Development and homeostasis of the haematopoietic system is dependent upon stem cells that have the unique ability to both self‐renew and to differentiate in all cell lineages of the blood. The crucial decision between haematopoietic stem cell (HSC) self‐renewal and differentiation must be tightly controlled. Ultimately, this choice is regulated by the integration of intrinsic signals together with extrinsic cues provided by an exclusive microenvironment, the so‐called haematopoietic niche. Although the haematopoietic system of vertebrates has (...) been studied extensively for many decades, the specification of the HSC niche and its signals involved are poorly understood. Much of our current knowledge of how niches regulate long‐term maintenance of stem cells is derived from studies on Drosophila germ cells. Now, two recently published studies by Mandal et al.1 and Krezmien et al.2 describe the Drosophila haematopoietic niche and signal transduction pathways that are involved in the maintenance of haematopoietic precursors. Both reports emphasize several features that are important for controlling stem cell behavior and show parallels to both the vertebrate haematopoietic niche as well as the Drosophila germline stem cell niches in ovary and testis. The findings of both papers shed new light on the specific interactions between haematopoietic progenitors and their microenvironment. BioEssays 29:713–716, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Inflamm‐aging is a relatively new terminology used to describe the age‐related increase in the systemic pro‐inflammatory status of humans. Here, we represent inflamm‐aging as a breakdown in the multi‐shell cytokine network, in which stem cells and stromal fibroblasts (referred to as the stem cell niche) become pro‐inflammatory cytokine over‐expressing cells due to the accumulation of DNA damage. Inflamm‐aging self‐propagates owing to the capability of pro‐inflammatory cytokines to ignite the DNA‐damage response in other cells surrounding DNA‐damaged cells. (...) Macrophages, the major cellular player in inflamm‐aging, amplify the phenomenon, by broadcasting pro‐inflammatory signals at both local and systemic levels. On the basis of this, we propose that inflamm‐aging is a major contributor to the increase in cancer incidence and progression in aged people. Breast cancer will be presented as a paradigmatic example for this relationship. (shrink)

Wnt signalling through β‐catenin plays a pivotal role during embryonic pattern formation, cell fate determination and tissue homeostasis in the adult organism. In the skin, as in many other tissues, Wnt/β‐catenin signalling can control lineage determination and differentiation. However, it was not known whether Wnt/β‐catenin signalling is an immediate regulator of the stem cell niche in skin tissue. A recent publication now provides evidence that Wnt/β‐catenin signalling exerts a direct effect on the stem cell (...) compartment by inducing quiescent stem cells to enter the cell cycle during early stages of hair follicle regeneration. In addition, the authors demonstrate that β‐catenin is required for maintenance of the stem cell pool in the tissue.1 The data suggest that a gradient in Wnt/β‐catenin activity levels can induce different responses within distinct cell populations reflected by activation of distinct transcriptional profiles. BioEssays 28:1–5, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Two recent publications highlight the role of bone‐forming cells, the osteoblasts, in controlling the development of neighboring haematopoietic stem cells (HSCs).1,2 Using two distinct transgenic mouse models, one using the conditional deletion of the Bone Morphogenetic Protein Receptor 1A (BMPR1A) gene, the other using over‐expression of an active PTH/PTHrP receptor (PPR) mutant within osteoblasts, the authors show parallel, concordant increases in the generation of trabecular osteoblasts and the number of HSCs. In situ staining showed that rarely cycling HSCs sporadically (...) attach to endosteal osteoblasts, while in vitro assays indicated that ligation of Jag1 on osteoblasts by Notch1 on HSCs promotes HSC proliferation. These two independent works have revived and revitalized the notion that osteoblasts are a major, defining component of the HSC niche within the bone marrow (BM). This minireview discusses these results in the context of other recent studies of mesenchymal cells within the BM microenvironment, presents one potential unified model of the functional anatomy of the BM HSC niche, and highlights new questions raised by these and other studies of osteoblasts and HSCs. BioEssays 26:595–599, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. (...) Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo‐SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies. (shrink)

The behavior of somatic stem cells is regulated by their niche. Interaction between hematopoietic stem cells (HSCs) and their niches are a representative model to understand stem cell‐niche interplay. Here, we provide an overview of crosstalk between HSCs and their niches in bone marrow and extramedullary organs following the life journey of HSCs from emergence, development, maturation until aging. We highlight the unique differences of HSC niches in different life stages within various organs focusing (...) on recent literature to propose new speculations and hypotheses. (shrink)

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically (...) dynamic at quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings. (shrink)

I investigate the intrinsic/extrinsic nature of stemness in muscle stem cells (MSC) by relying on recent research on quiescence, with the aim of shedding light on the nature of dispositions and deriving some consequences about stem cells. First, I argue why the study of quiescence is the best available way to establish any claim about the intrinsicness/extrinsicness of stemness at least is some stem cells. Drawing on that, I argue that MSC’s stem capacities result from the (...) combination of intrinsic cues plus extrinsic factors from the stem cell niche, making stemness an extrinsic disposition in MSC. Importantly, it is shown that the niche allows the instantiation of stemness in MSC by acting as a masker of its manifestation. This shows that stemness is, at least in MSC, what I call an extrinsically structurally masked disposition (SMD); that is, a disposition whose instantiation requires, as a condition of possibility, the interaction between the bearer and a masker. Finally, I conclude by suggesting some potential consequences of this observation for the philosophical study of dispositions and for stem cell research. (shrink)

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non‐endosteal perisinusoidal niche. Single‐cell molecular profiling (...) and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor‐making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast‐chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell‐like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation. (shrink)

Stem cells and their malignant counterparts require the support of a specific microenvironment or “niche”. While various anti‐cancer therapies have been broadly successful, there are growing opportunities to target the environment in which these cells reside to further improve therapeutic efficacy and outcome. This is particularly true when the aim is to target normal or malignant stem cells. The field aiming to target or use the niches that harbor, protect, and support stem cells could be designated (...) as “nichotherapy”. In this essay, we provide a few examples of nichotherapies. Some have been employed for decades, such as hematopoietic stem cell mobilization, whereas others are emerging, such as chemosensitization of leukemia stem cells by targeting their niche. (shrink)

Given their heterogeneity and lack of defining markers, it is surprising that multipotent mesenchymal stem/stromal cells (MSCs) have attracted so much translational attention, especially as increasing evidence points to their predominant effect being not by donor differentiation but via paracrine mediators and exosomes. Achieving long-term MSC donor chimerism for treatment of chronic disease remains a challenge, requiring enhanced MSC homing/engraftment properties and manipulation of niches to direct MSC behaviour. Meanwhile advances in nanoparticle technology are furthering the development of MSCs (...) as vehicles for targeted drug delivery. For treatment of acute injuries, systemic cell-free exosome delivery may ultimately displace current emphasis on empiric donor-cell transplantation for anti-inflammatory, immunomodulatory and repair-promoting effects. Exploration of potential clinical sources of MSCs has led to increased utilisation of perinatal MSCs in allogeneic clinical trials, reflecting their ease of collection and developmentally advantageous properties. (shrink)

Adult stem cell populations must coordinate their own maintenance with the generation of differentiated cell types to sustain organ physiology, in a spatially controlled manner and over long periods. Quantitative analyses of clonal dynamics have revealed that, in epithelia, homeostasis is achieved at the population rather than at the single stem cell level, suggesting that feedback mechanisms coordinate stem cell maintenance and progeny generation. In the central nervous system, however, little is known of (...) the possible community processes underlying neural stem cell maintenance. Recent work, in part based on intravital imaging made possible in the adult zebrafish, conclusively highlights that homeostasis in neural stem cell pools may rely on population asymmetry and long‐term spatiotemporal coordination of neural stem cell states and fates. These results suggest that neural stem cell assemblies in the vertebrate brain behave as self‐organized systems, such that the stem cells themselves generate their own intrinsic niche. (shrink)

Neural Stem Cells (NSC) are present in the developing and adult CNS. In both the embryonic and adult neurogenic regions, β1 integrins may act as sensors for the changing extracellular matrix. Here we highlight the integrative functions that β1 integrins may play in the “niche” by regulating NSC growth factor responsiveness in a timely and spatially controlled manner. β1 integrins may provide NSC with the capacity to react to a dynamic “niche”, and to respond adequately by either (...) remaining as stem cells or by differentiating and migrating away to shape the developing cortex. © 2005 Wiley Periodicals, Inc. BioEssays 27:698–707, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and (...) is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. (shrink)

Previous work has suggested that many stem cells can be found in microanatomic niches, where adjacent somatic cells of the niche control the differentiation and proliferation states of their resident stem cells. Recently published work examining intestinal stem cells (ISCs) in the adult Drosophila midgut suggests a new paradigm where some stem cells actively control the cell fate decisions of their daughters. Here, we review recent literature(1) demonstrating that, in the absence of a detectable (...) stem cell niche, multipotent Drosophila ISCs modulate the Notch signaling pathway in their adjacent daughter cells in order to specify the differentiated lineages of their descendants. These observations made in Drosophila are challenging and advancing our understanding of stem cell biology. BioEssays 30:107–109, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an (...) anti‐tumourigenic mechanism. We describe how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

Epithelial stem cells have been identified in integumental structures such as hairs and continuously growing teeth of various rodents, and in the gut. Here we propose the involvement of epithelial stem cells in the continuous tooth replacement that characterizes non‐mammalian vertebrates, as exemplified by the zebrafish. Arguments are based on morphological observations of tooth renewal in the zebrafish and on the similarities between molecular control of hair and tooth formation. Dissection of the molecular cascades underlying the regulation of (...) the epithelial stem cell niche might open perspectives for new regenerative treatment strategies in clinical dentistry. BioEssays 26:665–671, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In (...) particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine. (shrink)

Stem cell self renewal, maintenance and differentiation are influenced by the convergence of intrinsic cellular signals and extrinsic microenvironmental cues from the surrounding stem cell niche. However, the specific signals involved are often still poorly understood. This is also true for skin epithelial stem cells. Recently, by transcriptionally profiling of embryonic hair progenitors in mice, Rhee et al.1 have managed to define how murine hair follicle epithelial stem cells are specified and maintained in (...) an undifferentiated state. These authors have identified Lhx2 as a transcription factor functionally positioned downstream of signals necessary to specify hair follicle stem cells such as p63 or NFκB, but upstream of signals like Wnt/β‐catenin, Bmp or Shh that are required to drive activated stem cells via the production of transient amplifying cells into terminal differentiation. BioEssays 28: 1157–1160, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory (...) pathways specifically in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. (shrink)

Unraveling molecular and functional heterogeneity of niche cells within the developing endoderm could resolve mechanisms of tissue formation and maturation. Here, we discuss current unknowns in molecular mechanisms underlying key developmental events in pancreatic islet and intestinal epithelial formation. Recent breakthroughs in single‐cell and spatial transcriptomics, paralleled with functional studies in vitro, reveal that specialized mesenchymal subtypes drive the formation and maturation of pancreatic endocrine cells and islets via local interactions with epithelium, neurons, and microvessels. Analogous to this, (...) distinct intestinal niche cells regulate both epithelial development and homeostasis throughout life. We propose how this knowledge can be used to progress research in the human context using pluripotent stem cell‐derived multilineage organoids. Overall, understanding the interactions between the multitude of microenvironmental cells and how they drive tissue development and function could help us make more therapeutically relevant in vitro models. (shrink)

Once hematopoiesis is established in the bone marrow, a continuous egress of hematopoietic stem cells (HSCs) to the periphery occurs at a low frequency. It has been proposed that this phenomenon is part of a regenerative homeostatic mechanism that ensures the maintenance of hematopoiesis through the life of the individual. The administration of certain cytotoxic drugs or cytokines can enhance the mobilization of hematopoietic progenitors to the periphery. During the past 15 years, granulocyte‐colony stimulating factor (G‐CSF) has been used (...) as a standard cytokine for mobilization protocols in experimental models and in humans. Despite extensive efforts by multiple groups, a definitive mechanism explaining its role in mobilization has not been provided. In a recent paper, Katayama et al.,1 through a series of clever associations supported by well‐defined experimental systems, proposed that signals through the sympathetic nervous system modify the activity of the hematopoietic niche, acting as regulators of the mobilization of hematopoietic progenitors. This surprising finding adds a new level of complexity to the cellular milieu responsible for generation and maintenance of the hematopoietic niche. BioEssays 28: 687–691, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Clinical success with human hematopoietic stem cell (HSC) transplantation establishes a paradigm for regenerative therapies with other types of stem cells. However, it remains generally challenging to therapeutically treat tissues after engineering of stem cells in vitro. Recent studies suggest that stem and progenitor cells sense physical features of their niches. Here, we review biophysical contributions to lineage decisions, maturation, and trafficking of blood and immune cells. Polarized cellular contractility and nuclear rheology are separately shown (...) to be functional markers of a hematopoietic hierarchy that predict the ability of a lineage to traffic in and out of the bone marrow niche. These biophysical determinants are regulated by a set of structural molecules, including cytoplasmic myosin‐II and nuclear lamins, which themselves are modulated by a diverse range of transcriptional and post‐translational mechanisms. Small molecules that target these mechanobiological circuits, along with novel bioengineering methods, could prove broadly useful in programming blood and immune cells for therapies ranging from blood transfusions to immune attack of tumors. (shrink)

Understanding in vivo regeneration of complex structures offers a fascinating perspective for translation into medical applications. Unfortunately, mammals in general lack large‐scale regenerative capacity, whereas planarians, newts or Hydra can regenerate complete body parts. Such organisms are, however, poorly annotated because of the lack of sequence information. This leads to limited access for molecular biological investigations. In the last decade, high throughput technologies and new methods enabling the effective generation of transgenic animals have rapidly evolved. These developments have allowed the (...) extensive use of niche model organisms as part of a trend towards the accessibility of a greater panel of model species for scientific research. The case study that follows provides an insight into the impact of high throughput techniques on the landscape of models of regeneration. The cases presented here give evidence of alternative stem cell maintenance pathways, the identification of new protein families and new stem cell markers. (shrink)

We recently discovered a novel subset of beta cells that resemble immature beta cells during pancreas development. We named these “virgin” beta cells as they do not stem from existing mature beta cells. Virgin beta cells are found exclusively at the islet periphery in areas that we therefore designated as the “neogenic niche.” As beta cells are our only source of insulin, their loss leads to diabetes. Islets also contain glucagon‐producing alpha cells and somatostatin‐producing delta cells, that are (...) important for glucose homeostasis and form a mantle surrounding the beta cell core. This 3D architecture is important and determines access to blood flow and innervation. We propose that the distinctive islet architecture may also play an important, but hitherto unappreciated role in generation of new endocrine cells, including beta cells. We discuss several predictions to further test the contribution of the neogenic niche to beta cell regeneration. (shrink)

In the adult mammalian brain, neurogenesis is restricted to few regions, while gliogenesis continues in a wide‐spread manner. Here we discuss our knowledge of extrinsic and intrinsic factors regulating neuro‐ and gliogenesis in the adult brain and propose a model of fate specification identifying the states of easiest transition between glio‐ and neurogenesis, highlighting the unique mechanisms stabilising the neural stem cell state. The model also encompasses the fate alterations achieved by direct reprogramming, and hence addresses a novel (...) avenue for repair, namely eliciting neurogenesis from glial cells outside the neurogenic niches. (shrink)

Parallels between cancer and ecological systems have been increasingly recognized and extensively reviewed. However, a more unified framework of understanding cancer as an evolving dynamical system that undergoes a sequence of interconnected changes over time, from a dormant microtumor to disseminated metastatic disease, still needs to be developed. Here, we focus on several examples of such mechanisms, namely, how in cancer niche construction a metabolic adaptation and consequent change to the tumor microenvironment becomes an important factor in evasion of (...) the predator, facilitating disease progression; how tumor establishment and propagation is driven by the tumor’s own keystone species, the cancer stem cells; and how the succession of stages of metastatic dissemination can be informed by ergodic theory and forest ecology. (shrink)

In this paper, we apply the perspective of intra-organismal ecology by investigating a family of ecological models suitable to describe a gene therapy to a particular metabolic disorder, the adenosine deaminase deficiency (ADA-SCID). The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the chosen order (a choice (...) that cannot be made on \textit{a priori} assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intra-organismal ecology. (shrink)

Bone‐marrow mesenchymal stem cell (BM‐MSC) proliferation and lineage commitment are under the coordinated control of metabolism and epigenetics; the MSC niche contains low oxygen, which is an important determinant of the cellular metabolic state. In turn, metabolism drives stem cell fate decisions via alterations of the chromatin landscape. Due to the fundamental role of BM‐MSCs in the development of adipose tissue, bones and cartilage, age‐associated changes in metabolism and the epigenome perturb the balance between (...) class='Hi'>stem cell proliferation and differentiation leading to stem cell depletion, fat accumulation and bone‐quality related diseases. Therefore, understanding the dynamics of the metabolism‐chromatin interplay is crucial for maintaining the stem cell pool and delaying the development and progression of ageing. This review summarizes the current knowledge on the role of metabolism in stem cell identity and highlights the impact of the metabolic inputs on the epigenome, with regards to stemness and pluripotency. (shrink)

Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non‐hematopoietic cells that contribute to stem cell dormancy, quiescence, self‐renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady‐state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and (...) disease, the spleen as an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes. (shrink)

During postembryonic development, all organs of a plant are ultimately derived from a few pluripotent stem cells found in specialized structures called apical meristems. Here we discuss our current knowledge about the regulation of plant stem cells and their environments with main emphasis on the shoot apical meristem of Arabidopsis thaliana. Recent studies suggest that stem cells are localized in specialized niches where signals from surrounding cells maintain their undifferentiated state. In the shoot meristem, initiation of (...) class='Hi'>stem cells during embryogenesis, regulation of stem‐cell homeostasis and termination of stem‐cell maintenance during flower development appear to primarily involve regulation of the stem‐cell niche. BioEssays 25:961–970, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Ramathal et al. have employed an elegant xenotransplantation technique to study the fate of human induced pluripotent stem cells (hiPSCs) from fertile males and from males carrying Y chromosome deletions of the azoospermia factor (AZF) region. When placed in a mouse testis niche, hiPSCs from fertile males differentiate into germ cell‐like cells (GCLCs). Highlighting the crucial role of cell autonomous factors in male sterility, hiPSCs derived from azoospermic males prove to be less successful under similar circumstances. (...) Their studies argue that the agametic “Sertoli cell only” phenotype of two of the AZF deletions likely arises from a defect in the maintenance of germline stem cells (GSCs) rather than from a defect in their specification. These observations underscore the importance of the dialogue between the somatic niche and its inhabitant stem cells, and open up interesting questions concerning the functioning of the somatic niche and how it communicates to the GSCs. (shrink)

The primitive streak establishes the antero‐posterior body axis in all amniote species. It is thought to be the conduit through which mesoderm and endoderm progenitors ingress and migrate to their ultimate destinations. Despite its importance, the streak remains poorly defined and one of the most enigmatic structures of the animal kingdom. In particular, the posterior end of the primitive streak has not been satisfactorily identified in any species. Unexpectedly, and contrary to prevailing notions, recent evidence suggests that the murine posterior (...) primitive streak extends beyond the embryo proper. In its extraembryonic site, the streak creates a node‐like cell reservoir from which the allantois, a universal caudal appendage of all amniotes and the future umbilical cord of placental mammals, emerges. This new insight into the fetal/umbilical relationship may explain the etiology of a large number of umbilical‐associated birth defects, many of which are correlated with abnormalities of the embryonic midline. (shrink)

Once regarded as cellular ‘debris’ extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor (...) receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. (shrink)

If stem cell-based therapies are developed, we will likely confront a difficult problem of justice: for biological reasons alone, the new therapies might benefit only a limited range of patients. In fact, they might benefit primarily white Americans, thereby exacerbating long-standing differences in health and health care.

Stem cell research has entered the public consciousness through the media. Proponents and opponents of all such research, or of human embryonic stem cell research specifically, engage in heated exchanges in the modern public forum where stakeholders negotiate, the agora. One common claim that emerges from the fray is that a particular type of stem cell research should be pursued as the most promising path toward the reduction of suffering and untimely death for all (...) of humanity. Upon evaluation, experimental data regarding the potential role of stem cells in regenerative therapies for three conditions—spinal cord injury, type 1 diabetes, and cardiovascular disease—tell distinct, complex, and inconclusive stories. Further analyses in this article incorporate realistic considerations of a broad range of relevant factors--limited funding for biomedical research, media motives, the discordance hypothesis of evolutionary medicine, the relationship between religion and science, medical care in developing nations, and culture wars over abortion. Holistic investigation inspired by the current agora conversation supports the need to drastically change interactions regarding stem cell research so that its potential to benefit humanity may be more fully realized. (shrink)

While the clinical promise of much stem cell research remains largely theoretical, patients are nonetheless pursuing unproven stem cell therapies in jurisdictions around the world—a phenomenon referred to as “stem cell tourism.” These treatments are generally advertised on a direct-to-consumer basis via the Internet. Research shows portrayals of stem cell medicine on such websites are overly optimistic and the claims made are unsubstantiated by published evidence. However, anecdotal evidence suggests that parents are (...) pursing these “treatments” for their children, despite potential physical and financial risk. Physicians are in a unique position as they can be expected to be involved in, or privy to, such decisions. In this paper, we consider what duties physicians may have toward minor patients whose parents/guardians wish to engage in stem cell tourism on their behalf. We use the Canadian perspective to address the broadly relevant issues raised by this trend. (shrink)

Skeletal muscle stem cells or satellite cells are responsible for muscle regeneration in the adult. Although satellite cells are highly resistant to stress, and display greater capacity to repair molecular damage than the committed progeny, their regenerative potential declines with age. During ageing, satellite cells switch to a state of permanent cell cycle arrest or senescence which prevents their activation. A recent study reveals that the senescence of satellite cell relies on defective autophagy, the quality control mechanism (...) that degrades damaged proteins and organelles. Molecular damage is generated by oxidative stress that also promotes epigenetic changes that activate the expression of master genes, in a double‐hit mechanism that ensures senescence. Importantly, genetic, and pharmacological correction of defective autophagy reverses satellite cell senescence and restores muscle regeneration in geriatric mice, with perspectives of modulating age‐related functional decline of muscle. This study provides new clues to understand stem cell and organismal ageing. (shrink)

A new therapeutic strategy could break the stalemate in the war on cancer by targeting not all cancerous cells but the small fraction that lie at the root of cancers. Lucie Laplane offers a comprehensive analysis of cancer stem cell theory, based on an original interdisciplinary approach that combines biology, biomedical history, and philosophy.

Self‐renewal and differentiation of stem cells are tightly regulated processes subject to intrinsic and extrinsic signals. Molecular chaperones and co‐chaperones, especially heat shock proteins (Hsp), are ubiquitous molecules involved in the modulation of protein conformational and complexation states. The function of Hsp, which are typically associated with stress response and tolerance, is well characterized in differentiated cells, while their role in stem cells remains unclear. It appears that embryonic stem cells exhibit increased stress tolerance and concomitant high (...) levels of chaperone expression. This review critically evaluates stem cell research from a molecular chaperone perspective. Furthermore, we propose a model of chaperone‐modulated self‐renewal in mouse embryonic stem cells. (shrink)

Ontologies of living things are increasingly grounded on the concepts and practices of current life science. Biological development is a process, undergone by living things, which begins with a single cell and (in an important class of cases) ends with formation of a multicellular organism. The process of development is thus prima facie central for ideas about biological individuality and organismality. However, recent accounts of these concepts do not engage developmental biology. This paper aims to fill the gap, proposing (...) the lineage view of stem cells as an ontological framework for conceptualizing organismal development. This account is grounded on experimental practices of stem cell research, with emphasis on new techniques for generating biological organization in vitro. On the lineage view, a stem cell is the starting point of a cell lineage with a specific organismal source, time-interval of existence, and ‘tree topology’ of branch-points linking the stem to developmental termini. The concept of ‘enkapsis’ accommodates the cell-organism relation within the lineage view; this hierarchical notion is further explicated by considering the methods and results of stem cell experiments. Results of this examination include a (partial) characterization of stem cells’ developmental versatility, and the context-dependence of developmental processes involving stem cells. (shrink)

Hematopoietic stem cell transplantation is a widely accepted practice in the United Kingdom (UK). The relatively liberal UK law permits donation both within families and from strangers, and even allows the creation of “saviour siblings” who are brought into being with the specific intent of having them donate stem cells to save other members of their family. This chapter describes the regulation of HSCT in the UK and highlights some ethical issues related to discrimination against some categories (...) of potential donors, the accuracy of the information provided to potential donors, and the controversy concerning saviour siblings. (shrink)

Stem cell research is the product of cumulative, integrated effort between and within laboratories and disciplines. The many collaborative steps that lead to that special “Eureka moment”, when something that has been a puzzle perhaps for years suddenly become clear, is among the greatest pleasures of a scientific career. In this essay, the serendipitous pathway from first acquaintance with pluripotent stem cells to advanced cardiovascular models that emerged from studying development and disease will be described. Perhaps inspiration (...) for later generations of stem cell researchers simply to follow whatever they find interesting. (shrink)

In this paper the permissibility of stem cell research on early human embryos is defended. It is argued that, in order to have moral status, an individual must have an interest in its own wellbeing. Sentience is a prerequisite for having an interest in avoiding pain, and personhood is a prerequisite for having an interest in the continuation of one's own existence. Early human embryos are not sentient and therefore they are not recipients of direct moral consideration. Early (...) human embryos do not satisfy the requirements for personhood, but there are arguments to the effect that they should be treated as persons nonetheless. These are the arguments from potentiality, symbolic value and the principle of human dignity. These arguments are challenged in this paper and it is claimed that they offer us no good reason to believe that early human embryos should be treated as persons. (shrink)

The possibility of obtaining stem cells from human embryos has given rise to an intensive legal and ethical debate. In this paper, attention is paid to the normative disparity and ambiguity in Europe. An argument for the need for a minimal legal harmonization is made; and a prudent and flexible way to reach this successfully is suggested. Establishing a common legal framework seems to be the only way to guarantee true competitiveness for the European scientific community.

The research on stem cell-based therapies has greatly expanded in recent years. Our text attempts to seek those religious and ethical challenges that stem cell therapy and research bring into debate. Our thesis is that bioethics can defend its principle without a religious background. We will develop our argumentation on three major points: firstly, a comparison between secular ethics and religious views will clarify why stem cell therapy and research are important from a scientific (...) point of view, addressing the very center of the human being; in our view, being based on secular society, bioethics can answer the challenges of stem cell therapy and research; secondly, following Hans Jonas' perspective on experimenting on humans, we seek to understand the philosophical guidance that sciences dealing with stem cell need; thirdly, we will map the ethical guidelines for clinical translational research that have been adopted by the International Society for Stem Cell Research. . (shrink)

This book explores the ethical and governance concerns of stem cell technology, taking a comparative approach between countries of differing socio-economic status. The book provides a typology of different stem cell types and discusses key ethical issues surrounding the use of human stem cells in research. Topics covered include the moral status of human embryos, various religious perspectives, and the challenges posed by unproven stem cell interventions. The book also examines the existing governance (...) frameworks in the UK, Singapore, and Malaysia, identifying the laws, guidelines, and advisory bodies established to address the identified ethical issues. Applicable lessons on establishing robust regulatory frameworks, fostering public trust, and ensuring responsible research practices are outlined. By providing a comparative analysis of the interplay between ethics, governance, and the socio-economic contexts of these three commonwealth countries, this book will interest health law, research ethics and bioethics scholars. (shrink)

In 1998, researchers established the first human embryonic stem cell line. Their scientific triumph triggered an ethics and policy argument that persists today. Bioethicists, religious leaders, government officials, patient advocates, and scientists continue to debate whether this research poses a promise, a threat, or a mixed ethical picture for society.Scientists are understandably excited about the knowledge that could come from studying human embryonic stem cells. Most of them believe these cells offer a precious opportunity to learn more (...) about why diseases develop and how they might be prevented or attacked. In their quest to gain support for stem cell research, scientists and others have claimed that the research could generate cures and treatment for everything from heart disease to cancer. (shrink)

This paper explores the notions of hope and how individual patient autonomy can trump carefully reasoned ethical concerns and policies intended to regulate stem cell transplants. We argue that the same limits of knowledge that inform arguments to restrain and regulate unproven treatments might also undermine our ability to comprehensively dismiss or condemn them. Incautiously or indiscriminately reasoned policies and attitudes may drive critical information and data underground, impel patients away from working with clinical researchers, and tread needlessly (...) on hope, the essential motivator of patients, advocates and researchers alike. We offer recommendations to clinicians and health care providers to help balance the discourse with individuals seeking treatment while guarding against fraud, misconception, and patient harm. (shrink)

Week-old embryos are considered the richest source of stem cells usable in medical treatments. Because the embryos are destroyed when the stem cells are removed, the debate over the embryo's legal, moral, political, and scientific status has exploded. In this debate, Sheldon Krimsky's Stem Cell Dialogues: A Philosophical and Scientific Inquiry into Medical Frontiers is the single best book. Evenhanded, eminently readable, up to date, educational, scientifically precise, powerfully researched, and very entertaining, Krimsky's slim volume is (...) one that no scientist, policy-maker, ethicist, or intelligent reader should miss. (shrink)