. H. The journey of developing hematopoietic stem cells. Development 133, 3733–3744 (2006).
Christensen, J. L., Wright, D. E., Wagers, A. J. & Weissman, I. L. Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol. 2, e75 (2004).
Kyba, M., Perlingeiro, R. C. & Daley, G. Q. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002).
Johnson, S. A. & Yoder, M. C. Reconstitution of hematopoiesis following transplantation into neonatal mice. Methods Mol. Med. 105, 95–106 (2005).
Kikuchi, K. & Kondo, M. Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth. Proc. Natl Acad. Sci. USA 103, 17852–17857 (2006).
Ara, T. et al. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Proc. Natl Acad. Sci. USA 100, 5319–5323 (2003).
Molyneaux, K. A. et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130, 4279–4286 (2003).
Stallock, J., Molyneaux, K., Schaible, K., Knudson, C. M. & Wylie, C. The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo. Development 130, 6589–6597 (2003).
Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005).
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).
Carlson, M. E. & Conboy, I. M. Loss of stem cell regenerative capacity within aged niches. Aging Cell 6, 371–382 (2007).
Pan, L. et al. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 1, 458–469 (2007).
Zhang, X., Ebata, K. T., Robaire, B. & Nagano, M. C. Aging of male germ line stem cells in mice. Biol. Reprod. 74, 119–124 (2006).
Carlson, B. M. & Faulkner, J. A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989).
Zacks, S. I. & Sheff, M. F. Age-related impeded regeneration of mouse minced anterior tibial muscle. Muscle Nerve 5, 152–161 (1982).
Bintliff, S. & Walker, B. E. Radioautographic study of skeletal muscle regeneration. Am. J. Anat. 106, 233 (1960).
LeGros Clark, W. E. An experimental study of regeneration of mammalian striped muscle. J. Anat. 80, 24–36 (1946).
Schultz, E., Gibson, M. C. & Champion, T. Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study. J. Exp. Zool. 206, 451–456 (1978).
Morrison, S. J., Wright, D. E. & Weissman, I. L. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl Acad. Sci. USA 94, 1908–1913 (1997).
Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).
Morrison, S. J., Hemmati, H. D., Wandycz, A. M. & Weissman, I. L. The purification and characterization of fetal liver hematopoietic stem cells. Proc. Natl Acad. Sci. USA 92, 10302–10306 (1995).
Bowie, M. B. et al. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J. Clin. Invest. 116, 2808–2816 (2006).
Bowie, M. B. et al. Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties. Proc. Natl Acad. Sci. USA 104, 5878–5882 (2007).
Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).
Wolf, N. S. & Trentin, J. J. Hematopoietic colony studies: V. Effect of hematopoietic organ stroma on differentiation of pluripotent stem cells. J. Exp. Med. 127, 205–214 (1968). Early evidence that the microenvironment can determine precursor cell differentiation outcomes in the haematopoietic system.
Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007). Demonstrates that HSCs can complete a full circuit of migration in the body, passing from the marrow into the blood, from the blood into the tissues and lymphatic system, and then back through the bloodstream to return to the marrow.
Clarke, M. F. et al. Cancer stem cells – perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). Suggests that specialized marrow-derived cells may be established in 'pre-metastatic' niches of distant tissue sites, thus enabling the spread of metastatic cells and directing their tissue tropism.
Adams, G. B. et al. Therapeutic targeting of a stem cell niche. Nature Biotechnol. 25, 238–243 (2007). Evidence that therapeutic strategies that target niche cells can succeed in increasing haematopoietic stem cell number in the clinically relevant settings of transplant, mobilization and recovery from chemotherapy.
Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006).
Decotto, E. & Spradling, A. C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev. Cell 9, 501–510 (2005).
Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).
Stier, S. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201, 1781–1791 (2005).
Nilsson, S. K. et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106, 1232–1239 (2005).
Barker, J. E. Sl/Sld hematopoietic progenitors are deficient in situ. Exp. Hematol. 22, 174–177 (1994).
Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).
Haramis, A. P. et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684–1686 (2004).
Jones, P. H. & Watt, F. M. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73, 713–724 (1993).
Zhu, A. J. & Watt, F. M. Expression of a dominant negative cadherin mutant inhibits proliferation and stimulates terminal differentiation of human epidermal keratinocytes. J. Cell Sci. 109, 3013–3023 (1996).
Zhu, A. J. & Watt, F. M. β-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development 126, 2285–2298 (1999).
Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M. Stimulation of human epidermal differentiation by delta–notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).
Silva-Vargas, V. et al. β-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev. Cell 9, 121–131 (2005).
Kobielak, K., Pasolli, H. A., Alonso, L., Polak, L. & Fuchs, E. Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA. J. Cell Biol. 163, 609–623 (2003).
Jamora, C., DasGupta, R., Kocieniewski, P. & Fuchs, E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422, 317–322 (2003).
Palma, V. et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132, 335–344 (2005).
Lim, D. A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).
Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).
Lie, D. C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).
Meng, X. et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1493 (2000).
Kubota, H., Avarbock, M. R. & Brinster, R. L. Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Proc. Natl Acad. Sci. USA 101, 16489–16494 (2004).
Chen, C. et al. ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436, 1030–1034 (2005).
Ohta, H., Yomogida, K., Dohmae, K. & Nishimune, Y. Regulation of proliferation and differentiation in spermatogonial stem cells: the role of c-kit and its ligand SCF. Development 127, 2125–2131 (2000).
The authors would like to thank H. Mikkola, D. Laird, N. Geijsen and members of the Jones and Wagers laboratories for advice and comments on the manuscript. D.L.J. is supported by an Ellison Medical Foundation New Scholar Award, the American Federation for Aging Research, the G. Harold and Leila Y. Mathers Charitable Foundation, and a National Institutes of Health grant. A.J.W. is supported by a Burroughs Wellcome Fund Career Award, a Pilot Grant from the Paul F. Glenn Laboratories, and by the Harvard Stem Cell Institute. We apologize to those colleagues whose work has not been cited directly owing to space limitations.
An anatomical structure, including cellular and acellular components, that integrates local and systemic factors to regulate stem cell proliferation, differentiation, survival and localization.
- Stromal cell
A type of cell that contributes to the structure and connective tissue aspects of an organ.
- Trabecular bone
A porous, or spongy, type of bone that is filled with red bone marrow, which appears to be enriched for HSCs in adults.
A cell that is responsible for bone formation and maintenance.
- Seminiferous tubule
The site of spermatogenesis in the testis. The tubules are lined with spermatogonial stem cells and spermatogonia that will eventually progress through meiosis and differentiate into mature spermatozoa. Somatic Sertoli cells also line the tubules and support spermatogenesis by promoting germ cell proliferation and survival.
- Transit amplifying cell
A proliferating cell, derived from tissue stem cells, that lacks long-term self-renewal activity and serves as a precursor for more differentiated cell types.
- Adherens junction
A protein complex that occurs at cell–cell junctions in epithelial tissues. It is usually situated more basally than tight junctions. The primary proteins involved in forming adherens junctions are cadherins.
One of a family of transmembrane proteins that form homodimers in a Ca2+-dependent manner with other cadherin molecules on adjacent cells.
A stem cell that is derived from the neural ectoderm (neurectoderm) and produces cells that subsequently differentiate into neurons.
- Mast cells
A haematopoietic lineage cell that is rich in cytoplasmic granules that contain protein mediators, such as histamine, which are released on cell activation. Mast cells are found in many tissues and are implicated in allergy and host defence.
- Niche cell
A cell that interacts with a stem cell in a defined anatomical microenvironment (niche). Niche cells can also be referred to as 'support cells' and /or 'supporting stromal cells'.
- Primordial germ cell
An embryonic cell that serves as a precursor for the germline (egg and sperm).
A term referring to animals that are surgically joined such that they share a common blood circulation.
- Glial cell-line-derived neurotrophic factor
(GDNF). A cytokine, often primarily considered to be a neurotrophic factor, that has a role in numerous biological processes including cell survival, neurite outgrowth, cell differentiation and cell migration. GDNF is also secreted by Sertoli cells in the seminiferous tubules, and activates the maintenance of spermatogonial stem cells.
About this article
Cite this article
Jones, D., Wagers, A. No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9, 11–21 (2008). https://doi.org/10.1038/nrm2319
This article is cited by
BMC Biology (2022)
Regional gain and global loss of 5-hydroxymethylcytosine coexist in genitourinary cancers and regulate different oncogenic pathways
Clinical Epigenetics (2022)
Acta Biotheoretica (2022)
The mini player with diverse functions: extracellular vesicles in cell biology, disease, and therapeutics
Protein & Cell (2022)