Stalk Jail cell Niches

D. Leanne Jones , Margaret T. Fuller , in Essentials of Stem Prison cell Biology (Third Edition), 2014

half dozen.8 Summary

Stem prison cell niches have been proposed to play a critical role in the maintenance of stalk cells in the male germ-line, the hematopoietic system, the epidermis, the abdominal epithelium, and the adult nervous organization. Characterization of these stem cell niches depends on the ability to identify stalk cells in vivo in their normal environment. Through comparison of unlike stem cell systems, some themes emerge that indicate possible full general characteristics of the human relationship between stem cells and their supporting niche.

First, secreted factors elaborated by or induced by cells composing the stem prison cell niche can function to direct stem cell fate decisions. Still, the precise signaling pathway or pathways may exist different for each stem cell type and within each stem cell niche. Studies in Drosophila signal that support cells next to stem cells secrete factors required for maintaining stalk cell identity and for specifying stem cell self-renewal. Both JAK-STAT signaling and TGF-β signaling have been implicated in the regulation of stem jail 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 prison 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 besides be involved in directing the proliferation of stem cells, transit-amplifying cells, or both in the abdominal epithelium. Still, the same signaling pathway may be exploited for distinct purposes in dissimilar stem prison cell systems. In the mammalian epidermis, Wnt signaling is likely involved in specifying the fate of hair follicle precursors rather than in specifying cocky-renewal of the multipotent stem cells in the bulge.

Cell adhesion is also emerging equally an of import characteristic of the interactions of stem cells with the niche. Adhesion between stalk cells and niche cells is required for stem cell maintenance in the Drosophila male and female person germ-line, ensuring that GSCs are held close to cocky-renewal signals emanating from the niche. Attachment to niche cells or to a basal lamina may likewise be important for stem cell maintenance within adult mammalian tissues, hence the loftier levels of the β1 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 β1 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 function of adherens junctions in maintaining Drosophila GSCs in the niche, β1 integrin-mediated adhesion may be required to hold multipotent epidermal stem cells inside the niche and close to self-renewal signals. In the mammalian testis, α6 integrin has been identified as a prison cell surface marker for the enrichment of spermatogonial stem cells, although a specific role for α6 integrin in spermatogonial stalk cell maintenance has not yet been directly demonstrated. Similarly, α6 integrin is expressed by basal keratinocytes in the epidermis; however, there is no stiff correlation betwixt α6 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 amongst dissimilar stem cell niche systems.

3rd, the precise cellular organisation of stem cells with respect to surrounding back up cells may play an important role in the regulation of appropriate stalk prison cell numbers. In the Drosophila ovary and testis, where the stem cells normally divide with invariant disproportion, the mitotic spindle is oriented to place the daughter cell that will retain stem jail cell identity inside the stem cell niche; the daughter cell destined to differentiate is placed outside of the 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 stalk cells can orient during division. This stereotyped division plane can in plough specify an asymmetric outcome to stem prison cell divisions, in which i daughter prison cell retains zipper to niche cells and the other is displaced out of the stalk cell niche. As stem cells are definitively identified in vivo, in the context of their normal back up cell microenvironment, it will exist 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.

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Stem Prison cell Niches

D.Leanne Jones , Margaret T. Fuller , in Essentials of Stem Cell Biological science (Second Edition), 2009

Summary

Stalk cell niches have been proposed to play a critical role in the maintenance of stem cells in the male person germline, the hematopoietic arrangement, the epidermis, the intestinal epithelium, and the adult nervous arrangement. Characterization of these stem prison cell niches depends on the ability to identify stem cells in vivo in their normal environment. Through comparison of dissimilar stem cell systems, some themes emerge that indicate possible general characteristics of the relationship between stem cells and their supporting niche.

Offset, secreted factors elaborated by or induced by cells composing the stem cell niche can function to direct stem cell fate decisions. Nonetheless, the precise signaling pathway or pathways may be unlike for each stalk cell type and within each stem jail cell niche. Studies in Drosophila point that support cells next to stem cells secrete factors required for maintaining stem cell identity, and for specifying stem cell self-renewal. Both JAK-STAT signaling and TGF-β 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 prison cell proliferation. Wnt signaling may besides exist involved in directing the proliferation of stem cells, transit-amplifying cells, or both, in the abdominal epithelium. Yet, 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.

Second, cell adhesion is also emerging equally an important characteristic of the interactions of stem cells with the niche. Adhesion between stalk cells and niche cells is required for stem cell maintenance in the Drosophila male and female person germline, 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 loftier levels of the β1 integrin feature of stem cells in the interfollicular epidermis and in the multipotent stem cells inside the bulge region of the outer root sheath. Interestingly, targeted disruption of β1 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 function of adherens junctions in maintaining Drosophila GSCs in the niche, β1 integrin-mediated adhesion may be required to hold multipotent epidermal stalk cells within the niche and close to self-renewal signals. In the mammalian testis, α6 integrin has been identified equally a cell surface marker for the enrichment of SSCs, although a specific role for α6 integrin in SSC maintenance has not nonetheless been straight demonstrated. Similarly, α6 integrin is expressed by basal keratinocytes in the epidermis; however, at that place is no strong correlation between α6 expression and proliferative potential. Therefore, although prison cell adhesion is frequently a conserved characteristic of stalk cell maintenance in supportive niches, the specific types of junctions and cell adhesion molecules that play roles may differ amidst unlike stem jail cell niche systems.

3rd, the precise cellular organization of stem cells with respect to surrounding support cells may play an important role in the regulation of appropriate stem prison cell numbers. In the Drosophila ovary and testis, where the stem cells normally divide with invariant asymmetry, the mitotic spindle is oriented to identify the girl jail cell that will retain stem cell identity within the stem prison cell niche; the girl cell destined to differentiate is placed outside of the niche and abroad from self-renewal signals. Either attachment to niche cells or the extracellular matrix via junctional complexes, or localized signals inside the niche may provide polarity cues toward which stalk cells tin can orient during sectionalization. This stereotyped sectionalisation plane tin in plow specify an disproportionate outcome to stem cell divisions. As stem cells are definitively identified in vivo, in the context of their normal back up cell microenvironment, it will exist interesting to determine if stem cell divisions are likewise oriented in the seminiferous tubules, os marrow, and within neurogenic regions of the adult encephalon.

Understanding the roles and mechanism of action of niches in controlling stalk cell behavior is critical for growing and expanding stem cells in vitro, while maintaining stem prison cell characteristics and the total assortment of differentiation potential, an essential first footstep in the use of stem cells in regenerative medicine. Recent evidence indicating that the stem jail cell niche changes with historic period and may become less capable of supporting stem prison cell maintenance, however, suggests that co-transplantation of new niche cells or rejuvenation of niche maintenance programs may be a necessary component of stem cell therapies used to care for older individuals. Final, understanding the interactions between stalk cells and the niche may besides exist important for understanding tumor initiation, growth and metastasis. Emerging testify points toward the possibility that cancer cells either find, or induce, local stromal niches that can provide signals that enable cancer jail cell maintenance and/or growth. Targeting the signals and pathways that promote an contradistinct or expanded niche that supports the growth of tumor cells could provide another strategy to be used equally a potent anti-cancer therapeutic. In summary, future studies that reveal the central components of stem cell niches inside human tissues, in combination with bioengineering approaches to recreate niches in vitro, will rapidly accelerate the development of stem prison cell-based therapies and regenerative medicine.

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Pluripotent Stem Cells

D. Leanne Jones , Margaret T. Fuller , in Handbook of Stem Cells (Second Edition), 2013

Summary

Stem jail cell niches take been proposed to play a critical role in the maintenance of stalk cells in the male germ line, the hematopoietic organization, the epidermis, the intestinal epithelium, and the developed nervous system. Characterization of these stem cell niches depends on the ability to identify stalk cells in vivo in their normal environment. Through comparison of dissimilar stem cell systems, some themes emerge that indicate possible general characteristics of the human relationship between stalk cells and their supporting niche.

First, secreted factors elaborated by or induced by cells composing the stalk jail cell niche can office to direct stem jail cell fate decisions. However, the precise signaling pathway or pathways may be different for each stalk jail cell blazon and within each stem cell niche. Studies in Drosophila indicate that back up cells adjacent to stem cells secrete factors required for maintaining stem cell identity and for specifying stem cell self-renewal (reviewed by Spradling et al., 2001 and Lin, 2002). Both JAK-STAT signaling and TGF-β signaling have been implicated in the regulation of stem cell behavior by surrounding back up 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 betoken may be secreted from the stem cells themselves and may act in an autocrine loop to control stalk cell proliferation (Willert et al., 2003; Huelsken and Behrens, 2002). Wnt signaling may besides 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 unlike stem cell systems. In the mammalian epidermis, Wnt signaling is likely involved in specifying the fate of pilus 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). Zipper to niche cells or to a basal lamina may also exist important for stem cell maintenance within adult mammalian tissues, hence the loftier levels of the β1 integrin feature 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 β1 integrin in cells within the burl region of the outer root sheath severely dumb the proliferation of precursor cells that contributed to the interfollicular epidermis, pilus follicle, and sebaceous glands (Callahan and Oro, 2001). Thus, like to the role of adherens junctions in maintaining Drosophila GSCs in the niche, β1 integrin-mediated adhesion may exist required to concord multipotent epidermal stalk cells within the niche and close to self-renewal signals. In the mammalian testis, α6 integrin has been identified as a jail cell surface marker for the enrichment of spermatogonial stem cells, although a specific role for α6 integrin in spermatogonial stem cell maintenance has not yet been directly demonstrated (Kubota et al., 2005; Shinohara et al., 1999). Similarly, α6 integrin is expressed past basal keratinocytes in the epidermis; nonetheless, there is no strong correlation between α6 expression and proliferative potential (Reynolds and Jahoda, 1992). Therefore, although cell adhesion is frequently a conserved feature of stalk prison cell maintenance in supportive niches, the specific types of junctions and jail cell adhesion molecules that play roles may differ among unlike 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 stalk cells normally separate with invariant disproportion, the mitotic spindle is oriented to place the daughter cell that will retain stem cell identity within the stalk 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 sectionalization. This stereotyped division plane can in plow specify an disproportionate result to stem cell divisions, in which one daughter jail cell retains attachment to niche cells and the other is displaced out of the stem cell niche. As stalk cells are definitively identified in vivo, in the context of their normal back up jail cell microenvironment, it will be interesting to determine if stem cell divisions are also oriented in the seminiferous tubules, bone marrow, follicular burl, and intestinal crypts, inside neurogenic regions of the adult encephalon.

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Cloning and Stem Cells

David P. Clark , Nanette J. Pazdernik , in Biotechnology (2nd Edition), 2016

The Key Features of a Stalk Prison cell Niche

A stalk cell niche is a local microenvironment that direct promotes or protects a population of stem cells. There are two cardinal components to a stem cell niche, the microenvironment and the stem jail cell, and each of their functions relies on the other. The environment emits cues or signals to the stem cells that continue the cells from differentiating—that is, keeps the cells competent to develop into a variety of dissimilar cells. Some of these signals originate from cells that encase the niche, and in other cases, the extracellular matrix provide the cues. In improver, autocrine signals from the stem cell itself can keep the cells in their undifferentiated state (Fig. xviii.7). The stalk cells that stay encased in the niche provide a pool of cells that can be triggered to form the other cells of our body. If the stem prison 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 likewise many stem cells, leads to tumors. Therefore, proper niche function requires a residual, and there cannot be also many stem cells or too few.

FIGURE 18.vii. Stalk Cell Niche

The stalk cells found in a niche interact with the niche cells and the extracellular matrix. The stalk jail cell tin receive signals from both components via directly interactions (cell to cell or jail cell to matrix). Stem cells can also receive signals such as growth factors that are secreted from themselves (autocrine) or from the niche cells (paracrine). These signals demark to cell surface receptors and trigger the stem jail cell to stay undifferentiated.

The cells and extracellular matrix that brand up the environment depend on the type of stalk prison cell that they house. For example, the model organism C. elegans has a stem cell population that can generate more than oocytes or eggs for the worm (Fig. xviii.8). These stem cells are kept in a niche that is created by one single cell, called the distal tip prison cell, which caps the surface area and sends long processes or fibrils that surround the area. This single jail cell emits a signal that prevents the stem cells from becoming an egg. If this single cell is destroyed in any mode, the stem cells plough into eggs. If this single cell is moved to a different location, the nearby cells receiving its signals turn into stem cells.

FIGURE 18.viii. C. elegans Oocyte Stalk Cells Are Establish in a Defined Niche

The stalk cells responsible for creating more than oocytes for the C. elegans hermaphrodite are plant in a niche that is capped past a unmarried cell called the distal tip cell. This cell emits signals that activate the Notch signal transduction pathway, which in turn keeps the stalk cell from differentiation. As the stem cell moves away from the niche, the Notch signals fade, and then the cell enters into meiosis to form a haploid oocyte. As the stem cells divide, cells on the periphery of the niche are displaced and go out the range of the distal tip jail cell signals.

Stem cells contained within a niche frequently undergo disproportionate cell division to produce i daughter cell that differentiates and another daughter cell to maintain the stalk cell population. The signals that impact each of the two daughters are different, and tin can either arise from an intrinsic disproportion between the ii daughters or from an extrinsic asymmetry (Fig. 18.9). In an intrinsic asymmetry, ane girl cell receives a signaling molecule such every bit a protein, RNA, or macromolecule, and the other daughter jail cell does not. Depending on the office of the intrinsic signal, the girl cell that receives the molecule either stays a stem cell or differentiates. External asymmetries also bulldoze one daughter cell to differentiate and the other to stay a stem cell. For example, if the cell sectionalization pushes one of the daughters besides far from the niche and the signals that keep the stem jail cell from differentiating, then this daughter will start to differentiate. Another possibility is that the girl cell in the new surroundings may receive new signals that cause information technology to differentiate. There tin can also exist symmetrical renewal where stem cell partition creates two more stem cells. Additionally, a mitotic division can also produce two cells that differentiate. This process is termed symmetrical differentiation (Fig. xviii.10). If all the stem cells in a niche had symmetrical differentiations, the organism would run out of stem cells. On the other hand, if the stem cell e'er divided with symmetrical renewal, the niche would have also many stem cells, which is a scenario that resembles a cancer.

Effigy 18.9. Asymmetrical Cell Divisions Are due to Intrinsic or Extrinsic Asymmetries

(A) Stalk cells may have intrinsic factors such every bit proteins, RNA, or macromolecules that are sequestered unequally during prison cell division. The signaling factors tin either induce the recipient prison cell to differentiate or may keep the cell from differentiating, depending on their role. (B) Extrinsic signals from the niche often maintain cells in their stalk prison cell fate, and when the daughter moves to a new environs, the loss of the signal or the addition of a new indicate triggers this daughter to differentiate. The other cell remains in the same environment and therefore remains a stem cell.

Figure xviii.10. Stem Cell Divisions Can Be Symmetrical or Asymmetrical

(A) Stem cells divide asymmetrically supplying the niche with a replacement stem jail cell and the other jail cell that differentiates into a specialized prison cell. (B) Stalk cells divide symmetrically, either providing 2 new stalk cells (symmetrical renewal) or two cells to differentiate (symmetrical differentiation).

One primal component to keeping the stem prison cell in a niche is the adherence to the extracellular matrix (ECM). This involves anchoring the stem prison cell to the ECM through prison cell surface receptors such every bit Due east-cadherin. If this surface receptor is removed from germline or follicular stalk cells, these stalk cells rapidly go out the niche and differentiate. Eastward-cadherin mediates stem cell adhesion in the Drosophila testes stalk prison cell niche, in the neuronal stem cells of the encephalon region called the subventricular zone, and the stalk cell niche for creating blood cells.

Stalk jail cell niches are quite varied throughout the body and tin can be categorized by their brand-upward. Open stem cell niches have no geographical boundaries for the microenvironment and the stem cells. In the open diversity of niche, interaction between neighboring niches is common, where stem cells from one region tin can drift to another. Lineage analysis has adamant that stem cells from 1 location have the ability to migrate from their niche and populate neighboring niches. An example of stem cells institute in open up environments is the seminiferous tubules in mammals (Fig. 18.11). In contrast, closed stalk prison cell niches have stock-still boundaries that enclose the environment and stem cells. A closed niche is surrounded by an extracellular matrix or capped by cells that preclude the stem cells from leaving the area. In C. elegans, the stalk jail cell niche has a airtight surround capped by a distal tip cell. Stem cells tin leave the area in only one point, and differentiation begins upon exiting of the niche (see Fig. 18.8).

Effigy eighteen.11. Open up Stem Cell Niche of Seminiferous Tubules

The spermatogonial stem cells (green ovals with red dots) are found in an open niche situated betwixt Sertoli cells (purple cells) and a basement membrane (blue line).

 Figure used with permission from L'Hernault SW (2013). Spermatogonia. In Brenner'south Encyclopedia of Genetics, 2nd ed. (London, Britain: Academic Press), pp. 533–535.

Stem cells reside in niches, or microenvironments that provide cues or signals to keep the stem cells from differentiating into adult cells. Autocrine signals from the stem cells themselves, signals from niche cells, and signals from the extracellular matrix act together to maintain a pool of stalk cells to furnish the organ or tissue. The niche tin can be a closed area that is encased by a layer of cells or an open niche that is more than open to the remainder of the tissues. Stalk cells divide asymmetrically, providing one daughter jail cell to maintain the stem cell puddle and one daughter cell to differentiate. The signal to differentiate or stay a stem cell can originate from an intrinsic signal or extrinsic bespeak. Stem cells can also separate symmetrically, producing either 2 new stem cells or two girl cells that differentiate.

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Functional Glycomics

Swetlana Sirko , ... Andreas Faissner , in Methods in Enzymology, 2010

Abstract

The stem cell niche plays an of import function for the maintenance and differentiation of neural stem/progenitor cells (NSPCs). It is composed of singled-out cell types that influence NSCPs by the release of paracrine factors, and a specialized extracellular matrix that structures the NSPC environment. During the past years, several components of the neural stem cell (NSC) niche could exist deciphered on the molecular level. One prominent constituent is the tenascin-C (Tnc) glycoprotein and its isoforms that arbitrate in NSPC proliferation and differentiation. Singled-out chondroitin sulfate proteoglycans (CSPGs) associate with Tnc in the niche territory and we could show that these have functional connotations in the stem cell compartment in their own rights. In this affiliate, we give an account of the tools and methods we developed to unravel the structures and functions of CSPGs in the NSC niche.

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Part of mesenchymal stalk cells in bone fracture repair and regeneration

Yishan Chen , ... Xiaotian Du , in Mesenchymal Stem Cells in Homo Wellness and Diseases, 2020

Sources of mesenchymal stalk cells for bone regeneration

MSC niches, which maintain tissue homeostasis and breed stalk cell populations (Frenette et al., 2013), reside near the perivascular region, on the endosteal surfaces of trabecular bone, adjacent to the myofiber plasma membrane, or within the interfibrillary spaces (Via et al., 2012). MSCs have also been institute in umbilical cord claret (Lee et al., 2004), dental tissues (Liu et al., 2015), and synovial fluid (Sekiya et al., 2012). Moreover, MSCs could besides be differentiated from induced pluripotent stalk cells (iPSCs; Chen et al., 2012). Although the sources of MSCs are widespread in the human body (Wang et al., 2013), an ideal stem cell source should exist attainable through noninvasive methods, and cells should be expandable through in vitro culture. Likewise, the cells should survive and integrate well inside the host bone tissue after transplantation, while showing no tumorigenicity.

Bone marrow has been proved to exist a more suitable source of cells for fracture repair (Freitas et al., 2017). Bone marrow–derived stalk cells (BMSCs) have been used for nonunion gap treatment in orthopedic surgery for many years. BMSCs were institute to localize in areas of active bone formation within the endosteal callus in a mouse fracture model (Granero-Moltó et al., 2009). Just it is difficult to harvest MSCs from periosteum. MSCs of perivascular origin (pericytes) could exist easily obtained because of the widespread vessel walls throughout the torso. Some studies have investigated the roles of pericytes in bone healing (König et al., 2016; Tawonsawatruk et al., 2016). Pericytes accept the ability to generate osteoblasts in vitro and successfully contribute to bone regeneration. Muscle-derived stem cells (MDSCs) take been shown to be qualified for regenerating os in a critical size calvarial defect model (Gao et al., 2014); however, the harvest of MDSCs is difficult and the differentiation chapters of MDSCs is limited. Encouragingly, iPSCs offering an advantage over traditional MSCs, as they can exist generated from almost any type of tissue in the human trunk, and display an unlimited growth capacity (Hynes et al., 2013). iPSC-derived MSCs (iPSC-MSCs) acquire an osteoblast phenotype and assistance in bone regeneration without ectopic bone formation compared with BMSCs (Sheyn et al., 2016).

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Biologically Inspired and Biomolecular Materials

S.A. Kobel , M.P. Lutolf , in Comprehensive Biomaterials, 2011

2.209.ii The Adult Stem Cell and Its Niche

Stem prison cell niches are anatomically distinct, spatially restricted milieus that host and regulate stem cells. The niche concept was beginning postulated by Schofield on HSCs in the late 1970s. 12 However, experimental support came only 10   years later on with the in vivo label of germline stem cells (GSCs) niches in Drosophila, demonstrating that short-range signals from niche cells are essential for stem cell maintenance. 13 Afterward, mammalian niches were identified in most all tissues including the pare (in the bulge region of the hair follicle), the brain (in the subventricular zone), bone marrow (on the endosteal surface and near blood vessels), or muscle (beneath the basal lamina of the muscle fiber). Some of these niches take been discussed in detail elsewhere. 14–19

Although mammalian niches significantly vary in construction and composition, they share common features that are schematically depicted in Figure two(a) . Stalk cells in the niche are in shut concrete contact with niche cells and are either interacting with a basal lamina (east.g., in the muscle) or a highly hydrated, fibrillar network of ECM proteins and sugars (east.g., in os marrow). By far, the best-studied types of niche signals are soluble factors. Niche cells secrete cytokines, growth factors, and developmental morphogen proteins such as Wnt proteins, hedgehog proteins, fibroblast growth factors (FGFs), or bone morphogenetic proteins (BMPs). Many of these proteins are believed to bind to the ECM by electrostatic interactions, in detail via heparan sulfate proteoglycans. 20,21 ECM-immobilization could thus prevent rapid deposition, localize growth factor distribution to the niche, and assistance institute stable gradients of signaling molecules that could ascertain the size and polarity of a niche.

Figure 2. The niche of stalk cells and its command of stem cell behavior. (a) In vivo, adult stem cells are located in tissue-specific microenvironments with well-defined architecture that protect and regulate stem cells. The niche is composed of extracellular matrix components and other niche (support) cells that present a complex mixture of extrinsic cues. (b) A well-characterized niche of the germline stalk cells in the gonad of Drosophila, where distal tip cells (DTC, in greenish) are located at the bottom of an ECM-supported cavity and confine the stalk cells through cell adhesion molecules to the niche. Loss of contact with the DTC will induce differentiation of stem cells (in red). (c) Appropriately, in the niche, cells can remain quiescent, proliferate, or differentiate.

 Adapted with permission from Kobel, Due south.; Lutolf, Chiliad. P. BioTechniques 2010, 48, Ix–XXII; Morrison, S. J.; Kimble, J. Nature 2006, 441, 1068–1074. © 2006 Nature Publishing Group and 2010 BioTechniques.

Another signal type emanating from the niche is the cross-linked ECM. Besides keeping stem cells at the right place, the ECM likewise directly interacts with stem cells which express ECM protein-bounden receptors such every bit integrins. Indeed, most stem cell types express a well-defined fix of integrins, and are therefore sensitive to composition of the niche ECM. 22 For example, apart from many other receptors, HSCs limited the cell surface glycoprotein CD44 and the two integrins α4 and α5β1 that both demark to osteopontin, a glycoprotein specifically found in the ECM of the bone marrow. 23 The anchoring of stem cells to the ECM via integrins has a dual office. Start, adhesion molecules transmit physical forces to the interior of the stem cell by linking the ECM with the cytoskeleton. Through this interaction, cells can sense external forces or mechanical backdrop of the niche. 24–26 Second, integrins act equally specific ECM protein receptors that upon bounden induce intracellular signaling involved in regulating stem cell maintenance. Noteworthy, signals from growth factors and the ECM often synergistically regulate cell behavior, either by proximity furnishings on the jail cell membrane or by cross-talk in the downstream indicate transduction pathways. 20,27

A 3rd form of niche cues worth mentioning are direct prison cell–prison cell interactions via cell adhesion molecules (CAMs) and other transmembrane receptors involved in juxtacrine signaling between adjacent cells. These proteins are either integrated into the prison cell membrane via transmembrane domains or covalently bound to its lipids and, by providing a very localized signal, preclude migration of stalk cells. 22,28 The signaling via prison cell–cell interactions can be crucial for stem cell regulation equally exemplified in the Drosophila gonads ( Figure 2(b) ). In that location, the niche cells limited cadherins that tether the GSCs to the niche. As the niche is small and tin host only few stem cells, some daughter cells generated via cell division quickly lose contact with the niche and initiate oogenesis.

Although the behavior of stalk cells is not only influenced by the localized cues just described (the activation of HSCs is earlier for example, known to follow circadian rhythms 29 ), the complex interplay of niche signals is key to the maintenance of stem cells. Best bear witness for this is the loss of stalk cell part due to stem prison cell removal from the niche. Arguably, the prime function of the niche is to retain stem cells in a quiescent state, as developed stem cells in vivo are believed to be mostly quiescent. 30 However, the niche presumably also regulates 'fate decisions' that can occur during prison cell division ( Figure two(c) ). A self-renewing sectionalisation of a stem cell can either issue in two daughter cells acquiring equal stem jail cell fates, or in one daughter stem cell and ane daughter that has started to undergo the first steps toward differentiation. These self-renewing divisions are either chosen symmetric (with respect to the potential of the ii girl cells) or disproportionate. Although physical experimental proof for disproportionate divisions of mammalian adult stem cells is yet missing, these divisions are assumed to be induced by an asymmetric distribution of cell-intrinsic, fate-determining proteins (such as Numb or Par proteins 31 ), and/or past a polarized distribution of extrinsic cues which betrayal two equal daughter cells to a dissimilar cell-instructive microenvironment. Conspicuously, these prison cell fate decisions need to be tightly balanced in response to the physiological demands of a tissue, as insufficient self-renewal would deplete the stalk cell puddle over time, impairing tissue maintenance and regeneration, and an overproduction of stalk cells could lead to cancer.

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Cellular and Molecular Mechanotransduction in Bone

Julia C. Chen , ... Christopher R. Jacobs , in Osteoporosis (Fourth Edition), 2013

Mesenchymal Stem Cells

The stem prison cell niche in adult os contains a milieu of biochemical factors that regulate stalk cell beliefs, but very fiddling is known about the mechanical nature of the niche and how concrete stimuli touch stem cell mobilization. Mechanical loading activates new os formation on the endosteal and periosteal surfaces, and initiates intracortical remodeling. Nevertheless, the contribution of marrow-derived stalk cells to these processes is unclear. Compressive, tensile, and fluid-induced shear forces are nowadays in the marrow [105], and all likely bear on stem cell function. In addition, at that place are intracellular tensile forces resulting from cell–extracellular matrix (ECM) interactions at focal adhesions. Data advise that externally applied forces, as well as intracellular tensile forces, play a critical part in mesenchymal stem cell differentiation [106]. Several reports take demonstrated the ability of mechanical forces to influence fate decisions. For instance, hydrostatic pressure level 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].

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Development, Differentiation and Disease of the Para-Alimentary Tract

Houda Darwiche , Bryon E. Petersen , in Progress in Molecular Biological science and Translational Scientific discipline, 2010

II Canals of Hering: The Putative Oval Cell Niche

A stem cell niche is described as the cellular and extracellular microenvironment which supports stem cells and contributes to sustain self-renewal. 29 In fact, the interaction of stalk cells with other cell types in this microenvironment is thought to be essential for regulating stem cell maintenance, as a plethora of unlike types of signaling and adhesion molecules exist inside the niche. Indeed, the stem jail cell niche has been attributed functions such as (i) the maintenance of stalk cell quiescence and (two) the provision of proliferation or differentiation-inducing signals when numerous progenitor cells are required to give rise to transit-amplifying cells committed to producing mature cell lineages. 29–32

In the stem cell niches of many organs, that is, bone marrow, intestine, and brain, signaling pathways such equally Wnt, Notch, and Hedgehog role in concert. The presence of these signals is thought to regulate the maintenance of stem jail cell quiescence, to command proliferation, and to govern cell fate decisions. In particular, Notch and Wnt signals overlap to command the detailed pattern of jail cell fate choices as stem cells divide and give ascension to differentiated progeny. 32

The hepatic stem cell niche is thought to be in the biliary tree at the level of the Canals of Hering. As is the case with niches in other organs, it is composed of numerous cell types, including portal myofibroblasts, hepatic stellate cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells, and immune cells. Any of these cell types can collaborate and cross-talk with oval cells, thereby influencing their proliferative and differentiative capacities from within the niche itself. 33

Wnt secretion, whether autocrine or paracrine, is conspicuously involved in the stem jail cell response seen in mice, rodents, and humans. 34–36 Besides, Hedgehog signaling is essential for survival of progenitor cells, equally evidenced by the activation of the specific receptor Patched (PTC) expressed by progenitors. 37 Furthermore, inflammatory cells nowadays in response to injury are responsible for producing a range of cytokines and chemokines that could potentially influence the progenitor cell response to liver injury. 33 For example, T cells express a tumor necrosis gene (TNF)-like weak inducer of apoptosis (TWEAK) which can stimulate progenitor cell proliferation by engaging its specific receptor, Fn14. 38 Hepatic progenitors tin can also potentially be stimulated by other diverse components of the inflammatory response, such equally lymphotoxin-β, IFNγ, TNF-α, and fifty-fifty histamine. 38,39 Furthermore, information technology has been proposed that resistance to transforming growth cistron (TGF)-β, which under normal circumstances works to subtract proliferative capacity, allows progenitors to split nether conditions that would normally inhibit hepatocyte proliferation. xl

Recent research has also clarified the relationship between progenitor cells and hepatic stellate cells. 41–44 Stellate cells serve as a key source of growth factors, such as TGF-α, hepatocyte growth cistron (HGF), and acidic fibroblast growth factor (aFGF). Because of the wide console of molecular intermediates they may produce and secrete, particularly after their sustained activation in a disease land, hepatic stellate cells are definitely involved in various liver pathologies, in addition to their well-known role in fibrosis and extracellular matrix remodeling. Specifically, there appears to be an clan between the degree of hepatic injury, progenitor cell expansion, and fibrosis in many human liver diseases such as viral hepatitis, steatohepatitis, and principal biliary cirrhosis.

It is possible that stellate cells can exist activated directly by hepatic progenitors or that activated stellate cells could promote progenitor cell expansion and bulldoze their differentiation into mature lineages. Information technology is also feasible that activation of both cell types could occur separately only simultaneously, through similar mediators or stimuli. 45 A recent study using murine models indicates that hepatic progenitors need a support matrix, idea to be provided past stellate cells or myofibroblasts, to aid in migration and anchorage, every bit well as progenitor cell differentiation and repopulation of the damaged liver. 46

Moreover, studies performed in our laboratory have demonstrated that when activation of stellate cells was inhibited, the oval cell response to ii-aceytlaminofluorene (2AAF)–PH treatment was drastically reduced, equally determined past expression levels of OV-six and AFP. 44 These observations reinforce the theory that niche compounds play a key part in progenitor proliferation and differentiation. Farther studies are necessary in order to delineate the mechanisms for cross talk between progenitors, stellate cells, and the extracellular matrix in human liver diseases.

Maybe well-nigh significantly, there is piddling known about the functions of specific growth factors and hormones present in the stem prison cell niche during the expansion of hepatic progenitors. For example, numerous previous studies have demonstrated that cholangiocyte proliferation during liver injury can exist regulated by several factors such as steroid hormones (i.eastward., estrogens, progesterone), growth factors (i.eastward., insulin-like growth gene 1, IGF1; vascular endothelial growth cistron, VEGF), and neurotransmitters (i.e., acetylcholine). 47–49 Moreover, cholangiocytes have been shown to secrete both autocrine and paracrine factors that regulate proliferation as well as actuate fibrogenic response of portal myofibroblasts and hepatic stellate cells. Studies in our laboratory have shown that loss of such factors every bit SDF-1 and IGFBP-3, which are produced by stellate cells, can lead to loss of activation of the oval prison cell compartment. l,51 Furthermore, cholangiocytes might be able to undergo epithelial–mesenchymal transition and thereby increment the number of fibrogenic cells in the portal triad. 47

One of the key factors in determining the developmental potential of a stem prison cell is its environment. It has been demonstrated in a rat model that hematopoietic stem cells tin give rise to oval cells, which retain hematopoietic markers such as Thy-1 but also gain expression of liver-specific markers such as AFP. Hematopoietic stem cells obtained from developed peripheral blood retain a tremendous developmental plasticity. 7,10,23 Taken together, this indicates that hematopoietic stem cells and oval cells may share a common developmental origin or may even arise straight from the same cell.

The role of these substances in the regulation of the stalk cell niche, equally well as possible cross talk between the progenitors and cholangiocytes, need to be further elucidated. Understanding of the signaling pathways that regulate progenitor prison cell proliferation during the progression of liver diseases and/or injury could open up the possibility for the development of therapeutic strategies. The hepatic progenitor compartment could represent an of import target for new therapeutic approaches to liver diseases through a correct pharmacological modulation. Regardless of origin, all the same, all stalk cells execute their developmental programs by regulating gene expression. Determining which signals are responsible for such processes equally consecration of differentiation, self-renewal and/or maintenance of pluripotentiality volition pb to a better understanding of the biology of oval cells and their role in the liver.

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BMP Signaling and Stem Cell Self-Renewal in the Drosophila Ovary

Darin Dolezal , Francesca Pignoni , in Principles of Developmental Genetics (Second Edition), 2015

A GSC Division Yields a Renewed GSC and a Differentiating CB

The GSC niche tightly regulates the remainder between the self-renewing SCs and their differentiating progeny, thus its cellular composition remains adequately constant through most of the wing'due south lifespan. Two to three GSCs are positioned at the tip of each germarium where they are anchored to CCs via adherens junctions (Song et al., 2002). In a specialized disproportionate partitioning, a GSC gives rising to two daughter cells that accept different fates: a renewed SC and a differentiating CB (Figure 5.one). This division occurs along an axis that is more or less perpendicular to the CC:GSC interface (Morris and Spradling, 2011), resulting in the retentiveness of 1 daughter cell in direct contact with the CCs and the placement of the other daughter cell outside the niche, one cell bore away. Because CCs are a source of cocky-renewal factors, the old daughter cell continues to receive self-renewal signals and persists equally a stem cell, whereas the latter ceases to respond and begins instead to undergo differentiation (Song et al., 2004; Rex et al., 2001; Cox et al., 2000; Xie and Spradling, 1998). In this manner, a unmarried GSC segmentation event produces both a replacement GSC and a differentiating CB.

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