Ecdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiation

Previously, it has been shown that in Drosophila steroid hormones are required for progression of oogenesis during late stages of egg maturation. Here, we show that ecdysteroids regulate progression through the early steps of germ cell lineage. Upon ecdysone signalling deficit germline stem cell progeny delay to switch on a differentiation programme. This differentiation impediment is associated with reduced TGF-β signalling in the germline and increased levels of cell adhesion complexes and cytoskeletal proteins in somatic escort cells. A co-activator of the ecdysone receptor, Taiman is the spatially restricted regulator of the ecdysone signalling pathway in soma. Additionally, when ecdysone signalling is perturbed during the process of somatic stem cell niche establishment enlarged functional niches able to host additional stem cells are formed.     

Age-related changes of germline stem cell activity, niche signaling activity and egg production in Drosophila

Adult stem cells are important in replenishing aged cells to maintain tissue homeostasis. Aging in turn may exert profound effects on stem cell's regenerative potential, but to date the mechanisms of such stem cell aging are poorly understood, and it is not clear to what extent stem cell aging contributes to tissue or organ aging. Here we show in female Drosophila that germline stem cell (GSC) division rate progressively declines with age, which is accompanied by reduced decapentaplegic (dpp) niche signaling pathway activation within GSCs. Egg production also rapidly declines with age, which is accompanied by both decreased stem cell division and increased incidence of cell death of developing eggs, especially in the oldest females. Genetically increasing dpp expression delays GSC activity decline and transiently increases egg production. We conclude that age-related decline of reproduction is caused by both decreased GSC activity and increased incidence of cell death during oogenesis, while decreased GSC activity is attributed to declined signaling from the regulatory niche. We suggest that niche functional decay may be an important mechanism for stem cell aging and system failure.     

The Drosophila ovary: an active stem cell community

Only a small number of cells in adult tissues (the stem cells) possess the ability to self-renew at every cell division,while producing differentiating daughter cells to maintain tissue homeostasis for an organism's lifetime.The Drosophilaovary harbors three different types of stem cell populations (germline stem cell (GSC),somatic stem cell (SSC) andescort stem cell (ESC)) located in a simple anatomical structure known as germarium,rendering it one of the best modelsystems for studying stem cell biology due to reliable stem cell identification and available sophisticated genetic toolsfor manipulating gene functions.Particularly,the niche for the GSC is among the first and best studied ones,and studieson the GSC and its niche have made many unique contributions to a better understanding of relationships between stemcells and their niche.So far,both the GSC and the SSC have been shown to be regulated by extrinsic factors originatingfrom their niche and intrinsic factors functioning within.Multiple signaling pathways are required for controlling GSCand SSC self-renewal and differentiation,which provide unique opportunities to investigate how multiple signals fromthe niche are interpreted in the stem cell.Since the Drosophila ovary contains three types of stem cells,it also providesoutstanding opportunities to study how multiple stem cells in a given tissue work collaboratively to contribute to tissuefunction and maintenance.This review highlights recent major advances in studying Drosophila ovarian stem cells andalso discusses future directions and challenges.     

Nuclear lamina builds tissues from the stem cell niche

Recent studies show that nuclear lamins, the type V intermediate filament proteins, are required for proper building of at least some organs. As the major structural components of the nuclear lamina found underneath the inner nuclear membranes, lamins are ubiquitously expressed in all animal cells. How the broadly expressed lamins support the building of specific tissues is not understood. By studying Drosophila testis, we have uncovered a mechanism by which lamin-B functions in the cyst stem cell (CySC) and its differentiated cyst cell, the cell types known to form the niche/microenvironment for the germline stem cells (GSC) and the developing germ line, to ensure testis organogenesis ¹. In this extra view, we discuss some remaining questions and the implications of our findings in the understanding of how the ubiquitous nuclear lamina regulates tissue building in a context-dependent manner.     

Stem cell review series: aging of the skeletal muscle stem cell niche

Declining stem cell function during aging contributes to impaired tissue function. Muscle-specific stem cells ('satellite cells') are responsible for generating new muscle in response to injury in the adult. However, aged muscle displays a significant reduction in regenerative abilities and an increased susceptibility to age-related pathologies. This review describes components of the satellite cell niche and addresses how age-related changes in these components impinge on satellite cell function. In particular, we review changes in the key niche elements, the myofiber and the basal lamina that are in intimate contact with satellite cells. We address how these elements are influenced by factors secreted by interstitial cells, cells of the immune system, and cells associated with the vasculature, all of which change with age. In addition, we consider more distant sources of influence on the satellite cell niche that change with age, such as neural-mediated trophic factors and electrical activity and systemic factors present in the circulation. A better understanding of the niche elements and their influence on the satellite cell will facilitate the development of therapeutic interventions aimed at improving satellite cell activity and ultimately tissue response to injury in aged individuals.     

Notch信号通路与生殖干细胞研究进展

Notch信号通路是一个在进化中高度保守的信号通道,具有调控细胞增殖、分化及凋亡的作用。近年来,随着研究的不断深入,发现Notch信号通路与生殖干细胞的增殖分化及干细胞微环境的作用机理密切关联,Notch信号通路在生殖系统发育及疾病治疗中的作用机制逐渐引起人们的广泛关注。该文综合论述了Notch信号通路的生理特性及功能,重点阐述Notch信号通路在精原干细胞、卵巢生殖干细胞及生殖干细胞微环境系统中的调控机制。     

干细胞壁龛功能的研究进展

随着干细胞研究的不断深入,人们愈来愈重视干细胞在机体组织中的居住环境——壁龛(niche)对干细胞的影响。干细胞的增殖分化行为受其所处微环境的影响。干细胞壁龛通过与干细胞之间的直接和(或)间接作用影响干细胞的命运。壁龛成分——壁龛细胞、细胞外基质和来源于壁龛细胞的可溶性因子在维持干细胞的特征、调控干细胞数量等方面发挥重要作用。     

果蝇干细胞研究进展

本文主要介绍了果蝇五种干细胞,包括生殖干细胞、神经干细胞、造血干细胞、小肠干细胞、肾干细胞及其微环境（niche）的组成成份;简述了五种干细胞系统对应的分子标记;最后重点介绍了调控每种干细胞系统的信号通路。     

Multifaceted control of adult SVZ neurogenesis by the vascular niche

The subventricular zone is one of the 2 germinal niches of the adult brain where neural stem cells (NSC) generate new neurons and glia throughout life. NSC behavior is controlled by the integration of intrinsic signals and extrinsic cues provided by the surrounding microenvironment, or niche. Within the niche, the vasculature has emerged as a critical compartment, to which both neural stem cells and transit-amplifying progenitors are closely associated. A key function of the vasculature is to deliver blood-borne and secreted factors that promote proliferation and lineage progression of committed neural progenitors. We recently found that, in contrast to the established role of soluble cues, juxtacrine signals on vascular endothelial cells maintain neural stem cells in a quiescent and undifferentiated state through direct cell-cell interactions. In this perspective, we discuss how, through these apparently opposing signals, the vascular niche might coordinate stem cell decisions between maintenance and proliferation.     

三种果蝇精巢生殖干细胞半衰期的研究

果蝇精巢生殖干细胞(Germline stem cells,GSCs)的数量伴随衰老呈现递减趋势。本文以两种野生型果蝇品系Oregon、W1118以及Stat基因突变体的精巢为研究材料,采用免疫荧光染色技术,标记果蝇精巢Hub组织及生殖干细胞,研究了室温(25℃)条件下三种果蝇羽化后六个时间点(第1、15、30、45、60、75 d)精巢GSC的数量。结果表明,两种野生型Oregon、W1118与stat突变体果蝇羽化后第1 d的GSC平均数分别为8.55、8.60与8.15,根据曲线图得到,两种野生型果蝇GSCs半衰期均为60 d左右,而stat突变体果蝇约为30 d,两者存在显著差异,表明stat基因突变加速了果蝇精巢GSCs的衰老。     

Two-photon live imaging of single corneal stem cells reveals compartmentalized organization of the limbal niche

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Stem cells signal to the niche through the Notch pathway in the Drosophila ovary

Stem cells are maintained and retain their capacity to continue dividing because of the influence of a niche. Although niches are important to maintain "stemness" in a wide variety of tissues, control of these niches is poorly understood. The Drosophila germline stem cells (GSCs) reside in a somatic cell niche. We show that Notch activation can induce the expression of niche-cell markers even in an adult fly; overexpression of Delta in the germline, or activated Notch in the somatic cells, results in extra niche cells, up to 10-fold over the normal number. In turn, these ectopic niche cells induce ectopic GSCs. Conversely, when GCSs do not produce functional Notch ligands, Delta and Serrate, the TGF-beta pathway is not activated in the GSCs, and they differentiate and subsequently leave the niche. Importantly, clonal analysis reveals that the receiving end of the Notch pathway is required in the somatic cells. These data show that a feedback loop exists between the stem cells and niche cells. Demonstration that stem cells can contribute to niche function has far-reaching consequences for stem cell therapies and may provide insight into how cancer can spread throughout an organism via populations of cancer stem cells.     

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.     

Multicellular cuddling in a stem cell niche

Haematopoietic stem and progenitor cells (HSPCs) can self-renew and differentiate in any blood cell type throughout life and thereby sustain the entire blood system. To do so, HSPCs had been shown to seed, in a multi-step process, intermediate haematopoietic niches before colonizing the adult marrow. While HSPC birth had been thoroughly characterized in the past, both in mammals and in zebrafish, how perivascular niches could host HSPCs and sustain their expansion was poorly understood. In an article published in the last issue of Cell, Tamplin et al.¹ elegantly exploited the many advantages provided by the zebrafish embryo to describe how endothelium remodeling in the perivascular niche, referred to as “cuddling,” favors HSPCs colonization and expansion.     

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.     

Notch signaling controls germline stem cell niche formation in the Drosophila ovary

Stem cells, which can self-renew and generate differentiated cells, have been shown to be controlled by surrounding microenvironments or niches in several adult tissues. However, it remains largely unknown what constitutes a functional niche and how niche formation is controlled. In the Drosophila ovary, germline stem cells (GSCs), which are adjacent to cap cells and two other cell types, have been shown to be maintained in the niche. In this study, we show that Notch signaling controls formation and maintenance of the GSC niche and that cap cells help determine the niche size in the Drosophila ovary. Expanded Notch activation causes the formation of more cap cells and bigger niches, which support more GSCs, whereas compromising Notch signaling during niche formation decreases the cap cell number and niche size and consequently the GSC number. Furthermore, the niches located away from their normal location can still sufficiently sustain GSC self-renewal by maintaining high local BMP signaling and repressing bam as in normal GSCs. Finally, loss of Notch function in adults results in rapid loss of the GSC niche, including cap cells and thus GSCs. Our results indicate that Notch signaling is important for formation and maintenance of the GSC niche, and that cap cells help determine niche size and function.     

Stem cell therapy: an exercise in patience and prudence

In recent times, the epigenetic study of pluripotency based on cellular reprogramming techniques led to the creation of induced pluripotent stem cells. It has come to represent the forefront of a new wave of alternative therapeutic approaches in the field of stem cell therapy. Progress in drug development has saved countless lives, but there are numerous intractable diseases where curative treatment cannot be achieved through pharmacological intervention alone. Consequently, there has been an unfortunate rise in incidences of organ failures, degenerative disorders and cancers, hence novel therapeutic interventions are required. Stem cells have unique self-renewal and multilineage differentiation capabilities that could be harnessed for therapeutic purposes. Although a number of mature differentiated cells have been characterized in vitro, few have been demonstrated to function in a physiologically relevant context. Despite fervent levels of enthusiasm in the field, the reality is that other than the employment of haematopoietic stem cells, many other therapies have yet to be thoroughly proven for their therapeutic benefit and safety in application. This review shall focus on a discussion regarding the current status of stem cell therapy, the issues surrounding it and its future prospects with a general background on the regulatory networks underlying pluripotency.