Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion‐dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue (...) homeostasis? Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others. (shrink)

Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of (...) tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

Long non‐coding RNAs (lncRNAs) have recently gained increasing attention because of their crucial roles in gene regulatory processes. Functional studies using mammalian skin as a model system have revealed their role in controlling normal tissue homeostasis as well as the transition to a diseased state. Here, we describe how lncRNAs regulate differentiation to preserve an undifferentiated epidermal progenitor compartment, and to maintain a functional skin permeability barrier. Furthermore, we will reflect on recent work analyzing the impact of lncRNAs (...) on the progression from normal epithelium to the development of skin disorders and cancer. (shrink)

Most tissues contain cells capable of the self‐renewal and differentiation necessary to maintain tissue and organ integrity. These somatic stem cells are generally thought to have limited developmental potential. The mechanisms that restrict cell fate decisions in somatic stem cells are only now being understood. This understanding will be important in the clinical exploitation of adult stem cells in tissue repair and replacement. Experiments performed over fifty years ago in Drosophila showed that developmental restriction could be relaxed in (...) the proliferating larval cells that are destined to form the adult fly integument. This phenomenon, called transdetermination, can serve as a model for mechanisms of stem‐cell commitment. A recent publication1 sheds new light on the mechanism of transdetermination by demonstrating that loss of homeotic gene silencing leads to increased frequency of transdetermination. In addition, the authors link a specific signaling pathway induced by tissue regeneration to the relaxation of homeotic gene silencing. The data identify key mechanisms that control developmental homeostasis and cell fate restriction that could be manipulated to make somatic stem‐cell engineering possible. BioEssays 28: 574–577, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of (...) neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. (shrink)

Perlecan is a ubiquitous proteoglycan of basement membrane and vascularized tissues but is also present in articular cartilage, meniscus and intervertebral disc, which are devoid of basement membrane and predominantly avascular. It is a prominent pericellular proteoglycan in the transitory matrix of the cartilaginous rudiments that develop into components of diarthrodial joints and the axial skeleton, and it forms intricate perichondrial vessel networks that define the presumptive articulating surfaces of developing joints and line the cartilage canals in cartilaginous rudiments. Such (...) vessels have roles in the nutrition of the expanding cell numbers in the developing joint. Perlecan sequesters a number of growth factors pericellularly (FGFs, PDGF, VEGF and CTGF) and through these promotes cell signalling, cell proliferation and differentiation. Perlecan also interacts with a diverse range of extracellular matrix proteins, stabilising and organising the ECM, and promoting collagen fibrillogenesis. Perlecan is a prominent pericellular component of mesenchymal cells from their earliest developmental stages through to maturation, forming cell–cell and cell–ECM interconnections that are suggestive of a role in mechanosensory processes important to tissue homeostasis. BioEssays 30:457–469, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An (...) age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

This article reviews and discusses emerging evidence suggesting an evolutionarily‐conserved connection between injury‐associated exposure of cytoskeletal proteins and the induction of tolerance to infection, repair of tissue damage and restoration of homeostasis. While differences exist between vertebrates and invertebrates with respect to the receptor(s), cell types, and effector mechanisms involved, the response to exposed cytoskeletal proteins appears to be protective and to rely on a conserved signaling cassette involving Src family kinases, the nonreceptor tyrosine kinase Syk, and tyrosine (...) phosphatases. A case is made for research programs that integrate different model organisms in order to increase the understanding of this putative response to tissue damage. (shrink)

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls.Our approach combines a model of (...) cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs, Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. (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)

This essay summarizes recent advances made in the analysis of mosaic patches in chimaeric epithelia of the mouse. The conclusions drawn from the observed patterns are relevant to the behaviour of expanding cell populations during tissue growth and homeostasis. References are made to clonal analysis of Drosophila.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue‐level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue‐level impacts of genetic mosaicism can (...) be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non‐Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far‐reaching implications for practical applications. (shrink)

Carotenoids play pivotal roles in vision as light filters and precursor of chromophore. Many vertebrates also display the colorful pigments as ornaments in bare skin parts and feathers. Proteins involved in the transport and metabolism of these lipids have been identified including class B scavenger receptors and carotenoid cleavage dioxygenases. Recent research implicates members of the Aster protein family, also known as GRAM domain‐containing (GRAMD), in carotenoid metabolism. These multi‐domain proteins facilitate the intracellular movement of carotenoids from their site of (...) cellular uptake by scavenger receptors to the site of their metabolic processing by carotenoid cleavage dioxygenases. We provide a model how the coordinated interplay of these proteins and their differential expression establishes carotenoid distribution patterns and function in tissues, with particular emphasis on the human retina. (shrink)

Embryonic development and adult tissue homeostasis are controlled through activation of intracellular signal transduction pathways by extracellular growth factors. In the past, signal transduction has largely been regarded as a linear process. However, more recent data from large‐scale and high‐throughput experiments indicate that there is extensive cross‐talk between individual signaling cascades leading to the notion of a signaling network. The behavior of such complex networks cannot be predicted by simple intuitive approaches but requires sophisticated models and computational simulations. (...) The purpose of such models is to generate experimentally testable hypotheses and to find explanations for unexpected experimental results. Here, we discuss the need for, and the future impact of, mathematical models for exploring signal transduction in different biological contexts such as for example development. BioEssays 30:1110–1125, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made (...) in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell‐based regenerative medicine for diseases of lung and airways. (shrink)

Mononuclear phagocytes (MPs), which consist of dendritic cells, monocytes, and macrophages, are distributed throughout the body and actively eliminate invading microorganisms and abnormal cells. Depending on the local microenvironment, MPs manifest considerably various lifespans and phenotypes to maintain tissue homeostasis. Vascular‐associated mononuclear phagocytes (VaMPs) are the special subsets of MPs that are localized either within the lumen side or on the apical surface of vessels, acting as the critical sentinels to recognize and defend against disseminated tumor cells. In (...) this review, we introduce three major types of VaMPs, patrolling monocytes, Kupffer cells, and perivascular macrophages, and discuss their emerging roles in immunosurveillance during incipient metastasis. We also explore the roles of lineage‐determining transcription factors and cell surface receptors that endow VaMPs with potent anti‐tumor activity. Finally, we highlight the molecular and cellular mechanisms that drive the phenotypic plasticity of VaMPs and summarize combinatory strategies for targeting VaMPs in overt metastasis. (shrink)

Human neoplasms develop following the progressive accumulation of genetic and epigenetic alterations to oncogenes and tumor suppressor genes. These alterations confer a growth advantage to the cancer cell, leading to its clonal proliferation, invasion into surrounding tissues, and spread to distant organs. Genes that are altered in neoplasia affect three major biologic pathways that normally regulate cell growth and tissue homeostasis: the cell cycle, apoptosis, and differentiation. While each of these pathways can be defined by a unique set (...) of molecular events, they are not biologically separate. Rather, they function more as an integrated molecular network, and perturbations in one pathway can have profound consequences on another. Insights into what distinguishes the regulation of growth and differentiation in a normal cell versus a cancer cell have led to the development of novel anticancer therapies. BioEssays 24:83–90, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Hydra are remarkable because they are immortal. Much of immortality can be ascribed to the asexual mode of reproduction by budding, which requires a tissue consisting of stem cells with continuous self‐renewal capacity. Emerging novel technologies and the availability of genomic resources enable for the first time to analyse these cells in vivo. Stem cell differentiation in Hydra is governed through the coordinated actions of conserved signaling pathways. Studies of stem cells in Hydra, therefore, promise critical insights of general (...) relevance into stem cell biology including cellular senescence, lineage programming and reprogramming, the role of extrinsic signals in fate determination and tissue homeostasis, and the evolutionary origin of these cells. With these new facts as a backdrop, this review traces the history of studying stem cells in Hydra and offers a view of what the future may hold. (shrink)

Cytokines, also referred to as interleukins, are the major orchestrators of host defence processes, and, as such, are involved in insults, repair and restoration of tissue homeostasis. This review summarises recent findings on and emerging models of the biological roles of the double-edged sword interleukin-13 (IL-13), which have been principally obtained from studies in mice that are deficient for IL-13, or its components. IL-13-mediated functions not only contribute to the susceptible phenotype in Leishmania major infection but also seem (...) to play a protective role in chronic leishmaniasis. Moreover, IL-13 plays a key protective role in the expulsion of helminths from the gut while also actively contributing to the pathology in schistosomiasis. In allergic asthma, IL-13 has also been found to be a key factor. Therapeutic administration of an IL-13 inhibitor in mice successfully prevents both the allergic disease phenotype and schistosoma egg-induced lung pathology. If this scenario holds true in humans, we soon may have an efficient drug for treatment of IL-13-mediated diseases. BioEssays 22:646–656, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, (...) and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (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)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

Signaling through the Wnt/β‐catenin pathway is relayed through three multiprotein complexes: (1) the membrane‐associated signalosome, which includes the activated Wnt receptors, (2) the cytoplasmic destruction complex that regulates turnover of the transcriptional coactivator β‐catenin, and (3) the nuclear enhanceosome that mediates pathway‐specific transcription. Recent discoveries have revealed that Wnt receptor activities are tightly regulated to maintain proper tissue homeostasis and that aberrant receptor upregulation enhances Wnt signaling to drive tumorigenesis, highlighting the importance of signalosome control. These studies have (...) focused on the detailed process by which Wnt ligands engage their coreceptors, LRP5/6 and Frizzled. However, the components that constitute the signalosome and the regulation of their assembly remain undefined. In this review, we discuss Wnt/β‐catenin signalosome composition and the mechanisms that regulate signalosome assembly, including the role of biomolecular condensates and ubiquitylation. We also summarize the evidence for the presence of Wnt ligand‐independent signalosome formation. (shrink)

The developing mammalian heart responds to a variety of conditions, including changes in nutrient availability, blood oxygenation, hemodynamics, or tissue homeostasis, with impressive growth plasticity. This ensures the formation of a functional and normal sized organ by birth. During embryonic and fetal development the heart is exposed to various physiological and potentially pathological changes in the intrauterine environment which dramatically impact on normal cardiac function, tissue composition, and morphology. This paper summarizes the mechanisms employed by the embryonic (...) and fetal heart to adapt to various intrauterine challenges to prevent or minimize postnatal consequences of impaired cardiac development. Future investigations of this growth plasticity might lead to new therapeutic strategies for the prevention of cardiac disease in postnatal life. (shrink)

Ecological developmental biology (eco‐devo) explores the mechanistic relationships between the processes of individual development and environmental factors. Recent studies imply that some of these relationships have deep evolutionary origins, and may even pre‐date the divergences of the simplest extant animals, including cnidarians and sponges. Development of these early diverging metazoans is often sensitive to environmental factors, and these interactions occur in the context of conserved signaling pathways and mechanisms of tissue homeostasis whose detailed molecular logic remain elusive. Efficient (...) methods for transgenesis in cnidarians together with the ease of experimental manipulation in cnidarians and sponges make them ideal models for understanding causal relationships between environmental factors and developmental mechanisms. Here, we identify major questions at the interface between animal evolution and development and outline a road map for research aimed at identifying the mechanisms that link environmental factors to developmental mechanisms in early diverging metazoans.Also watch the Video Abstract. (shrink)

Wnt signaling plays pivotal roles during our entire lives, from conception to death, through the regulation of morphogenesis in developing embryos and the maintenance of tissue homeostasis in adults. The regulation of Wnt signaling occurs on several levels: at the receptor level on the plasma membrane, at the β‐catenin protein level in the cytoplasm, and through transcriptional regulation in the nucleus. Several recent studies have focused on the mechanisms of Wnt receptor regulation, following the discovery that the Wnt (...) receptor frizzled (Fzd) is a target of the ubiquitin ligases, RNF43 and ZNRF3. RNF43 and ZNRF3 are homologous genes that are mutated in several cancers. The details underlying their mechanism of action continue to unfold, while at the same time raising many new questions. In this review, we discuss advances and controversies in our understanding of Wnt receptor regulation. (shrink)

Despite promising early work into the role of immune cells such as eosinophils in adipose tissue (AT) homeostasis, recent findings revealed that elevating the number of eosinophils in AT alone is insufficient for improving metabolic impairments in obese mice. Eosinophils are primarily recognized for their role in allergic immunity and defence against parasitic worms. They have also been detected in AT and appear to contribute to adipose homeostasis and drive energy expenditure, but the underlying mechanisms remain elusive. (...) It has long been recognized that immune cells such as macrophages respond to external signals to regulate adipose homeostasis and energy balance, however, less is known about the relevance of eosinophil activity in AT. As the authors propose in this review, given recent debate over the relative importance of their tissue‐specific abundance, the stage is now set for exploring the functionality and activation states of AT eosinophils. (shrink)

Graphical AbstractA cell translocation mechanism displaces sporadic mutant cells from normal, suppressive epithelial environment during early steps of tumor initiation. This epithelial cell translocation process exerts a selective pressure on early mutant cells to survive and grow in new microenvironment outside of their native niches.

It has recently been shown that stem and progenitor cells undergo population self‐renewal to maintain epithelial homeostasis. The fate of individual cells is stochastic but the production of proliferating and differentiating cells is balanced across the population. This new paradigm, originating in mouse epidermis and since extended to mouse oesophagus and mouse and Drosophila intestine, is in contrast to the long held model of epithelial maintenance by exclusively asymmetric division of stem cells. Recent lineage tracing studies have now shown (...) that wound responses vary between tissues, and that a stem cell reserve is not essential as cycling progenitors and even differentiating cells contribute to regeneration. (shrink)

Mesenchymal stem cells (MSCs) are present in fat tissues throughout the body, yet little is known regarding their biological role within epidural fat. We hypothesize that debridement of epidural fat and/or subsequent loss of MSCs within this tissue, disrupts homeostasis in the vertebral environment resulting in increased inflammation, fibrosis, and decreased neovascularization leading to poorer functional outcomes post‐injury/operatively. Clinically, epidural fat is commonly considered a space‐filling tissue with limited functionality and therefore typically discarded during surgery. However, the (...) presence of MSCs within epidural fat suggests that itis more biologically active than historically believed and may contribute to the regulation of homeostasis and regeneration in the dural environment. While the current literature supports our hypothesis, it will require additional experimentation to determine if epidural fat is an endogenous driver of repair and regeneration and if so, this tissue should be minimally perturbed from its original location in the spinal canal. Also see the video abstract here https://youtu.be/MIol_IWK1os. (shrink)

Epithelial tissues serve as critical barriers in metazoan organisms, maintaining structural integrity and facilitating essential physiological functions. Epithelial cell polarity regulates mechanical properties, signaling, and transport, ensuring tissue organization and homeostasis. However, the barrier function is challenged by cell turnover during development and maintenance. To preserve tissue integrity while removing dying or unwanted cells, epithelial tissues employ cell extrusion. This process removes both dead and live cells from the epithelial layer, typically causing detached cells to undergo apoptosis. (...) Transformed cells, however, often resist apoptosis, leading to multilayered structures and early carcinogenesis. Malignant cells may invade neighboring tissues. Loss of cell polarity can lead to multilayer formation, cell extrusion, and invasion. Recent studies indicate that multilayer formation in epithelial cells with polarity loss involves a mixture of wild‐type and mutant cells, leading to apical or basal accumulation. The directionality of accumulation is regulated by mutations in polarity complex genes. This phenomenon, distinct from traditional apical or basal extrusion, exhibits similarities to the endophytic or exophytic growth observed in human tumors. This review explores the regulation and implications of these phenomena for tissue biology and disease pathology. (shrink)

Cellular circadian clocks represent ancient anticipatory systems which co‐evolved with the first cells to safeguard their survival. Cyanobacteria represent one of the most ancient cells, having essentially invented photosynthesis together with redox‐based cellular circadian clocks some 2.7 billion years ago. Bioelectricity phenomena, based on redox homeostasis associated electron transfers in membranes and within protein complexes inserted in excitable membranes, play important roles, not only in the cellular circadian clocks and in anesthetics‐sensitive cellular sentience (awareness of environment), but also in (...) the coupling of single cells into tissues and organs of unitary multicellular organisms. This integration of cellular circadian clocks with cellular basis of sentience is an essential feature of the cognitive CBC‐Clock basis of cellular life. (shrink)

How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity in (...) stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue-specific stem cells, merging the Hu et al. study together with our current knowledge of YAP/TAZ. The Hippo pathway effectors YAP and TAZ broadly regulate adult stem cells, and have recently been implicated in dental epithelial stem cell proliferation and restricted differentiation via an Integrin-FAK-CDC42-PP1A cascade. Here, we discuss the extracellular cues which control YAP/TAZ activity and examine downstream pathways that direct stem cell fate. (shrink)

Introduction of human plasma protein genes into the mouse genome to produce transgenic mice furnishes an in vivo model for correlating chromosomal DNA sequences with developmental and tissue‐specific expression. The liver produces an array of plasma proteins that circulate throughout the body contributing to homeostasis. Non‐hepatic tissue sites of synthesis have been identified where a local provision of plasma proteins in needed. Analysis of expression of human plasma protein genes in ageing transgenic mice appears especialy promising in (...) identifying DNA sequences that respond to environmental adversities such as inflammatory factors, hormonal changes and metal toxicity. The results indicate that human genes encoding and controlling liver plasma proteins serve as useful models for studying genetic regulation in the background of development and ageing. (shrink)

B cell activation is accompanied by metabolic adaptations to meet the increased energetic demands of proliferation. The metabolic composition of the microenvironment is known to change during a germinal center response, in inflamed tissue and to vary significantly between different organs. To sustain cellular homeostasis B cells need to be able to dynamically adapt to changes in their environment. An inability to take up and process available nutrients can result in impaired B cell growth and a diminished humoral (...) immune response. Furthermore, the metabolic microenvironment can affect B cell signaling and provide a means to avoid aberrant proliferation or modulate B cell function. Thus, a better understanding of the intricate interplay between cell signaling and metabolism could provide novel insight into how B cell function is regulated and have implications for the development of vaccines or treatment of autoimmune disorders and B cell derived malignancies. Throughout their lifespan, B cells are exposed to different metabolic environments. Signaling pathways regulating cellular responses to metabolic stress not only help to maintain B cell viability and to facilitate cellular functions but may also play an important role in preventing excessive proliferation and malignant transformation. (shrink)

Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of (...) platelet aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. (shrink)

The Krüppel‐like factors (KLFs) comprise a family of evolutionarily conserved zinc finger transcription factors that regulate numerous biological processes including proliferation, differentiation, development and apoptosis. KLF4 and KLF5 are two closely related members of this family and are both highly expressed in epithelial tissues. In the intestinal epithelium, KLF4 is expressed in terminally differentiated epithelial cells at the villus borders of the mucosa and inhibits cell growth, while KLF5 is expressed in proliferating epithelial cells at the base of the intestinal (...) crypts and promotes cell growth. KLF4 and KLF5 respond to a myriad of external stress stimuli and are likely involved in restoring cellular homeostasis following exposure to stressors. Confirming their importance in maintaining tissue integrity, KLF4 and KLF5 are both dysregulated in various types of cancer. Here we review the recent advances in defining the physiological and pathobiological roles of KLF4 and KLF5, focusing on their functions in the intestinal epithelium. BioEssays 29:549–557, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Apoptotic pathways have always been regarded as a key‐player in preserving tissue and organ homeostasis. Excessive activation or resistance to activation of cell death signaling may indeed be responsible for several mechanisms of disease, including malignancy and chronic degenerative diseases. Therefore, targeting apoptotic factors gained more and more attention in the scientific community and novel strategies emerged aimed at selectively blocking or stimulating cell death signaling. This is also the case for the TMEM219 death receptor, which is activated (...) by a circulating ligand, the Insulin‐like growth factor binding protein 3 (IGFBP3) and induces a caspase‐8‐dependent apoptosis of the target cells. Interestingly, stimulation of the IGFBP3/TMEM219 axis exerts an anti‐proliferative effect, while blockade of the TMEM219 deleterious signal protects TMEM219‐expressing cells of the endocrine pancreas, lung, and intestine from damage and death. Here, we summarize the most updated reports on the role of the IGFBP3/TMEM219 apoptotic axis in disease conditions, including intestinal disorders and diabetes, and we describe the advancements in designing and testing novel TMEM219‐based targeting approaches in emerging potential clinical applications. (shrink)

Immune cells are highly dynamic in their response to the tissue environment. Most immune cells rapidly change their metabolic profile to obtain sufficient energy to engage in defensive or homeostatic processes. Such “immunometabolism” is governed through intermediate metabolites, and has a vital role in regulating immune‐cell function. The underlying metabolic reactions are shaped by the abundance and accessibility of specific nutrients, as well as the overall metabolic status of the host. Here, we discuss how different immune‐cell types gain a (...) sufficient energy supply. We then explain how immune cells perform various functions under challenged conditions and expend energy to sustain homeostasis. Finally, we speculate on how the immune‐cell metabolic profile might be modulated in health and disease, by manipulating nutrient availability. By such intervention, the recovery of patient with dysregulated immune system responses might be sped up and the fitness of an individual efficiently restored. (shrink)

Does the ability of some brain dead bodies to maintain homeostasis with the help of artificial life support actually imply that those bodies are living human organisms? Or might it be possible that a brain dead body on life support is a mere collection of still-living cells, organs and tissues which can coordinate with one another, but which lack the genuine integration that is the hallmark of a unified human organism as a whole? To foster further study of these (...) difficult and timely questions, a Symposium on the Definition of Death was held at The Catholic University of America in June 2014. The Symposium brought together scholars from a variety of disciplines—law, medicine, biology, philosophy and theology—who all share a commitment to the dead donor rule and to a biological definition of death, but who have differing opinions regarding the validity of neurological criteria for human death. The papers found in this special issue are among the fruits of this Symposium. (shrink)

The application of in vivo genetic lineage tracing has advanced our understanding of cellular mechanisms for tissue renewal in organs with slow turnover, like the lung. These studies have identified an adult stem cell with very different properties than classically understood ones that maintain continuously cycling tissues such as the intestine. A portrait has emerged of an ensemble of cellular programs that replenish the cells that line the gas exchange (alveolar) surface, enabling a response tailored to the extent of (...) cell loss. A capacity for differentiated cells to undergo direct lineage transitions allows for local restoration of proper cell balance at sites of injury. We present these recent findings as a paradigm for how a relatively quiescent tissue compartment can maintain homeostasis throughout a lifetime punctuated by injuries ranging from mild to life‐threatening, and discuss how dysfunction or insufficiency of alveolar repair programs produce serious health consequences like cancer and fibrosis. (shrink)

The macrophage plays an important role in host development and physiology, and in pathogenesis of many infectious, immunologic and degenerative disease processes. It displays marked heterogeneity of phenotype in different tissues, reflecting local interactions with other cell types, and contributes to host homeostasis through a varied repertoire of plasma membrane and secretory molecules. Upon isolation from the body it continues to express special, as well as general, features of cellular organisation and function, which make it a delight to study (...) in cell culture. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models (...) have been proposed to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

We present here the hypothesis that the unique microenvironmental pH landscape of acid‐base transporting epithelia is an important factor in development of epithelial cancers, by rendering the epithelial and stromal cells pre‐adapted to the heterogeneous extracellular pH (pHe) in the tumor microenvironment. Cells residing in organs with net acid‐base transporting epithelia such as the pancreatic ductal and gastric epithelia are exposed to very different, temporally highly variable pHe values apically and basolaterally. This translates into spatially and temporally non‐uniform intracellular pH (...) (pHi) patterns. Disturbed pHe‐ and pHi‐homeostasis contributes to essentially all hallmarks of cancer. Our hypothesis, that the physiological pHe microenvironment in acid‐base secreting epithelia shapes cancers arising in these tissues, can be tested using novel imaging tools. The acidic tumor pHe in turn might be exploited therapeutically. Pancreatic cancers are used as our prime example, but we propose that this concept is also relevant for other cancers of acid‐base transporting epithelia. (shrink)

The temporal behaviour of the nonlinear compartmental model we have developed for rat calcium metabolism is discussed with respect to the theoretical properties of the self-oscillating autocatalytic subunit around which the model is constructed. Depending on the approximations made, this subunit is described by a minimal two-variable model, SU2, or by a three-variable one, SU3. The diversity of the theoretical dynamic behaviours possible with SU2 is greatly increased with SU3. But the identification of SU3 parameter values in three different experimental (...) situations reveals that biological constraints efficiently preserve a simple circadian rhythm for bone metabolism. This analysis indicates the significant contribution of the available bone crystal pool to the dynamic organization of this tissue, and hence to extracellular calcium homeostasis. (shrink)

In eukaryotes, small amounts of nitrite confer cytoprotection against ischemia/reperfusion‐related tissue damage in vivo, possibly via reduction to nitric oxide (NO) and inhibition of mitochondrial function. Several hemeproteins are involved in this protective mechanism, starting with deoxyhemoglobin, which is capable of reducing nitrite. In facultative aerobic bacteria, such as Pseudomonas aeruginosa, nitrite is reduced to NO by specialized heme‐containing enzymes called cd1 nitrite reductases. The details of their catalytic mechanism are summarized below, together with a hypothesis on the biological (...) role of the unusual d1‐heme, which, in the reduced state, shows unique properties (very high affinity for nitrite and exceptionally fast dissociation of NO). Our results support the idea that the nitrite‐based reactions of contemporary eukaryotes are a vestige of earlier bacterial biochemical pathways. The evidence that nitrite reductase activities of enzymes with different cellular roles and biochemical features still exist today highlights the importance of nitrite in cellular homeostasis. (shrink)

Extracellular ATP released from necrotic cells in inflamed tissues activates the P2X7 receptor, stimulates the exposure of phosphatidylserine, and causes cell lysis. Recent findings indicated that XK, a paralogue of XKR8 lipid scramblase, forms a complex with VPS13A at the plasma membrane of T cells. Upon engagement by ATP, an unidentified signal(s) from the P2X7 receptor activates the XK‐VPS13A complex to scramble phospholipids, followed by necrotic cell death. P2X7 is expressed highly in CD25+CD4+ T cells but weakly in CD8+ T (...) cells, suggesting a role of this system in the activation of the immune system to prevent infection. On the other hand, a loss‐of‐function mutation in XK or VPS13A causes neuroacanthocytosis, indicating the crucial involvement of XK‐VPS13A‐mediated phospholipid scrambling at plasma membranes in the maintenance of homeostasis in the nervous and red blood cell systems. (shrink)