Stem Cell Niche Related terms: ‘stem cell niche can be defined as an environment where supporting cells Hematopoietic Stem Cell, release factors that promote stem cell maintenance, regulating self renewal and Regeneration, Cell differentiation.27,28 Population, Signal Transduction, Bone From: Cardiac Regeneration and Repair, 2014 Se ell, Adult Stem Cell, Hair Follicle View all Topics > wh, Download as PDF QQ Setalert © About this page Stem Cell Niches D. Leanne Jones, Margaret T. Fuller, in Essentials of Stem Cell Biology (Third Edition), 2014 6.8 Summary ‘Stem cell niches have been proposed to play 2 critical role in the maintenance of stem cells in the male germ-line, the hematopoietic system, the epidermis, the intestinal epithelium, and the adult nervous system. Characterization of these stem cell niches depends on the ability to identify ster cells in vivo in their normal environment. Through comparison of different stem cell systems, some themes emerge that indicate possible general characteristics of the relationship between stem cells and their supporting niche. First, secreted factors elaborated by or induced by cells composing the stem cell niche can function to direct stem cell fate decisions. However, the precise signaling pathway or pathways may be different for each stem cell type and within each stem cell niche. Studies in Drosophila indicate that support cells adjacent to stem cells secrete factors required for maintaining stem cell identity and for specifying stem cell self-renewal. Both JAK-STAT signaling and TGF- signaling have been implicated in the regulation of stem cell behavior by surrounding support cells in Drosophila. In mammals, the Wnt signal transduction pathway has been demonstrated to play a role in specifying stem cell self-renewal in HSCs, although the Wnt signal may be secreted from the stem cells themselves and may act in an autocrine loop to control stem cell proliferation. Wnt signaling may also be involved in directing the proliferation of stem cells, transit-amplifying cells, or both in the intestinal epithelium. However, the same signaling pathway may be exploited for distinct purposes in different stem cell systems. In the mammalian epidermis, Wnt signaling is likely involved in specifying the fate of hair follicle precursors rather than in specifying self-renewal of the multipotent stem cells in the bulge. Cell adhesion is also emerging as an important characteristic of the interactions of stem cells with the niche. Adhesion between stem cells and niche cells is required for stem cell maintenance in the Drosophila male and female germ-line, ensuring that GSCs are held close to self-renewal signals emanating from the niche. Attachment to niche cells or to a basal lamina may also be important for stem cell maintenance within adult ‘mammalian tissues, hence the high levels of the B1 integrin characteristic of stem cells in the interfollicular epidermis and in the multipotent stem cells within the bulge region of the outer root sheath. Interestingly,targeted disruption of B1 integrin in cells within the bulge region of the outer root sheath severely impaired the proliferation of precursor cells that contributed to the interfollicular epidermis, hair follicle, and sebaceous glands. ‘Thus, similar to the role of adherens junctions in maintaining Dresophila GSCs in the niche, Bl integrin-mediated adhesion may be required to hold multipotent epidermal stem cells within the niche and close to self-renewal signals. In the mammalian testis, a6 integrin has been identified as a cell surface marker for the enrichment of spermatogonial stem cells, although a specific role for 06 integrin in spermatogonial stem cell maintenance has, not yet been directly demonstrated. Similarly, a6 integrin is expressed by basal keratinocytes in the epidermis; however, there is no strong correlation between a6 expression and proliferative potential. Therefore, although cell adhesion is frequently a conserved feature of stem cell maintenance in supportive niches, the specific types of junctions and cell adhesion molecules that play roles may differ among different stem cell niche systems. Third, the precise cellular organization of stem cells with respect to surrounding support cells may play an important role in the regulation of appropriate stem cell numbers. In the Drosophila ovary and testis, where the stem cells normally divide with invariant asymmetry, the mitotic spindle is oriented to place the daughter cell that will retain stern cell identity within the stem cell niche; the daughter cell destined to differentiate is placed outside ofthe niche and away from self-renewal signals. Either attachment to niche cells or the extracellular matrix via junctional complexes or localized signals within the niche may provide polarity cues toward which stem cells can orient during division. This stereotyped division plane can in turn specify an asymmetric outcome to stem cell divisions, in which one daughter cell retains attachment to niche cells and the other is displaced out of the stem cell niche. As stem cells are definitively identified in vivo, in the context of their normal support cell microenvironment, it will be interesting to determine if stem cell divisions are likewise oriented in the seminiferous tubules, bone marrow, follicular bulge, and intestinal crypts, within neurogenic regions of the adult brain. View chapter | | Purchase book Signature of Responders—Lessons from Clinical Samples Micheline Resende, ... Doris A. Taylor, in Stem Cell and Gene Therapy for Cardiovascular Disease, 2016 The “Niche” Concept of Stem Cells Stem cell niches are specialized regions or microenvironments with distinct properties that govern stem cell quiescence, self-renewal, survival, and differentiation. The primary components of a stem cell niche include stromal cells, which secrete soluble factors that signal stem cells; extracellular matrix proteins, which provide scaffold for stem cell attachment; blood vessels, which provide nutrition and a means for cells to move to distant tissues; and neural inputs, which integrate signals from different organ systems [59]. The relationships between stem cells and their niches are dynamic; alterations in the niche can induce stem cell proliferation, retention, or mobilization [60-63]. Most adult tissues have resident stem cells that are responsible for maintaining that tissue. These tissue stem cells, represent a population of slow-cycling cells that persist in a quiescent state [64,65]. This quiescent state is necessary to maintain the long-term viability of these primitive cells and preserve their “stemness.” When outside of their niches, stem cells are more likely to differentiate, which may lead to exhaustion of the stem cell pool. When tissue repair is required, stem cell progeny give rise to differentiating progenitor cells that maintain tissue integrity [64-66l. The two prominent niches relevant to cardiac reoair are bone marrow and the heart itself.Schofield et al. identified the bone marrow niche for HSCs in 1978 [67]. The bone marrow has two specialized compartments: the osteoblastic niche, which preserves HSCs in an undifferentiated, quiescent state; and the vascular niche, which contains cells that are lineage-committed and proliferative [68,68]. Studies have revealed the properties of the osteoblastic niche that are necessary to preserve stem cells in their primitive quiescent state [70,71], such as low oxygen tension [55]. For example, direct in vivo measurements of oxygen tension in the bone marrow of live mice have shown partial oxygen pressure (pO,) to be as low as 1.3% in deep peri-sinusoidal regions [72-75]. Hypoxia-inducible factor 1-a (HIF-10) activates the expression of genes encoding proteins that regulate many hematopoietic functions, including proliferation and cell cycle quiescence [76,77]. Mice with mutations in the heterodimeric transcription factor HIF-10 develop extensive hematopoietic pathologies [78]. HIF-10 also regulates the gene expression of many chemokines, cytokines, and growth factors involved in HSC maintenance within the bone marrow niche, including vascular endothelial growth factor (VEGF), stromal cell- derived factor-1a/chemokine (C-X-C motif) ligand 12 (SDF-1/CXCL12), angiopoietin-2, platelet-derived growth factor-B, and kit ligand (KitL)/stem cell factor [79-82]. In addition, it has been shown that an increase in hypoxic zones correlates with increases in SDF-1 levels and hematopoietic cell tropism to these areas due to increased chemokine levels [83]. Bone marrow niches are also affected by ischemic injuries, such as myocardial infarction and vascular trauma, which lead to mobilization of HPCs and pro-angiogenic cells and the incorporation of these cells into the ischemic areas [84,85]. Stem cell riches have been identified in most tissues, including those with rapid cell turnover (e.g., epidermis and intestine) [72-74] and those with slow cell turnover (e.g., vascular wall of large and mid-sized blood vessels, adipose tissue, and the heart) [86,87). Recent studies have shown that adipose tissue contains significant numbers of hematopoietic stem and progenitor cells that may participate in the repair of injured organs [88]. Adipose tissue apparently serves as a suitable niche for the homing of heterogenous populations of circulating bone marrow-derived HSCs, indicating the presence of the so called bone-fat axis and suggesting that “cross-talk” occurs between the organs in which the metabolic status of the adipose tissue affects the function of the bone marrow [88]. The currently ongoing ATHENA clinical trial, which is being conducted by the Texas Heart Institute and collaborating institutions, will be the first US trial to assess the use of adipose-derived regenerative cells (ADRCs) to treat heart failure patients. Previous studies performed in Europe have shown that ADRCs improve cardiac function and blood flow in patients after myocardial infarction [89] and, more recently, improved functional capacity (MVO,) and remodeling (LVEDD) in patients with ischemic cardiomyopathy [90]. Resident Cardiac Progenitor Cells In previous decades, the heart was considered to be composed of terminally differentiated cells that are incapable of self-regeneration. However, recent studies have suggested that the heart possesses resident stem cells that contribute to cardiac tissue renewal throughout life [28,91,92]. Cardiac stem cell niches are dispersed throughout the myocardium [93,04] but are most frequently found in the atria and apex [95,96]. Although there is a current consensus regarding the potential for renewal of myocardial tissue throughout life, cardiac regenerative capacity is still very limited [97]. After an acute myocardial infarction, more than a billion cardiomyocytes may be lost, severely decreasing the potential for recovery of myocardial function. Multiple studies have recently examined the benefits of using intracardiac injections of bone marrow-derived progenitor cells to treat cardiovascular diseases; these studies have shown varying degrees of improvement in cardiac function [98-100]. Clinical trials conducted in the last 5 years have indicated that bone marrow cell therapy results in modest or no therapeutic benefits for patients with acute myocardial infarction or chronic heart failure [101-103]. These poor results may be due to the fact that the cells were injected directly into the injured myocardium, a region which may have inadequate blood supply and insufficient viable tissue or matrix for cell attachment. Another possibility is that the autologous stem and progenitor cells collected from individuals who are older and/or have advanced disease could possess limited regenerative capacity [104-108]. Finally, it has been shown that transplanted stemcells interact with cardiac niches. A preclinical study in pigs showed that transendocardial injection of allogeneic bone marrow-derived MSCs into infarcted hearts appears to stimulate and recruit cells from the local CSC pool, leading to an increase in myocyte progeny and cardiac vessel density [109]. After the MSCs were injected, chimeric clusters containing exogenous MSCs and endogenous CSCs were identified in the infarcted and border-zone myocardium. Itis not known if these interactions are compromised or how depleted these niches may be in older patients with cardiovascular diseases or other comorbidities. As indicated above, there is a great deal of interaction, or cross-talk, between transplanted therapeutic cells, the pool of resident CSCs, and the bone marrow and adipose tissue niches (Figure 35.1). A better understanding of these interactions and how diseases and aging can alter them will likely lead to improvements in cell therapy. Future studies should take into account not only the regenerative capacities of transplanted stem cells but also the condition of the stem cell niches regulating their activities. View chapter | | Purchase book The Need to Study, Mimic, and Target Stem Cell Niches Ajaykumar Vishwakarma, .. Jeffrey M. Karp, Biology and Engineering of Stem Cell Niches, 2017 1.2 Components of Stem Cell Niche The stem cell niche is @ complex, heterotypic, and dynamic structure, which includes supporting ECM, neighboring niche cells, secreted soluble signaling factors (such as growth factors and cytokines), physical parameters (such as shear stress, tissue stiffness, and topography), and environmental signals (metabolites, hypoxia, inflammation, etc.) (Fig. 1.1)” Stem cell niches are highly innervated and densely vascularized, thus are directly or indirectly influenced by vascular and neural inputs. In addition to matrix and cel signaling elements mentioned above, niche cells form functional units within the stem cell niche. These are neighboring tissue-specific stem or somatic cell populations that interact with resident stem cells to regulate cel fate. For example, mesenchymal stromal/stem cells in the HSC niche or parenchymal hepatocytes in liver. In addition to stem cell themselves, niche cells provide a source of physical and biochemical signals within the niche microenvironment by building extracellular matrix and producing cell surface or soluble signaling factors. Importantly therefore, stem cell microenvironments are highly dynamic and display temporal variations. Such variations in direct cell-cell contacts and ECM components, as well as their interaction with regulatory molecules secreted by stem or niche cells and the spatial organization of niche components, ultimately enable the regulation of stem cells to render tissue homeostasis and regeneration.” View chapter | | Purchase book Danone Chow OnUaULer SLE Cru ‘Qiang Liu, ... Er-Wei Song, in Recent Advances in Cancer Research and Therapy, 2012 8.6.2 Mechanism of Cancer Metastasis Regulated by Niche The stem cell niche is the microenvironment surrounding stem cells that maintain their steriness and prevent them from differentiating, The niche consists mainly of fibroblasts, ECM, vasculature, and infiltrating immune and/or inflammatory cells, and has features helping CSCs undergoing metastasis, CSCs secrete growth factors and cytokines, which activate and recruit fibroblasts and inflammatory cells to the tumor. These infiltrated cells, in concert with CSCs, further remodel the microenvironment by secreting growth factors, proteinases, and ECM components.!!° This not only has an influence on the tumor cells but also affects normal epithelial cells, ECM, and stromal cells. The growth factor-enriched niche facilitates the EMT and angiogenesis of CSCs that contribute to its metastasis. View chapter Purchase book Cellular and Molecular Mechanotransduction in Bone Julia C. Chen, ... Christopher R. Jacobs, in Osteoporosis (Fourth Edition), 2013 Mesenchymal Stem Cells The stem cell niche in adult bone contains a milieu of biochemical factors that regulate stem cell behavior, but very little is known about the mechanical nature of the niche and how physical stimuli affect stem cell mobilization. Mechanical loading activates new bone formation on the endosteal and periosteal surfaces, and initiates intracortical remodeling. However, the contribution of marrow-derived stem cells to these processes is unclear. Compressive, tensile, and fluid-induced shear forces are present in the marrow [108], and all likely affect ster cell function. In addition, there are intracellular tensile forces resulting from cell-extracellular matrix (ECM) interactions at focal adhesions. Data suggest that externally applied forces, as well as intracellular tensile forces, play a critical role in mesenchymal stem cell differentiation [106]. Several reports have demonstrated the ability of mechanical forces to influence fate decisions. For example, hydrostatic pressure induces chondrogenic differentiation of human mesenchymal stem cells. Similarly, tensile strain applied to cell monolayers enhances osteogenesis [107]. Finally, fluid flow has been shown to upregulate osteogenic genes [108] View chapter | | Purchase book Pluripotent Stem Cells D. Leanne Jones, Margaret T. Fuller, in Handbook of Stem Cells (Second Edition), 2013Summary ‘Stem cell niches have been proposed to play a critical role in the maintenance of stem cells in the male germ line, the hematopoietic system, the epidermis, the intestinal epithelium, and the adult nervous system. Characterization of these stem cell niches depends on the ability to identify stem cells in vivo in their normal environment. Through comparison of different stem cell systems, some themes emerge that indicate possible general characteristics of the relationship between stem cells and their supporting niche. First, secreted factors elaborated by or induced by cells composing the stem cell niche can function to direct ster cell fate decisions. However, the precise signaling pathway or pathways may be different for each stem cell type and within each stem cell niche. Studies in Drosophila indicate that support cells adjacent to stem cells secrete factors required for maintaining stem cell identity and for specifying stem cell self-renewal (reviewed by Spradiing et al, 2001 and Lin, 2002). Both JAK-STAT signaling and TGF-B signaling have been implicated in the regulation of stem cell behavior by surrounding support cells in Drosophila. In mammals, the Wnt signal transduction pathway has been demonstrated to play a role in specifying stem cell self-renewal in HSCs, although the Wnt signal may be secreted from the stem cells thernselves and may act in an autocrine loop to control stem cell proliferation (Willert et al, 2003; Huelsken and Behrens, 2002). Wit signaling may also be involved in directing, the proliferation of stem cells, transit-amplifying cells, or both in the intestinal epithelium (Korinek et al., 1997). However, the same signaling pathway may be exploited for distinct purposes in different stem cell systems. In the ‘mammalian epidermis, Wnt signaling is likely involved in specifying the fate of hair follicle precursors rather than in specifying self-renewal of the multipotent stem cells in the bulge (Brakebusch et al., 2000). Cell adhesion is also emerging as an important characteristic of the interactions of stem cells with the niche. Adhesion between stem cells and niche cells is required for stem cell maintenance in the Drosophila male and female germ line, ensuring that GSCs are held close to self-renewal signals emanating from the niche (Song et al, 2002c; Gonzalez-Reyes, 2003; Jones and Fuller, in preparation). Attachment to niche cells or to a basal lamina may also be important for ster cell maintenance within adult mammalian tissues, hence the high levels of the B1 integrin characteristic of stem cells in the interfollicular epidermis and in the multipotent stem cells within the bulge region of the outer root sheath (Taylor et al., 2000; Watt, 2002b; Shinohara et al., 1999). Interestingly, targeted disruption of B1 integrin in cells within the bulge region of the outer root sheath severely impaired the proliferation of precursor cells that contributed to the interfollicular epidermis, hair follicle, and sebaceous glands (Callahan and Oro, 2001). Thus, similar to the role of adherens junctions in maintaining Drosophila GSCs in the niche, BL integrin-mediated adhesion may be required to hold multipotent epidermal stem cells within the niche and close to self-renewal signals. In the mammalian testis, a6 integrin has been identified as a cell surface marker for the enrichment of spermatogonial stem cells, although a specific role for a6 integrin in spermatogonial ster cell maintenance has not yet been directly demonstrated (Kubota et al., 2005; Shinohara et al., 1999). Similarly, 06 integrin is expressed by basal keratinocytes in the epidermis; however, there is no strong correlation between a6 expression and proliferative potential (Reynolds and Jahoda, 1992). Therefore, although cell adhesion is frequently a conserved feature of stem cell maintenance in supportive niches, the specific types of junctions and cell adhesion molecules that play roles may differ among different stem cell niche systems. Third, the precise cellular organization of stem cells with respect to surrounding support cells may play an important role in the regulation of appropriate stem cell numbers. In the Drosophila ovary and testis, where the stem cells normally divide with invariant asymmetry, the mitotic spindle is oriented to place the daughter cell that will retain stem cell identity within the stem cell niche; the daughter cell destined to differentiate is placed outside of the niche and away from self-renewal signals (Deng and Lin, 1997; Yamashita et al, 2003). Either attachment to niche cells or the extracellular matrix via junctional complexes or localized signals within the niche may provide polarity cues toward which stem cells can orient during division. This stereotyped division plane can in turn specify an asymmetric outcome to stem cell divisions, in which one daughter cell retains attachment to niche cells and the other is displaced out of the stem cell niche. As stem cells are definitively identified in vivo, in the context of their normal support cell microenvironment, it will be interesting to determine if stem cell divisions arelikewise oriented in the seminiferous tubules, bone marrow, follicular bulge, and intestinal erypts, within neurogenic regions of the adult brain. View chapter | | Purchase book Cellular Senescence and Stem Cell Niche Arthur Krause, ... Irina M. Conboy, in Biology and Engineering of Stem Cell Niches, 2017 7 Effects of Aging and Senescence on the Stem Cell Niche Stem cell niche function is deregulated by age-associated changes. This was discovered in hematopoietic stem cells, It was demonstrated that niche cells are systemically regulated and the age of the organism plays an important role in stem cell supportive function of a niche. Experiments revealed age-dependent defects could be reversed by exposure to a young circulation in parabiosis or also by defined molecular approaches, such as neutralizing transforming growth factor-1, TGF-B1 or by providing “youthful” levels of oxytocin, MAPK activation, or Delta/Notch activation. This provides an indication that aged animals actively carry “aged” factors and are depleted of “youthful” factors, which together alter the stem cell niche function. With respect to senescence, chronic Wnt signaling can reinforce senescence in differentiated and stem cells” and hence Wint]6b was also proposed as a new marker for cellular senescence.” Wnt also has modulating activity on stem cell fate and self- renewal in different organs and in cancers.’? While critically needed for productive myogenesis, there is evidence for deterioration in tissue repair and maintenance through hyperactivation of Wnt and of p38 signaling in aged skeletal muscle, which resulted in fibrosis and decline in muscle stem cell function.44474 During aging, neurogenesis including stem cell number and proliferation are highly decreased in adult neurogenic niches due to a combination of intrinsic and extrinsic signals.’5 In addition to the changes of local and systemic regulators that modulate the activity of key cell fate signaling pathways, alteration in the ECM, as it oceurs with age, effectuate the behavior of the stem cells.”® These age-specific alterations can contribute to changes in hematopoietic stem cell activity, which is also regulated by intrinsic and extrinsic factors from the niiche.7” Stem cell aging manifests through multiple mechanisms (Fig. 12.2),”®7® but in every case it leads to a loss of stem cell function and thus, decline in tissue repair and maintenance, leading to pathologies. One mechanism was revealed as loss of lineage specificity that occurs in age, which results in changes to a different fate of stem cell progeny. Secondly, stem cells lose their ability of self-renewal, which causes a depletion of the stem cell pool. For example, the depletion of melanocyte stem cells in hair follicles and the nonexistence of mature pigmented ‘melanocytes in the stem cell niche in humans lead to the most famous phenotypic change in age, hair graying®°*" It is also believed that stem cells can underlay a malignant transformation leading to cancer due to stem cell miss function. Finally, an additional effect of aging is seen through the depletion of the stem cell pool due to senescence. Cont uting to senescence, p16!N** plays a major role in replicative failure of stem cells, and itis also established as a clear biomarker of aging.°2* Several experiments also demonstrated that stem cell senescence can cause a decrease in number of stem cells in their niche.** Such reduction of stem cells may have evolved to counter a potential malignant transformation. When cells become senescent; the development of malignancy of a cell is stopped, but afterward senescent cells accumulation with aging is deleterious, as senescent cells secrete bioactive molecules such as degradative enzymes, inflammatory cytokines, and factors, such as TGF- B, which most probably worsen the tissue homeostatic health and ironically with time promotes cancerprogression.” TGF-B is a known example for impairing tissue regeneration and stem cell proliferation in age 58586 Senescence has different causes and can act, depending on each, with different outcomes. Therefore, senescence is seen as a magnificent example of antagonistic pleiotropy (Fig. 12.3), where the needed-at-some-point phenomenon results in deleterious consequences for the same organism at a later developmental time. Genes, that are beneficial in early life, are conserved and selected for evolution, even though they could be detrimental in later life. Therefore senescence is seen as a pleiotropic but also as an antagonistic phenomenon.” In summary, a stem cell niche is composed of a subset of cells in a specific location that is responsible for the ‘maintenance of dedicated stem cells able to maintain themselves and the niche. The niche itself can vary but itis always a physical anchor for stem cells and always has control of stem cell behavior. Extrinsic factors that regulate the stem cell fate are produced by the niche and lead in mammals and invertebrates to asymmetric cell divisions, where one daughter cell remains a ster cell in the niche, while the other daughter cells proliferate as needed for tissue repair or maintenance and differentiates to a mature cell after leaving the niche.®* Through age, stem cells are not able any more to fulfill their task due to the changes in key intrinsic and extrinsic determinants of proliferation and activation for tissue repair. One of the age-imposed changes may be stem cell senescence, which acts in an antagonistic pleiotropic way, where initially less oncogenesis with age is a good adaptation to high cellularity and continuous regeneration in mammals; however, accumulated with age senescent cells deteriorate their surrounding environment. View chapter Purchase book Intestinal Stem Cell Niche Sang-Eun Lee, .. Vivian S.W. Li, in Advances in Stem Cells and their Niches, 2018 6 Conclusion ‘Stem cell niche plays an indispensable role in tissue homeostasis, regeneration, and disease. Current view of ISC niche focuses mainly on mesenchymal cells and Paneth cells, while the importance of ECM is less revealed. In this chapter, we provided an overview of the ECM composition and remodeling in intestinal homeostasis, inflammation, and cancer. In addition to the structural support, ECM provides both biophysical and biochemical cues to regulate cell behavior via cell-ECM interaction and the availability of growth factors. The epithelial and stromal cells produce ECM remodeling enzymes to modify the ECM microenvironment, which, in turn, regulates ISC fate decision. Such feedback regulation between cells and ECM is crucial in shaping the microenvironment for tissue homeostasis, while disruption of the process often leads to diseases such as IBD and cancer. ECM remodeling enzymes are the central players in the ISC niche to support tissue homeostasis, wound healing, and ‘tumor growth in different contexts. ECM components therefore lend promises to CRC drug development as an alternative therapeutic strategy. On the other hand, the natural ECM obtained from decellularized intestine offers an excellent biological scaffold for tissue engineering. Ex vivo reconstruction of CRC using such tissue engineering technology further allows incorporation of the tumor microenvironment to cancer cells, representing a promising biomimetic tool for disease modeling and drug testing. View chapter Purchase bookCloning and Stem Cells David P. Clark, Nanette J. Pazdernik, in Biotechnology (Second Edition), 2016 The Key Features of a Stem Cell Niche Astem cell niche is a local microenvironment that directly promotes or protects a population of stem cells. There are two key components to a stem cell niche, the microenvironment and the stem cell, and each of their functions relies on the other. The environment emits cues or signals to the stem cells that keep the cells from differentiating—that is, keeps the cells competent to develop into a variety of different cells. Some of these signals originate from cells that encase the niche, and in other cases, the extracellular matrix provide the cues. In addition, autocrine signals from the stem cell itself can keep the cells in their undifferentiated state (Fig. 18.7). The stem cells that stay encased in the niche provide a pool of cells that can be triggered to form the other cells of. our body. Ifthe stem cell niche runs out of cells, then there are no precursors for tissues to regenerate. In contrast, an extracellular environment that causes overproliferation, that is, creates too many stem cells, leads to tumors. Therefore, proper niche function requires 2 balance, and there cannot be too many stem cells or too few. The cells and extracellular matrix that make up the environment depend on the type of stem cell that they house. For example, the model organism C. elegans has a stem cell population that can generate more oocytes or eggs for the worm (Fig. 18.8) These stem cells are kept in a niche that is created by one single cell, called the distal tip cel, which caps the area and sends long processes or fibrils that surround the area. This single cell emits a signal that prevents the stem cells from becoming an egg: If this single cell is destroyed in any way, the stem cells turn into eggs. this single cell is moved to a different location, the nearby cells receiving its signals turn into stem cells. ‘Stem cells contained within a niche often undergo asymmetric cell division to produce one daughter cell that differentiates and another daughter cell to maintain the ster cell population. The signals that affect each of the two daughters are different, and can either arise from an intrinsic asymmetry between the two daughters or from an extrinsic asymmetry (Fig. 18.9) In an intrinsic asymmetry, one daughter cell receives a signaling molecule such as a protein, RNA, or macromolecule, and the other daughter cell does not. Depending on the role of the intrinsic signal, the daughter cell that receives the molecule either stays a stem cell or differentiates. External asymmetries also drive one daughter cell to differentiate and the other to stay a stem cell. For example, ifthe cell division pushes one of the daughters too far from the niche and the signals that keep the stem cell from differentiating, then this daughter will start to differentiate. Another possibility is that the daughter cell in the new environment may receive new signals that cause it to differentiate. There can also be symmetrical renewal where stem cell division creates two more stem cells. Additionally, a mitotic division can also produce two cells that differentiate. This process is termed symmetrical differentiation (Fig. 18.10). fall the ster cells in a niche had symmetrical differentiations, the organism would run out of stem cells. On the other hand, ifthe stem cell always divided with symmetrical renewal, the niche would have too many stem cells, which is @ scenario that resembles a (One key component to keeping the stem cell in a niche is the adherence to the extracellular matrix (ECM). This involves anchoring the stem cell to the ECM through cell surface receptors such as E-cadherin. Ifthis surface receptor is removed from germline or follicular stem cells, these stem cells rapidly leave the niche and differentiate. E-cadherin mediates stem cell adhesion in the Drosophila testes stem cell niche, in the neuronal stem cells of the brain region called the subventricular zone, and the stem cell niche for creating blood cells.hosts Get HGH aH YISE ¥arIGM SHIVUBIVME SE Uuuy en Catt We Sane gUrTESM Uy nc-up. pen a4cr west niches have no geographical boundaries for the microenvironment and the stem cells. In the open variety of niche, interaction between neighboring niches is common, where stem cells from one region can migrate to another. Lineage analysis has determined that stem cells from one location have the ability to migrate from their niche and populate neighboring niches. An example of stem cells found in open environments is the seminiferous tubules in mammals (Fig. 18.11). In contrast, closed stem cell niches have fixed boundaries that enclose the environment and stem cells. A closed niche is surrounded by an extracellular matrix or capped by cells that prevent the stem cells from leaving the area. In C. elegans, the stem cell niche has a closed environment capped by a distal tip cell. Stem cells can leave the area in only one point, and differentiation begins upon exiting of the niche (see Fig. 18.8). View chapter | | Purchase book