Stem cell maintenance in shoot apical meristems

Stem cell homeostasis in shoot apical meristems of higher plants is regulated through a dynamic balance between spatial regulation of gene expression, cell growth patterns and patterns of differentiation. Cell-cell communication mediated by both the local factors and long-range signals have been implicated in stem cell homeostasis. Here we have reviewed recent developments on spatio-temporal regulation of cell-cell communication processes with an emphasis on how ubiquitously utilized signals such as plant hormones function with local factors in mediating stem cell homeostasis. We also provide a brief overview of how the activity of ubiquitously utilized epigenetic regulators are modulated locally to orchestrate gene expression.     

Shaping the niche: lessons from the Drosophila testis and other model systems

Stem cells are fascinating, as they supply the cells that construct our adult bodies and replenish, as we age, worn out, damaged, and diseased tissues. Stem cell regulation relies on intrinsic signals but also on inputs emanating from the neighbouring niche. The Drosophila testis provides an excellent system for studying such processes. Although recent advances have uncovered several signalling, cytoskeletal and other factors affecting niche homeostasis and testis differentiation, many aspects of niche regulation and maintenance remain unsolved. In this review, we discuss aspects of niche establishment and integrity not yet fully understood and we compare it to the current knowledge in other model systems such as vertebrates and plants. We also address specific questions on stem cell maintenance and niche regulation in the Drosophila testis under the control of Hox genes. Finally, we provide insights on the striking functional conservation of homologous genes in plants and animals and their respective stem cell niches. Elucidating conserved mechanisms of stem cell control in both lineages could reveal the importance underlying this conservation and justify the evolutionary pressure to adapt homologous molecules for performing the same task.     

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.     

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.     

An amuse-bouche of stem cell regulation: Underlying principles and mechanisms from adult Drosophila intestinal stem cells

Stem cells have essential functions in the development and maintenance of our organs. Improper regulation of adult stem cells and tissue homeostasis can result in cancers and age-dependent decline. Therefore, understanding how tissue-specific stem cells can accurately renew tissues is an important aim of regenerative medicine. The Drosophila midgut harbors multipotent adult stem cells that are essential to renew the gut in homeostatic conditions and upon stress-induced regeneration. It is now a widely used model system to decipher regulatory mechanisms of stem cell biology. Here, we review recent findings on how adult intestinal stem cells differentiate, interact with their environment, and change during aging.     

Requirement of matrix metalloproteinase-1 for intestinal homeostasis in the adult Drosophila midgut

Stem cells are tightly regulated by both intrinsic and extrinsic signals as well as the extracellular matrix (ECM) for tissue homeostasis and regenerative capacity. Matrix metalloproteinases (MMPs), proteolytic enzymes, modulate the turnover of numerous substrates, including cytokine precursors, growth factors, and ECM molecules. However, the roles of MMPs in the regulation of adult stem cells are poorly understood. In the present study, we utilize the Drosophila midgut, which is an excellent model system for studying stem cell biology, to show that Mmp1 is involved in the regulation of intestinal stem cells (ISCs). The results showed that Mmp1 is expressed in the adult midgut and that its expression increases with age and with exposure to oxidative stress. Mmp1 knockdown or Timp-overexpressing flies and flies heterozygous for a viable, hypomorphic Mmp1 allele increased ISC proliferation in the gut, as shown by staining with an anti-phospho-histone H3 antibody and BrdU incorporation assays. Reduced Mmp1 levels induced intestinal hyperplasia, and the Mmp1depletion-induced ISC proliferation was rescued by the suppression of the EGFR signaling pathway, suggesting that Mmp1 regulates ISC proliferation through the EGFR signaling pathway. Furthermore, adult gut-specific knockdown and whole-animal heterozygotes of Mmp1 increased additively sensitivity to paraquat-induced oxidative stress and shortened lifespan. Our data suggest that Drosophila Mmp1 is involved in the regulation of ISC proliferation for maintenance of gut homeostasis.     

Skin stem cells: rising to the surface

The skin epidermis and its appendages provide a protective barrier that is impermeable to harmful microbes and also prevents dehydration. To perform their functions while being confronted with the physicochemical traumas of the environment, these tissues undergo continual rejuvenation through homeostasis, and, in addition, they must be primed to undergo wound repair in response to injury. The skin's elixir for maintaining tissue homeostasis, regenerating hair, and repairing the epidermis after injury is its stem cells, which reside in the adult hair follicle, sebaceous gland, and epidermis. Stem cells have the remarkable capacity to both self-perpetuate and also give rise to the differentiating cells that constitute one or more tissues. In recent years, scientists have begun to uncover the properties of skin stem cells and unravel the mysteries underlying their remarkable capacity to perform these feats. In this paper, I outline the basic lineages of the skin epithelia and review some of the major findings about mammalian skin epithelial stem cells that have emerged in the past five years.     

Plant stem cells and their regulations in shoot apical meristems

Stem cells in plants, established during embryogenesis, are located in the centers of the shoot apical meristem (SAM) and the root apical meristem (RAM). Stem cells in SAM have a capacity to renew themselves and to produce new organs and tissues indefinitely. Although fully differentiated organs such as leaves do not contain stem cells, cells in such organs do have the capacity to re-establish new stem cells, especially under the induction of phytohormones in vitro. Cytokinin and auxin are critical in creating position signals in the SAM to maintain the stem cell organizing center and to position the new organ primordia, respectively. This review addresses the distinct features of plant stem cells and focuses on how stem cell renewal and differentiation are regulated in SAMs.     

Upregulation of mitochondrial function and antioxidant defense in the differentiation of stem cells

Stem cell research has received increasing attention due to their invaluable potentials in the clinical applications to cure degenerative diseases, genetic disorders and even cancers. A great number of studies have been conducted with an aim to elucidate the molecular mechanisms involved in the regulation of self-renewal of stem cells and the mysterious circuits guiding them to differentiate into all kinds of progenies that can replenish the cell pools. However, little effort has been made in studying the metabolic aspects of stem cells. Mitochondria play essential roles in mammalian cells in the generation of ATP, Ca²⁺ homeostasis, compartmentalization of biosynthetic pathways and execution of apoptosis. Considering the metabolic roles of mitochondria, they must be also critical in stem cells. This review is primarily focused on the biogenesis and bioenergetic function of mitochondria in the differentiation process and metabolic features of stem cells. In addition, the involvement of reactive oxygen species and hypoxic signals in the regulation of stem cell pluripotency and differentiation is also discussed.     

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.     

Mesenchymal stem cells from development to postnatal joint homeostasis, aging, and disease

Joint morphogenesis involves signaling pathways and growth factors that recur in the adult life with less redundancy to safeguard joint homeostasis. Loss of such homeostasis due to abnormal signaling networks as in aging could lead to diseases such as osteoarthritis. Stem cells are the cellular counterpart and targets of the morphogenetic signals, and they function to maintain the tissues by ensuring replacement of cells lost to physiological turnover, injury, aging, and disease. Mesenchymal stem cells (MSCs) are key players in regenerative medicine for their ability to differentiate toward multiple lineages such as cartilage and bone, but they age along the host body and senesce when serially passaged in culture. Understanding correlations between aging and its effects on MSCs is of the utmost importance to explain how aging happens and unravel the underlying mechanisms. The investigation of the MSC senescence in culture will help in developing more efficient and standardized cell culture methods for cellular therapies in skeletal regenerative medicine. An important area to explore in biomedical sciences is the role of endogenous stem cell niches in joint homeostasis, remodeling, and disease. It is anticipated that an understanding of the stem cell niches and related remodeling signals will allow the development of pharmacological interventions to support effective joint tissue regeneration, to restore joint homeostasis, and to prevent osteoarthritis.     

Mechanosensitive channels and their functions in stem cell differentiation

Stem cells continuously perceive and respond to various environmental signals during development, tissue homeostasis, and pathological conditions. Mechanical force, one of the fundamental signals in the physical world, plays a vital role in the regulation of multiple functions of stem cells. The importance of cell adhesion to the extracellular matrix (ECM), cell-cell junctions, and a mechanoresponsive cell cytoskeleton has been under intensive study in the fields of stem cell biology and mechanobiology. However, the involvement of mechanosensitive (MS) ion channels in the mechanical regulation of stem cell activity has just begun to be realized. Here, we review the diversity and importance of mechanosensitive channels (MSCs), and discuss recently discovered functions of MSCs in stem cell regulation, especially in the determination of cell fate.     

Mesenchymal to epithelial transition during tissue homeostasis and regeneration: Patching up the Drosophila midgut epithelium

Stem cells are responsible for preserving morphology and function of adult tissues. Stem cells divide to self-renew and to generate progenitor cells to sustain cell demand from the tissue throughout the organism''s life. Unlike stem cells, the progenitor cells have limited proliferation potential but have the capacity to terminally differentiate and thereby to substitute older or damaged mature cells. Recent findings indicate that adult stem cells can adapt their division kinetics dynamically to match changes in tissue demand during homeostasis and regeneration. However, cell turnover not only requires stem cell division but also needs timed differentiation of the progenitor cells, which has been much less explored. In this Extra View article, we discuss the ability of progenitor cells to actively postpone terminal differentiation in the absence of a local demand and how tissue demand activates terminal differentiation via a conserved mesenchymal-epithelial transition program revealed in our recent EMBO J paper and other published and unpublished data. The extent of the significance of these results is discussed for models of tissue dynamics during both homeostasis and regeneration.     

From gut to glutes: The critical role of niche signals in the maintenance and renewal of adult stem cells

Stem cell behavior is tightly regulated by spatiotemporal signaling from the niche, which is a four-dimensional microenvironment that can instruct stem cells to remain quiescent, self-renew, proliferate, or differentiate. In this review, we discuss recent advances in understanding the signaling cues provided by the stem cell niche in two contrasting adult tissues, the rapidly cycling intestinal epithelium and the slowly renewing skeletal muscle. Drawing comparisons between these two systems, we discuss the effects of niche-derived growth factors and signaling molecules, metabolic cues, the extracellular matrix and biomechanical cues, and immune signals on stem cells. We also discuss the influence of the niche in defining stem cell identity and function in both normal and pathophysiologic states.     

Mesenchymal to epithelial transition during tissue homeostasis and regeneration: Patching up the Drosophila midgut epithelium

Stem cells are responsible for preserving morphology and function of adult tissues. Stem cells divide to self-renew and to generate progenitor cells to sustain cell demand from the tissue throughout the organism's life. Unlike stem cells, the progenitor cells have limited proliferation potential but have the capacity to terminally differentiate and thereby to substitute older or damaged mature cells. Recent findings indicate that adult stem cells can adapt their division kinetics dynamically to match changes in tissue demand during homeostasis and regeneration. However, cell turnover not only requires stem cell division but also needs timed differentiation of the progenitor cells, which has been much less explored. In this Extra View article, we discuss the ability of progenitor cells to actively postpone terminal differentiation in the absence of a local demand and how tissue demand activates terminal differentiation via a conserved mesenchymal-epithelial transition program revealed in our recent EMBO J paper and other published and unpublished data. The extent of the significance of these results is discussed for models of tissue dynamics during both homeostasis and regeneration.     

Hair follicle stem cells as a skin‐organizing signaling center during adult homeostasis

Stem cells are the essential source of building blocks for tissue homeostasis and regeneration. Their behavior is dictated by both cell‐intrinsic cues and extrinsic cues from the microenvironment, known as the stem cell niche. Interestingly, recent work began to demonstrate that hair follicle stem cells (HFSCs) are not only passive recipients of signals from the surroundings, but also actively send out signals to modulate the organization and function of their own niches. Here, we discuss recent findings, and briefly refer to the old, on the interaction of HFSCs and their niches with the emphasis on the outwards signals from HFSCs toward their niches. We also highlight recent technology advancements that further promote our understanding of HFSC niches. Taken together, the HFSCs emerge as a skin‐organizing center rich in signaling output for niche remodeling during various stages of adult skin homeostasis. The intricate crosstalk between HFSCs and their niches adds important insight to skin biology that will inform clinical and bioengineering fields aiming to build complete and functional 3D organotypic cultures for skin replacement therapies.     

Stem cell niches in mammals

Stem cells safeguard tissue homeostasis and guarantee tissue repair throughout life. The decision between self-renewal and differentiation is influenced by a specialized microenvironment called stem cell niche. Physical and molecular interactions with niche cells and orientation of the cleavage plane during stem cell mitosis control the balance between symmetric and asymmetric division of stem cells. Here we highlight recent progress made on the anatomical and molecular characterization of mammalian stem cell niches, focusing particularly on bone marrow, tooth and hair follicle. The knowledge of the regulation of stem cells within their niches in health and disease will be instrumental to develop novel therapies that target stem cell niches to achieve tissue repair and re-establish tissue homeostasis.     

The stem-cell niche theory: lessons from flies

Stem cells are characterized by their ability to self-renew and to produce numerous differentiated cell types, and are directly responsible for generating and maintaining tissues and organs. This property has long been attributed to the instructive signals that stem cells receive from their microenvironment - the so-called 'stem-cell niche'. Studies of stem cells in the Drosophila gonad have yielded much exciting insight into the structure of the niche and the signalling pathways that it produces to regulate the self-renewal of stem cells. These findings are illuminating our understanding of the self-renewing mechanisms of tissue stem cells in general.     

Molecular mechanisms controlling germline and somatic stem cells: similarities and differences

Germline and somatic stem cells are distinct types of stem cells that are dedicated to reproduction and somatic tissue homeostasis, respectively. Extensive studies on these two stem cell types in different organisms over the past few years have revealed some commonalities in the mechanisms controlling their self-renewal and differentiation. Furthermore, germline or somatic cells in various organisms and sexes also exhibit their own unique ways of regulating stem cell function. By understanding these similarities and differences we might gain a better insight into how stem cells are regulated in general and how germline and somatic stem cell types are regulated differently.