An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement

Adult epithelial stem cells are thought to reside in specific niches, where they are maintained by adhesion to stromal cells and by intercellular signals. In niches that harbor multiple adjacent stem cells, such as those maintaining Drosophila germ cells, lost stem cells are replaced by division of neighboring stem cells or reversion of transit cells. We have characterized the Drosophila follicle stem cell (FSC) niche as a model of the epithelial niche to learn whether nonneighboring cells can also generate stem cell replacements. Exactly two stroma-free FSC niches holding single FSCs are located in fixed locations on opposite edges of the Drosophila ovariole. FSC daughters regularly migrate across the width of the ovariole to the other niche before proliferating and contributing to the follicle cell monolayer. Crossmigrating FSC daughters compete with the resident FSC for niche occupancy and are the source of replacement FSCs. The ability of stem cell daughters to target a distant niche and displace its resident stem cell suggests that precancerous mutations might spread from niche to niche within stem cell-based tissues.     

Anchoring stem cells in the niche by cell adhesion molecules

Adult stem cells generally reside in supporting local micro environments or niches, and intimate stem cell and niche association is critical for their long-term maintenance and function. Recent studies in model organisms especially Drosophila have started to unveil the underlying mechanisms of stem anchorage in the niche at the molecular and cellular level. Two types of cell adhesion molecules are emerging as essential players: cadherin-mediated cell adhesion for keeping stem cells within stromal niches, whereas integrin-mediated cell adhesion for keeping stem cells within epidermal niches. Further understanding stem cell anchorage and release in coupling with environmental changes should provide further insights into homeostasis control in tissues that harbor stem cells.Key words: stem cell, niche, anchorage, cell adhesion, extracellular matrix, cadherin, integrinTissue-specific adult stem cells are characterized by their prolonged self-renewal ability and potentiality to differentiate into one or more types of mature cells. These unique properties make stem cells essential for maintaining tissue homeostasis throughout life. It is generally believed that all adult stem cells reside in specific microenvironments named niches, which provide physical support and produce critical signals to maintain stem cell identity and govern their behavior.^1–4 Consequently, intimate stem cell and niche association is a pre-requisite for stem cell''s long-term maintenance and function. How stem cells are kept within the niche is thus an important issue in stem cell biology. Characterization of a number of stem cell niches in model organisms has led to the classification of niches into two general types: stromal niches where stem cells have direct membrane contact with the niche cells and epidermal niches where stem cells are usually associated with the extracellular matrix (ECM), and do not directly contact any fixed stromal cells.¹ Studies in Drosophila have led to the cellular and functional verification of the stem cell niche theory^5,6 and not surprisingly, have also led to the discovery of the molecular mechanisms anchoring stem cells to the niche. Here I consider recent studies in Drosophila on types of cell adhesions used to anchor stem cells in the niches, and summarize cell adhesion molecules utilized in the most characterized niches in the mammalian tissues, and suggest that cadherin-mediated cell-to-cell adhesion and integrin-mediated cell-to-ECM adhesion are possibly two general mechanisms that function in respective stromal or epidermal niches for stem cell anchorage in diverse organisms.     

干细胞巢研究进展

干细胞巢即干细胞周围的微环境构成,一般包括干细胞的相邻细胞、粘附分子及基质等,但不同的干细胞有不同的巢结构。干细胞巢通过不同信号途径调控着干细胞的行为,使干细胞的自我更新和分化处于平衡状态。根据近年来有关干细胞巢的研究,本文从果蝇生殖系干细胞巢、哺乳动物造血干细胞巢、肠干细胞巢、毛囊表皮干细胞巢和神经干细胞巢等五个系统分别综述了干细胞巢的构成及其对干细胞的调节作用,探讨了干细胞巢作用于干细胞的内在机制。     

Stem cells and niches: mechanisms that promote stem cell maintenance throughout life

Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.     

Tooth,hair and claw: Comparing epithelial stem cell niches of ectodermal appendages

The vertebrate ectoderm gives rise to organs that produce mineralized or keratinized substances, including teeth, hair, and claws. Most of these ectodermal derivatives grow continuously throughout the animal?s life and have active pools of adult stem cells that generate all the necessary cell types. These organs provide powerful systems for understanding the mechanisms that enable stem cells to regenerate or renew ectodermally derived tissues, and remarkable progress in our understanding of these systems has been made in recent years using mouse models. We briefly compare what is known about stem cells and their niches in incisors, hair follicles, and claws, and we examine expression of Gli1 as a potential example of a shared stem cell marker. We summarize some of the features, structures, and functions of the stem cell niches in these ectodermal derivatives; definition of the basic elements of the stem cell niches in these organs will provide guiding principles for identification and characterization of the niche in similar systems.     

No place like home: anatomy and function of the stem cell niche

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.     

Plant and animal stem cells: conceptually similar, molecularly distinct?

Animals and plants maintain small pools of stem cells that continuously provide the precursors of more-specialized cells to sustain growth or to replace tissues. A comparison of plant and animal stem cells can highlight core aspects of stem-cell biology. In both types of organism, stem cells are maintained by intercellular signals that are available only in defined regions (niches) in the tissues. Although plants use different signals and are more flexible at establishing stem-cell niches in new locations, recent evidence suggests that the mechanisms restricting cell fate in stem-cell progeny are similar in both kingdoms and might pre-date the evolution of multicellular organisms.     

Identification of the endostyle as a stem cell niche in a colonial chordate

Stem cell populations exist in "niches" that hold them and regulate their fate decisions. Identification and characterization of these niches is essential for understanding stem cell maintenance and tissue regeneration. Here we report on the identification of a novel stem cell niche in Botryllus schlosseri, a colonial urochordate with high stem cell-mediated developmental activities. Using in vivo cell labeling, engraftment, confocal microscopy, and time-lapse imaging, we have identified cells with stemness capabilities in the anterior ventral region of the Botryllus' endostyle. These cells proliferate and migrate to regenerating organs in developing buds and buds of chimeric partners but do not contribute to the germ line. When cells are transplanted from the endostyle region, they contribute to tissue development and induce long-term chimerism in allogeneic tissues. In contrast, cells from other Botryllus' regions do not show comparable stemness capabilities. Cumulatively, these results define the Botryllus' endostyle region as an adult somatic stem cell niche.     

CNS regeneration: a morphogen's tale

Tissue regeneration will soon become an avenue for repair of damaged or diseased tissues as stem cell niches have been found in almost every organ of the vertebrate body including the CNS. In addition, different animals display an array of regenerative capabilities that are currently being researched to dissect the molecular mechanisms involved. This review concentrates on the different ways in which CNS tissues such as brain, spinal cord and retina can regenerate or display neurogenic potential and how these abilities are modulated by morphogens.     

Extracellular matrix: A dynamic microenvironment for stem cell niche

Background

Extracellular matrix (ECM) is a dynamic and complex environment characterized by biophysical, mechanical and biochemical properties specific for each tissue and able to regulate cell behavior. Stem cells have a key role in the maintenance and regeneration of tissues and they are located in a specific microenvironment, defined as niche.

Scope of review

We overview the progresses that have been made in elucidating stem cell niches and discuss the mechanisms by which ECM affects stem cell behavior. We also summarize the current tools and experimental models for studying ECM–stem cell interactions.

Major conclusions

ECM represents an essential player in stem cell niche, since it can directly or indirectly modulate the maintenance, proliferation, self-renewal and differentiation of stem cells. Several ECM molecules play regulatory functions for different types of stem cells, and based on its molecular composition the ECM can be deposited and finely tuned for providing the most appropriate niche for stem cells in the various tissues. Engineered biomaterials able to mimic the in vivo characteristics of stem cell niche provide suitable in vitro tools for dissecting the different roles exerted by the ECM and its molecular components on stem cell behavior.

General significance

ECM is a key component of stem cell niches and is involved in various aspects of stem cell behavior, thus having a major impact on tissue homeostasis and regeneration under physiological and pathological conditions. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.     

Ultrastructure of the putative stem cell niche in rat mammary epithelium

There is now strong evidence that the stem cells of many tissues reside in specialized structures termed niches. The stem cell niche functions to house and regulate symmetric and asymmetric mitosis of stem cells in mammalian skin, mouse and human bone marrow, mouse brain, gut, and hair follicle, and Drosophila ovary and testis. This regulation is effected through the action of various signaling pathways such as Notch, Hedgehog, Wnt and others. The hormones of the estrous cycle, pregnancy and lactation that initiate growth in mouse mammary epithelium appear to act at a paracrine level to regulate mitosis through Notch receptors. Previous work has established that the putative stem cells of the mammary epithelium in several animal species reside near the basement membrane and never make contact with the ductal lumen. We show that these putative stem cells are found in anatomically specialized places created by the cytoplasmic extensions and modifications of neighboring differentiated cells. Such specializations may help to regulate stem cell activity by modulating molecular traffic to putative stem cells and contact with signaling molecules in the basement membrane. The histological characteristics of these putative niches vary as to the kinds of relationships the cells can have with the basement membrane and neighboring cells and as to how many stem or progenitor cells they may contain. This suggests a plasticity that may be relevant to the response of niches to tissue demands, such as wound healing, the periodic growth and regression of mammary epithelium, the process of mammary tumorigenesis therapeutic strategies for breast cancer.     

Breaking out of the mold: diversity within adult stem cells and their niches

During the past several years, it has become increasingly possible to study adult stem cells in their native territories within tissues. These studies have provided new evidence for the existence of stem cells in the breast, muscle, lung and kidney and have led to a deeper understanding of the best-known stem cells in Drosophila and mice. Tissue stem cells are turning out to be diverse, with varying division rates, lineage lengths, and mechanisms of regulation. In addition, stem cells are now known to engage in a wide variety of interactions with neighboring cells and extracellular matrices, and to respond to various neural and hormonal signals. Stem cell niches are also diverse, sometimes harboring multiple stem cell types. Internally, a stem cell's chromatin and cytoskeletal organization play key roles. Understanding how stem cells and their progeny are controlled will illuminate fundamental biological mechanisms that govern the construction and maintenance of tissues within metazoan animals.     

Loss of stem cell regenerative capacity within aged niches

This work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post-natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs.     

The stem cell potential of glia: lessons from reactive gliosis

Astrocyte-like cells, which act as stem cells in the adult brain, reside in a few restricted stem cell niches. However, following brain injury, glia outside these niches acquire or reactivate stem cell potential as part of reactive gliosis. Recent studies have begun to uncover the molecular pathways involved in this process. A comparison of molecular pathways activated after injury with those involved in the normal neural stem cell niches highlights strategies that could overcome the inhibition of neurogenesis outside the stem cell niche and instruct parenchymal glia towards a neurogenic fate. This new view on reactive glia therefore suggests a widespread endogenous source of cells with stem cell potential, which might potentially be harnessed for local repair strategies.     

The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals

The stem cell niches at the apex of Drosophila ovaries and testes have been viewed as distinct in two major respects. While both contain germline stem cells, the testis niche also contains "cyst progenitor" stem cells, which divide to produce somatic cells that encase developing germ cells. Moreover, while both niches utilize BMP signaling, the testis niche requires a key JAK/STAT signal. We now show, by lineage marking, that the ovarian niche also contains a second type of stem cell. These "escort stem cells" morphologically resemble testis cyst progenitor cells and their daughters encase developing cysts before undergoing apoptosis at the time of follicle formation. In addition, we show that JAK/STAT signaling also plays a critical role in ovarian niche function, and acts within escort cells. These observations reveal striking similarities in the stem cell niches of male and female gonads, and suggest that they are largely governed by common mechanisms.     

Local signaling within stem cell niches: insights from Drosophila

Tissue stem cells are found in specialized microenvironments (niches) where they are exposed to diverse systemic and local signals that are integrated with cell intrinsic factors to regulate stem cell behavior. In general, systemic signals are utilized to coordinate the response of tissues to acute or long-term changes that affect the whole organism, such as variations in nutrient availability or aging. In contrast, local signaling regulates tissue maintenance by balancing stem cell self-renewal with differentiation under homeostatic conditions and in response to local damage. In this review, we highlight the role of the JAK-STAT pathway in two Drosophila stem cell systems, the testis and intestine, and compare and contrast how activation of this pathway leads to tissue maintenance under both homeostatic conditions and in response to stress or injury.     

Plant stem cell niches

Stem cells are required to support the indeterminate growth style of plants. Meristems are a plants stem cell niches that foster stem cell survival and the production of descendants destined for differentiation. In shoot meristems, stem cell fate is decided at the populational level. The size of the stem cell domain at the meristem tip depends on signals that are exchanged with cells of the organizing centre underneath. In root meristems, individual stem cells are controlled by direct interaction with cells of the quiescent centre that lie in the immediate neighbourhood. Analysis of the interactions and signaling processes in the stem cell niches has delivered some insights into the molecules that are involved and revealed that the two major niches for plant stem cells are more similar than anticipated.     

Cellular and molecular attributes of neural stem cell niches in adult zebrafish brain

Adult neurogenesis is a complex, presumably conserved phenomenon in vertebrates with a broad range of variations regarding neural progenitor/stem cell niches, cellular composition of these niches, migratory patterns of progenitors and so forth among different species. Current understanding of the reasons underlying the inter‐species differences in adult neurogenic potential, the identification and characterization of various neural progenitors, characterization of the permissive environment of neural stem cell niches and other important aspects of adult neurogenesis is insufficient. In the last decade, zebrafish has emerged as a very useful model for addressing these questions. In this review, we have discussed the present knowledge regarding the neural stem cell niches in adult zebrafish brain as well as their cellular and molecular attributes. We have also highlighted their similarities and differences with other vertebrate species. In the end, we shed light on some of the known intrinsic and extrinsic factors that are assumed to regulate the neurogenic process in adult zebrafish brain. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1188–1205, 2017