Contrasting mechanisms of stem cell maintenance in Drosophila

Stem cells are self-renewing multipotent cells essential for development or homeostasis of many tissues. Stem cell populations can be found in most multicellular plants and animals. The mechanisms by which these populations are maintained are diverse, utilizing both intrinsic and extrinsic factors to regulate cell division and differentiation. The genetic tools of the fruitfly, Drosophila melanogaster, have permitted detailed characterization of two stem cell populations. In this review, we will examine these contrasting stem cell model systems from Drosophila and their relevance to stem cell populations in other organisms.     

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.     

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.     

EvoRegen in animals: Time to uncover deep conservation or convergence of adult stem cell evolution and regenerative processes

How do animals regenerate specialised tissues or their entire body after a traumatic injury, how has this ability evolved and what are the genetic and cellular components underpinning this remarkable feat? While some progress has been made in understanding mechanisms, relatively little is known about the evolution of regenerative ability. Which elements of regeneration are due to lineage specific evolutionary novelties or have deeply conserved roots within the Metazoa remains an open question. The renaissance in regeneration research, fuelled by the development of modern functional and comparative genomics, now enable us to gain a detailed understanding of both the mechanisms and evolutionary forces underpinning regeneration in diverse animal phyla. Here we review existing and emerging model systems, with the focus on invertebrates, for studying regeneration. We summarize findings across these taxa that tell us something about the evolution of adult stem cell types that fuel regeneration and the growing evidence that many highly regenerative animals harbor adult stem cells with a gene expression profile that overlaps with germline stem cells. We propose a framework in which regenerative ability broadly evolves through changes in the extent to which stem cells generated through embryogenesis are maintained into the adult life history.     

A review of insect stem cell types

Insect stem cells have been described from both embryonic and adult tissues from a diversity of insect species, although much of the focus in insect stem cell research has been on Drosophila. Insects are a vast and diverse group and it is surprising that a critical aspect of their development like stem cells has not received more attention. In this review we discuss the current state of knowledge of insect stem cell types. We examine what stem cell types have been identified from insects, and briefly discuss what is known about their regulation.     

Stem cells in the embryonic cerebral cortex: Their role in histogenesis and patterning

The cytoarchitectural simplicity of the cerebral cortex makes it an attractive system to study central nervous system (CNS) histogenesis—the process whereby diverse cells are generated in the right numbers at the appropriate place and time. Recently, multipotent stem cells have been implicated in this process, as progenitor cells for diverse types of cortical neurons and glia. Continuous analysis of stem cell clone development reveals stereotyped division patterns within their lineage trees, highly reminiscent of neural lineage trees in arthropods and Caenorhabditis elegans. Given that these division patterns play a critical part in generating diverse neural types in invertebrates, we speculate that they play a similar role in the cortex. Because stereotyped lineage trees can be observed from cells growing at clonal density, cell-intrinsic factors are likely to have a key role in stem cell behavior. Cortical stem cells also respond to environmental signals to alter the types of cells they generate, providing the means for feedback regulation on the germinal zone. Evidence is accumulating that cortical stem cells, influenced by intrinsic programs and environmental signals, actually change with development—for example, by reducing the number and types of neurons they produce. Age-related changes in the stem cell population may have a critical role in orchestrating development; whether these cells truly self-renew is a point of discussion. In summary, we propose that cortical stem cells are the focus of regulatory mechanisms central to the development of the cortical cytoarchitecture. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 162–174, 1998     

The stem cell niche: theme and variations

Stem cells in animal tissues are often located and controlled by special tissue microenvironments known as niches. Studies of stem cell niches in model systems such as Drosophila have revealed adhesive interactions, cell cycle modifications and intercellular signals that operate to control stem cell behavior. Candidate niches and regulatory molecules have also been identified in many mammalian tissues, including bone marrow, skin, gut and brain. While niches are an ancient evolutionary device with conserved features across diverse organisms, we suggest that certain niches display important differences in their organization and function.     

The stem cell niche: lessons from the Drosophila testis

In metazoans, tissue maintenance and regeneration depend on adult stem cells, which are characterized by their ability to self-renew and generate differentiating progeny in response to the needs of the tissues in which they reside. In the Drosophila testis, germline and somatic stem cells are housed together in a common niche, where they are regulated by local signals, epigenetic mechanisms and systemic factors. These stem cell populations in the Drosophila testis have the unique advantage of being easy to identify and manipulate, and hence much progress has been made in understanding how this niche operates. Here, we summarize recent work on stem cells in the adult Drosophila testis and discuss the remarkable ability of these stem cells to respond to change within the niche.     

Subversion of phosphoinositide metabolism by intracellular bacterial pathogens

Phosphoinositides are short-lived lipids, whose production at specific membrane locations in the cell enables the tightly controlled recruitment or activation of diverse cellular effectors involved in processes such as cell motility or phagocytosis. Bacterial pathogens have evolved molecular mechanisms to subvert phosphoinositide metabolism in host cells, promoting (or blocking) their internalization into target tissues, and/or modifying the maturation fate of their proliferating compartments within the intracellular environment.     

A quantitative and dynamic model for plant stem cell regulation

Plants maintain pools of totipotent stem cells throughout their entire life. These stem cells are embedded within specialized tissues called meristems, which form the growing points of the organism. The shoot apical meristem of the reference plant Arabidopsis thaliana is subdivided into several distinct domains, which execute diverse biological functions, such as tissue organization, cell-proliferation and differentiation. The number of cells required for growth and organ formation changes over the course of a plants life, while the structure of the meristem remains remarkably constant. Thus, regulatory systems must be in place, which allow for an adaptation of cell proliferation within the shoot apical meristem, while maintaining the organization at the tissue level. To advance our understanding of this dynamic tissue behavior, we measured domain sizes as well as cell division rates of the shoot apical meristem under various environmental conditions, which cause adaptations in meristem size. Based on our results we developed a mathematical model to explain the observed changes by a cell pool size dependent regulation of cell proliferation and differentiation, which is able to correctly predict CLV3 and WUS over-expression phenotypes. While the model shows stem cell homeostasis under constant growth conditions, it predicts a variation in stem cell number under changing conditions. Consistent with our experimental data this behavior is correlated with variations in cell proliferation. Therefore, we investigate different signaling mechanisms, which could stabilize stem cell number despite variations in cell proliferation. Our results shed light onto the dynamic constraints of stem cell pool maintenance in the shoot apical meristem of Arabidopsis in different environmental conditions and developmental states.     

Slicing across kingdoms: regeneration in plants and animals

Multicellular organisms possessing relatively long life spans are subjected to diverse, constant, and often intense intrinsic and extrinsic challenges to their survival. Animal and plant tissues wear out as part of normal physiological functions and can be lost to predators, disease, and injury. Both kingdoms survive this wide variety of insults by strategies that include the maintenance of adult stem cells or the induction of stem cell potential in differentiated cells. Repatterning mechanisms often deploy embryonic genes, but the question remains in both plants and animals whether regeneration invokes embryogenesis, generic patterning mechanisms, or unique circuitry comprised of well-established patterning genes.     

Human parthenogenetic embryonic stem cells: one potential resource for cell therapy

Pluripotent stem cells derived from somatic cells through such processes as nuclear transfer or induced pluripotent stem (iPS) cells present an important model for biomedical research and provide potential resources for cell replacement therapies. However, the overall efficiency of the conversional nuclear transfer is very low and the safety issue remains a major concern for iPS cells. Embryonic stem cells (ESCs) generated from parthenogenetic embryos are one attractive alternative as a source of histocompatible cells and tissues for cell therapy. Recent studies on human parthenogenetic embryonic stem cells (hPG ESCs) have revealed that these ESCs are very similar to the hESCs derived from IVF or in vivo produced blastocysts in gene expression and other characteristics, but full differentiation and development potential of these hPG ESCs have to be further investigated before clinical research and therapeutic interventions. To generate various pluripotent stem cells, diverse reprogramming techniques and approaches will be developed and integrated. This may help elucidate the fundamental mechanisms underlying reprogramming and stem cell biology, and ultimately benefit cell therapy and regenerative medicine. Supported by the National High Technology Research and Development Program of China (Grant No. 2006AA02A101).     

Developmental Changes in the in Vitro Activated Regenerative Activity of Primitive Mammary Epithelial Cells

Many normal adult tissues contain rare stem cells with extensive self-maintaining regenerative potential. During development, the stem cells of the hematopoietic and neural systems undergo intrinsically specified changes in their self-renewal potential. In the mouse, mammary stem cells with transplantable regenerative activity are first detectable a few days before birth. They share some phenotypic properties with their adult counterparts but are enriched in a subpopulation that displays a distinct gene expression profile. Here we show that fetal mammary epithelial cells have a greater direct and inducible growth potential than their adult counterparts. The latter feature is revealed in a novel culture system that enables large numbers of in vitro clonogenic progenitors as well as mammary stem cells with serially transplantable activity to be produced within 7 days from single fetal or adult input cells. We further show that these responses are highly dependent on novel factors produced by fibroblasts. These findings provide new avenues for elucidating mechanisms that regulate normal mammary epithelial stem cell properties at the single-cell level, how these change during development, and how their perturbation may contribute to transformation.     

Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.