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  • Pancreatic α-cells – The unsung heroes in islet function
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-24
    Anna Wendt; Lena Eliasson

    The pancreatic islets of Langerhans consist of several hormone-secreting cell types important for blood glucose control. The insulin secreting β-cells are the best studied of these cell types, but less is known about the glucagon secreting α-cells. The α-cells secrete glucagon as a response to low blood glucose. The major function of glucagon is to release glucose from the glycogen stores in the liver. In both type 1 and type 2 diabetes, glucagon secretion is dysregulated further exaggerating the hyperglycaemia, and in type 1 diabetes α-cells fail to counter regulate hypoglycaemia. Although glucagon has been recognized for almost 100 years, the understanding of how glucagon secretion is regulated and how glucagon act within the islet is far from complete. However, α-cell research has taken off lately which is promising for future knowledge. In this review we aim to highlight α-cell regulation and glucagon secretion with a special focus on recent discoveries from human islets. We will present some novel aspects of glucagon function and effects of selected glucose lowering agents on glucagon secretion.

    更新日期:2020-01-24
  • Cellular and molecular basis of liver regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-22
    Sushant Bangru; Auinash Kalsotra

    Recent advances in genetics and genomics have reinvigorated the field of liver regeneration. It is now possible to combine lineage-tracing with genome-wide studies to genetically mark individual liver cells and their progenies and detect precise changes in their genome, transcriptome, and proteome under normal versus regenerative settings. The recent use of single-cell RNA sequencing methodologies in model organisms has, in some ways, transformed our understanding of the cellular and molecular biology of liver regeneration. Here, we review the latest strides in our knowledge of general principles that coordinate regeneration of the liver and reflect on some conflicting evidence and controversies surrounding this topic. We consider the prominent mechanisms that stimulate homeostasis-related vis-à-vis injury-driven regenerative responses, highlight the likely cellular sources/depots that reconstitute the liver following various injuries and discuss the extrinsic and intrinsic signals that direct liver cells to proliferate, de-differentiate, or trans-differentiate while the tissue recovers from acute or chronic damage.

    更新日期:2020-01-22
  • Unraveling the complexity of γ-secretase
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-21
    Michael S. Wolfe

    γ-Secretase was initially defined as a proteolytic activity that cleaves within the transmembrane of the amyloid precursor protein (APP) to produce the amyloid β-peptide of Alzheimer’s disease. The discovery of mutations in APP and the presenilins associated with familial Alzheimer’s disease and their effects on APP processing dovetailed with pharmacological studies on γ-secretase, leading to the revelation that presenilins are unprecedented membrane-embedded aspartyl proteases. Other members of what became known as the γ-secretase complex were subsequently identified. In parallel with these advances, connections between presenilins and Notch receptors essential to metazoan development became evident, resulting in the concurrent realization that γ-secretase also carries out intramembrane proteolysis of Notch as part of its signaling mechanism. Substantial progress has been made toward elucidating how γ-secretase carries out complex processing of transmembrane domains, how it goes awry in familial Alzheimer’s disease, the scope of its substrates, and the atomic details of its structure. Critical questions remain for future study, toward further unraveling the complexity of this unique membrane-embedded proteolytic machine and its roles in biology and disease.

    更新日期:2020-01-22
  • Regulation of succinate dehydrogenase and role of succinate in cancer
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-01
    Elisa Dalla Pozza; Ilaria Dando; Raffaella Pacchiana; Elio Liboi; Maria Teresa Scupoli; Massimo Donadelli; Marta Palmieri

    Succinate dehydrogenase (SDH) has been classically considered a mitochondrial enzyme with the unique property to participate in both the citric acid cycle and the electron transport chain. However, in recent years, several studies have highlighted the role of the SDH substrate, i.e. succinate, in biological processes other than metabolism, tumorigenesis being the most remarkable. For this reason, SDH has now been defined a tumor suppressor and succinate an oncometabolite. In this review, we discuss recent findings regarding alterations in SDH activity leading to succinate accumulation, which include SDH mutations, regulation of mRNA expression, post-translational modifications and endogenous SDH inhibitors. Further, we report an extensive examination of the role of succinate in cancer development through the induction of epigenetic and metabolic alterations and the effects on epithelial to mesenchymal transition, cell migration and invasion, and angiogenesis. Finally, we have focused on succinate and SDH as diagnostic markers for cancers having altered SDH expression/activity.

    更新日期:2020-01-17
  • Fumarate hydratase in cancer: A multifaceted tumour suppressor
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Christina Schmidt; Marco Sciacovelli; Christian Frezza

    Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the stepwise neoplastic progression after FH loss.

    更新日期:2020-01-17
  • Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    José M. Matés; Floriana J. Di Paola; José A. Campos-Sandoval; Sybille Mazurek; Javier Márquez

    Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutaminase isoenzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms’ fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including the use of specific allosteric inhibitors of glutaminase that can evoke synergistic effects for the therapy of cancer patients. We also review other clinical applications of in vivo assessment of glutaminolysis by metabolomic approaches, including diagnosis and monitoring of cancer.

    更新日期:2020-01-17
  • Stromal-induced mitochondrial re-education: Impact on epithelial-to-mesenchymal transition and cancer aggressiveness
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Marina Bacci; Luigi Ippolito; Lucia Magnelli; Elisa Giannoni; Paola Chiarugi

    Metabolic reprogramming as well as the flexible utilisation of fuel sources by tumour cells has been considered not only intrinsic to malignant cells but also sustained by resident and/or recruited stromal cells. The complexity of tumour-stroma cross-talk is experienced by neoplastic cells through profound changes in the own metabolic machinery. In such context, mitochondria are dynamic organelles that receive, orchestrate and exchange a multiplicity of stromal cues within the tumour cells to finely regulate key metabolic and signalling pathways, allowing malignant cells to adapt and thrive in an ever-changing environment. In this review, we focus on how tumour mitochondria are coached by stromal metabolic supply and how this re-education sustains tumour malignant traits.

    更新日期:2020-01-17
  • Mitochondrial metabolism: Inducer or therapeutic target in tumor immune-resistance?
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-18
    Joanna Kopecka; Elena Gazzano; Barbara Castella; Iris C. Salaroglio; Eleonora Mungo; Massimo Massaia; Chiara Riganti

    Mitochondria have been considered for a long time only as the principal source of building blocks and energy upon aerobic conditions. Recently they emerged as key players in cell proliferation, invasion and resistance to therapy. The most aggressive tumors are able to evade the immune-surveillance. Alterations in the mitochondria metabolism either in cancer cells or in host immune system cells are involved in such tumor-induced immune-suppression. This review will focus on the main mitochondrial dysfunctions in tumor and immune cell populations determining immune-resistance, and on the therapies that may target mitochondrial metabolism and restore a powerful anti-tumor immune-activity.

    更新日期:2020-01-17
  • The multifaceted effects of metformin on tumor microenvironment
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Ivana Kurelac; Nikkitha Umesh Ganesh; Maria Iorio; Anna Maria Porcelli; Giuseppe Gasparre

    The efficacy of metformin in treating cancer has been extensively investigated since epidemiologic studies associated this anti-diabetic drug with a lower risk of cancer incidence. Since tumors are complex systems, in which cancer cells coexist and interact with several different types of non-malignant cells, it is not surprising that anti-cancer drugs affect not only cancer cells, but also the abundance and functions of cells of the tumor microenvironment. Recent years have seen a wide collection of reports showing how metformin, as well as other complex I inhibitors, may influence cancer progression by modulating the phenotype of non-transformed cells in a tumor. In this review, we particularly focus on the effect of metformin on angiogenesis, cancer-associated fibroblasts, tumor-associated macrophages and cancer immunosuppression.

    更新日期:2020-01-17
  • Wild type- and mutant p53 proteins in mitochondrial dysfunction: emerging insights in cancer disease
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-23
    Giovanni Blandino; Fabio Valenti; Andrea Sacconi; Silvia Di Agostino

    Deregulated cell metabolism is one of the cancer hallmarks. Mitochondrial DNA mutations and enzyme defects, aberrant tumor suppressor or oncogenic activities cause mitochondrial dysfunction leading to deregulated cellular energetics. The tumor suppressor protein, p53 is a tetrameric transcription factor that in response to diverse genotoxic and non-genotoxic insults activates a plethora of target genes to preserve genome integrity. In the last two decades the discovery of cytoplasmic p53 localization focused intense research on its extra-nuclear functions. The ability of p53 to induce apoptosis acting directly at mitochondria and the related mechanisms of p53 localization and translocation in the cytoplasm have been investigated. A role of cytoplasmic p53 in autophagy, pentose phosphate pathway, fatty acid synthesis and oxidation, and drug response has been proposed. TP53 gene is mutated in more than half of human cancers. In parallel to loss of tumor suppressive functions, mutant p53 proteins often gain new tumorigenic activities (GOF, gain of function). It has been recently shown that mutant p53 proteins mediate metabolic changes thereby promoting cancer development and metastases. Here we review the contribution of either wild-type p53 or mutant p53 proteins to the fine-tuning of mitochondrial metabolism of both normal and cancer cells. Greater knowledge at the mechanistic level might provide insights to develop new cancer therapeutic approaches.

    更新日期:2020-01-17
  • Interorganellar calcium signaling in the regulation of cell metabolism: A cancer perspective
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-24
    Alessandro Rimessi; Gaia Pedriali; Bianca Vezzani; Anna Tarocco; Saverio Marchi; Mariusz R. Wieckowski; Carlotta Giorgi; Paolo Pinton

    Organelles were originally considered to be individual cellular compartments with a defined organization and function. However, recent studies revealed that organelles deeply communicate within each other via Ca2+ exchange. This communication, mediated by specialized membrane regions in close apposition between two organelles, regulate cellular functions, including metabolism and cell fate decisions. Advances in microscopy techniques, molecular biology and biochemistry have increased our understanding of these interorganelle platforms. Research findings suggest that interorganellar Ca2+ signaling, which is altered in cancer, influences tumorigenesis and tumor progression by controlling cell death programs and metabolism. Here, we summarize the available data on the existence and composition of interorganelle platforms connecting the endoplasmic reticulum with mitochondria, the plasma membrane, or endolysosomes. Finally, we provide a timely overview of the potential function of interorganellar Ca2+ signaling in maintaining cellular homeostasis.

    更新日期:2020-01-17
  • Reconciling environment-mediated metabolic heterogeneity with the oncogene-driven cancer paradigm in precision oncology
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-22
    Catherine Vander Linden; Cyril Corbet

    Precision oncology is the practice of matching one therapy to one specific patient, based on particular genetic tumor alterations, in order to achieve the best clinical response. Despite an expanding arsenal of targeted therapies, many patients still have a poor outcome because tumor cells show a remarkable capacity to develop drug resistance, thereby leading to tumor relapse. Besides genotype-driven resistance mechanisms, tumor microenvironment (TME) peculiarities strongly contribute to generate an intratumoral phenotypic heterogeneity that affects disease progression and treatment outcome. In this Review, we describe how TME-mediated metabolic heterogeneities actively participate to therapeutic failure. We report how a lactate-based metabolic symbiosis acts as a mechanism of adaptive resistance to targeted therapies and we describe the role of mitochondrial metabolism, in particular oxidative phosphorylation (OXPHOS), to support the growth and survival of therapy-resistant tumor cells in a variety of cancers. Finally, we detail potential metabolism-interfering therapeutic strategies aiming to eradicate OXPHOS-dependent relapse-sustaining malignant cells and we discuss relevant (pre)clinical models that may help integrate TME-driven metabolic heterogeneity in precision oncology.

    更新日期:2020-01-17
  • Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT)
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-14
    Valentina Audrito; Antonella Managò; Federica Gaudino; Silvia Deaglio

    Cancer cells rewire their metabolism to support proliferation, growth and survival. In metastatic melanoma the BRAF oncogenic pathway is a master regulator of this process, highlighting the importance of metabolic reprogramming in the pathogenesis of this tumor and offering potential therapeutic approaches. Metabolic adaptation of melanoma cells generally requires increased amounts of NAD+, an essential redox cofactor in cellular metabolism and a signaling molecule. Nicotinamide phosphoribosyltransferase (NAMPT) is the most important NAD+ biosynthetic enzyme in mammalian cells and a direct target of the BRAF oncogenic signaling pathway. These findings suggest that NAMPT is an attractive new therapeutic target, particularly in combination strategies with BRAF or MEK inhibitors. Here we review current knowledge on how oncogenic signaling reprograms metabolism in BRAF-mutated melanoma, and discuss how NAMPT/NAD+ axis contributes to these processes. Lastly, we present evidence supporting a role of NAMPT as a novel therapeutic target in metastatic melanoma.

    更新日期:2020-01-17
  • Synovial fibroblasts and articular tissue remodelling: Role and mechanisms
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-16
    Thomas Pap; Berno Dankbar; Corinna Wehmeyer; Adelheid Korb-Pap; Joanna Sherwood

    Synovial joints are unique functional elements of the body and provide the ability for locomotion and for physical interaction with the environment. They are composed of different connective tissue structures, of which the synovial membrane is one central component. It shows a number of peculiarities that makes it different from other membranes in our body, while several lines of evidence suggest that synovial fibroblasts, also termed fibroblast-like synoviocytes (FLS) critically contribute to these peculiarities. This becomes evident particularly under disease conditions such as in rheumatoid arthritis and osteoarthritis, where the synovium is a key pathophysiological component. Therefore, an in-depth knowledge of FLS biology is not only important for understanding key features of articular function but also provides explanations for important characteristics of both degenerative and inflammatory joint diseases. This article reviews the structure, biochemical composition and functions of the synovial membrane and by focusing on the role of synovial fibroblasts explains key features of articular tissue remodelling particularly under disease conditions.

    更新日期:2020-01-17
  • The De-, Re-, and trans-differentiation of β-cells: Regulation and function
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2020-01-13
    Jingjing Zhang; Feng Liu

    Diabetes is a serious, costly, and major health problem worldwide. Whereas diabetes could be alleviated by medication, this disease could not be fully cured at the present time due to the lack of effective therapeutic treatment for β-cell loss and/or dysfunction. Increased β-cell mass or volume could be achieved via differentiation of embryonic stem (ES) cells or pluripotent stem cells or through β-cell renewal, including proliferation, redifferentiation, and transdifferentiation. Data cumulated over the past several years suggest that increased β-cell dedifferentiation plays a crucial role in the progression of diabetes, shedding new light on potential targets for β-cell replacement therapy. In this review, we summarize current views on β-cell dedifferentiation, redifferentiation, and transdifferentiation. We also discuss potential mechanisms regulating these key processes to maintain β-cell homeostasis. Understanding pancreatic β-cell differentiation and dedifferentiation could be provide important information on developing effective strategies to cure diabetes.

    更新日期:2020-01-13
  • NetLogo agent-based models as tools for understanding the self-organization of cell fate, morphogenesis and collective migration of the zebrafish posterior Lateral Line primordium
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-31
    Damian Dalle Nogare; Ajay B Chitnis

    Interactions between primordium cells and their environment determines the self-organization of the zebrafish posterior Lateral Line primordium as it migrates under the skin from the ear to the tip of the tail forming and depositing neuromasts to spearhead formation of the posterior Lateral Line sensory system. In this review we describe how the NetLogo agent-based programming environment has been used in our lab to visualize and explore how self-generated chemokine gradients determine collective migration, how the dynamics of Wnt signaling can be used to predict patterns of neuromast deposition, and how previously defined interactions between Wnt and Fgf signaling systems have the potential to determine the periodic formation of center-biased Fgf signaling centers in the wake of a shrinking Wnt system. We also describe how NetLogo was used as a database for storing and visualizing the results of in toto lineage analysis of all cells in the migrating primordium. Together, the models illustrate how this programming environment can be used in diverse ways to integrate what has been learnt from biological experiments about the nature of interactions between cells and their environment, and explore how these interactions could potentially determine emergent patterns of cell fate specification, morphogenesis and collective migration of the zebrafish posterior Lateral Line primordium.

    更新日期:2020-01-01
  • Omic approaches to decipher the molecular mechanisms of fibrosis, and design new anti-fibrotic strategies
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-27
    Sylvie Ricard-Blum; Adriana E. Miele

    We review here omics approaches including transcriptomics, proteomics, glycomics, metabolomics and interactomics, databases and computational tools for omic and multi-omic investigations of fibrosis to understand the molecular mechanisms underlying fibrogenesis and fibrosis, to identify biomarkers of diagnosis, prognosis or disease progression, and new therapeutic targets and to design new anti-fibrotic drugs. We also provide perspectives for future studies including lipid and glycosaminoglycan profiling, and the design of virtual patient models as a basis for personalised medicine and virtualisation of drug development.

    更新日期:2019-12-27
  • Non-canonical (non-SMAD2/3) TGF-β signaling in fibrosis: Mechanisms and targets
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-26
    Kenneth W. Finnson; Yasser Almadani; Anie Philip

    Transforming growth factor (TGF)-β uses several intracellular signaling pathways besides canonical ALK5-Smad2/3 signaling to regulate a diverse array of cellular functions. Several of these so-called non-canonical (non-Smad2/3) pathways have been implicated in the pathogenesis of fibrosis and may therefore represent targets for therapeutic intervention. This review summarizes our current knowledge on the mechanisms of non-canonical TGF-β signaling in fibrosis, the potential molecular targets and the use of agonists/antagonists for therapeutic intervention.

    更新日期:2019-12-27
  • TGF-β1 – A truly transforming growth factor in fibrosis and immunity
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-24
    Monika Lodyga; Boris Hinz

    ‘Jack of all trades, master of everything’ is a fair label for transforming growth factor β1 (TGF-β) – a cytokine that controls our life at many levels. In the adult organism, TGF-β1 is critical for the development and maturation of immune cells, maintains immune tolerance and homeostasis, and regulates various aspects of immune responses. Following acute tissue damages, TGF-β1 becomes a master regulator of the healing process with impacts on about every cell type involved. Divergence from the tight control of TGF-β1 actions, for instance caused by chronic injury, severe trauma, or infection can tip the balance from regulated physiological to excessive pathological repair. This condition of fibrosis is characterized by accumulation and stiffening of collagenous scar tissue which impairs organ functions to the point of failure. Fibrosis and dysregulated immune responses are also a feature of cancer, in which tumor cells escape immune control partly by manipulating TGF-β1 regulation and where immune cells are excluded from the tumor by fibrotic matrix created during the stroma ‘healing’ response. Despite the obvious potential of TGF-β-signalling therapies, globally targeting TGF-β1 receptor, downstream pathways, or the active growth factor have proven to be extremely difficult if not impossible in systemic treatment regimes. However, TGF-β1 binding to cell receptors requires prior activation from latent complexes that are extracellularly presented on the surface of immune cells or within the extracellular matrix. These different locations have led to some divergence in the field which is often either seen from the perspective of an immunologists or a fibrosis/matrix researcher. Despite these human boundaries, there is considerable overlap between immune and tissue repair cells with respect to latent TGF-β1 presentation and activation. Moreover, the mechanisms and proteins employed by different cells and spatiotemporal control of latent TGF-β1 activation provide specificity that is amenable to drug development. This review aims at synthesizing the knowledge on TGF-β1 extracellular activation in the immune system and in fibrosis to further stimulate cross talk between the two research communities in solving the TGF-β conundrum.

    更新日期:2019-12-25
  • Senotherapeutics: Targeting senescence in idiopathic pulmonary fibrosis
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-24
    Wolfgang Merkt; Marta Bueno; Ana L. Mora; David Lagares

    Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no cure for IPF, and current anti-fibrotic treatments modestly arrest its further progression. IPF prevalence and incidence increase with age, which is a recognized risk factor. Intense clinical and basic research over the last fifteen years has shown that hallmarks of accelerated aging are present in the lungs of patients with IPF. Different cell types in IPF lungs exhibit premature hallmarks of aging, including telomere attrition and cellular senescence. In this Review, we discuss recent insights into the mechanisms behind these age-related alterations and their contribution to the development of lung fibrosis. We focus on the genetic and molecular basis of telomere attrition in alveolar type II epithelial cells, which promote cellular senescence and lung fibrosis. Mechanistically, senescent cells secrete pro-fibrotic factors that activate scar-forming myofibroblasts. Ultimately, senescent alveolar epithelial cells lose their regenerative capacity, impeding fibrosis resolution. In addition, mitochondrial dysfunction is strongly associated with the appearance of senescent epithelial cells and senescent myofibroblasts in IPF, which persist in the fibrotic tissue by adapting their metabolic pathways and becoming resistant to apoptosis. We discuss emerging novel therapeutic strategies to treat IPF by targeting cellular senescence with the so-called senotherapeutics.

    更新日期:2019-12-25
  • Germ cell migration—Evolutionary issues and current understanding
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-19
    Cecilia Grimaldi; Erez Raz

    In many organisms, primordial germ cells (PGCs) are specified at a different location than where the gonad forms, meaning that PGCs must migrate toward the gonad within the early developing embryo. Following species-specific paths, PGCs can be passively carried by surrounding tissues and also perform active migration. When PGCs actively migrate through and along a variety of embryonic structures in different organisms, they adopt an ancestral robust migration mode termed “amoeboid motility”, which allows cells to migrate within diverse environments. In this review, we discuss the possible significance of the PGC migration process in facilitating the evolution of animal body shape. In addition, we summarize the latest findings relevant for the molecular and cellular mechanisms controlling the movement and the directed migration of PGCs in different species.

    更新日期:2019-12-19
  • The role of actin and myosin in antigen extraction by B lymphocytes
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-18
    Jia C. Wang; John A. Hammer

    B cells must extract antigens attached to the surface of antigen presenting cells to generate high-affinity antibodies. Antigen extraction requires force, and recent studies have implicated actomyosin-dependent pulling forces generated within the B cell as the major driver of antigen extraction. These actomyosin-dependent pulling forces also serve to test the affinity of the B cell antigen receptor for antigen prior to antigen extraction. Such affinity discrimination is central to the process of antibody affinity maturation. Here we review the evidence that actomyosin-dependent pulling forces generated within the B cell promote affinity discrimination and power antigen extraction. Our take on these critical B cell functions is influenced significantly by the recent identification of formin-generated, myosin-rich, concentric actin arcs in the medial portion of the T cell immune synapse, as B cells appear to contain a similar contractile actomyosin structure.

    更新日期:2019-12-18
  • The many implications of actin filament helicity
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-18
    Antoine Jegou; Guillaume Romet-Lemonne

    One of the best known features of actin filaments is their helical structure. A number of essential properties emerge from this molecular arrangement of actin subunits. Here, we give an overview of the mechanical and biochemical implications of filament helicity, at different scales. In particular, a number of recent studies have highlighted the role of filament helicity in the adaptation to and the generation of mechanical torsion, and in the modulation of the filament’s interaction with very different actin-binding proteins (such as myosins, cross-linkers, formins, and cofilin). Helicity can thus be seen as a key factor for the regulation of actin assembly, and as a link between biochemical regulators and their mechanical context. In addition, actin filament helicity appears to play an essential role in the establishment of chirality at larger scales, up to the organismal scale. Altogether, helicity appears to be an essential feature contributing to the regulation of actin assembly dynamics, and to actin’s ability to organize cells at a larger scale.

    更新日期:2019-12-18
  • Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-18
    Nevin Witman; Chikai Zhou; Niels Grote Beverborg; Makoto Sahara; Kenneth R. Chien

    The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.

    更新日期:2019-12-18
  • Actin-based regulation of ciliogenesis – The long and the short of it
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-18
    John Copeland

    The primary cilia is found on the mammalian cell surface where it serves as an antenna for the reception and transmission of a variety of cellular signaling pathways. At its core the cilium is a microtubule-based organelle, but it is clear that its assembly and function are dependent upon the coordinated regulation of both actin and microtubule dynamics. In particular, the discovery that the centrosome is able to act as both a microtubule and actin organizing centre implies that both cytoskeletal networks are acting directly on the process of cilia assembly. In this review, we set our recent results with the formin FHDC1 in the context of current reports that show each stage of ciliogenesis is impacted by changes in actin dynamics. These include direct effects of actin filament assembly on basal body positioning, vesicle trafficking to and entry into the cilium, cilia length, cilia membrane organization and cilia-dependent signaling.

    更新日期:2019-12-18
  • Rationally-based therapeutic disease modification in systemic sclerosis: Novel strategies
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-16
    Yoshihide Asano; John Varga

    Systemic sclerosis (SSc) is a highly challenging chronic condition that is dominated by the pathogenetic triad of vascular damage, immune dysregulation/autoimmunity and fibrosis in multiple organs. A hallmark of SSc is the remarkable degree of molecular and phenotypic disease heterogeneity, which surpasses that of other complex rheumatic diseases. Disease trajectories in SSc are unpredictable and variable from patient to patient. Disease-modifying therapies for SSc are lacking, long-term morbidity is considerable and mortality remains unacceptably high. Currently-used empirical approaches to disease modification have modest and variable clinical efficacy and impact on survival, are expensive and frequently associated with unfavorable side effects, and none can be considered curative. However, research during the past several years is yielding significant advances with therapeutic potential. In particular, the application of unbiased omics-based discovery technologies to large and well-characterized SSc patient cohorts, coupled with hypothesis-testing experimental research using a variety of model systems is revealing new insights into SSc that allow formulation of a more nuanced appreciation of disease heterogeneity, and a deepening understanding of pathogenesis. Indeed, we are now presented with numerous novel and rationally-based strategies for targeted SSc therapy, several of which are currently, or expected to be shortly, undergoing clinical evaluation. In this review, we discuss promising novel therapeutic targets and rationally-based approaches to disease modification that have the potential to improve long-term outcomes in SSc.

    更新日期:2019-12-17
  • Filopodia and their links with membrane traffic and cell adhesion
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-13
    J.L. Gallop

    Filopodia are dynamic, narrow, plasma membrane protrusions filled with bundled actin filaments. Fresh actin monomers are incorporated at the tips furthest away from the cell body, where barbed end polymerases such as formins and Ena/VASP proteins are present in a complex with other regulatory proteins, including Myosin-X. The tightly packed, parallel alignment of actin filaments in the shaft is mediated by bundling, notably by fascin but also fimbrin and some formins. Filopodia often, but need not necessarily, emerge from areas of Arp2/3 complex nucleated F-actin. The membrane surrounding filopodia is tightly curved, where inverse-Bin-Amphiphysin-Rvs proteins deform the membrane, together with Ezrin-Radixin-Moesin proteins. Recent studies have revealed that phosphoinositide lipid metabolism and endophilin-dependent endocytosis are associated with filopodia and that filopodia are a site for virus and exosome internalization. The composition of filopodia can share similarity with the integrin adhesome, and adhesion plays mechanical and tissue matching roles in filopodia function. This review considers how filopodia form and discusses putative mechanistic integration between filopodia, endocytosis and adhesion.

    更新日期:2019-12-13
  • Tailored chromatin modulation to promote tissue regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-02
    Paloma Martinez-Redondo, Juan Carlos Izpisua Belmonte

    Epigenetic regulation of gene expression is fundamental in the maintenance of cellular identity and the regulation of cellular plasticity during tissue repair. In fact, epigenetic modulation is associated with the processes of cellular de-differentiation, proliferation, and re-differentiation that takes place during tissue regeneration. In here we explore the epigenetic events that coordinate tissue repair in lower vertebrates with high regenerative capacity, and in mammalian adult stem cells, which are responsible for the homeostasis maintenance of most of our tissues. Finally we summarize promising CRISPR-based editing technologies developed during the last years, which look as promising tools to not only study but also promote specific events during tissue regeneration.

    更新日期:2019-12-11
  • Chromatin dynamics underlying the precise regeneration of a vertebrate limb – Epigenetic regulation and cellular memory
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-13
    Shinichi Hayashi, Koji Tamura, Hitoshi Yokoyama

    Wound healing, tissue regeneration, and organ regrowth are all regeneration phenomena observed in vertebrates after an injury. However, the ability to regenerate differs greatly among species. Mammals can undergo wound healing and tissue regeneration, but cannot regenerate an organ; for example, they cannot regrow an amputated limb. In contrast, amphibians and fish have much higher capabilities for organ-level regeneration. In addition to medical studies and those in conventional mammalian models such as mice, studies in amphibians and fish have revealed essential factors for and mechanisms of regeneration, including the regrowth of a limb, tail, or fin. However, the molecular nature of the cellular memory needed to precisely generate a new appendage from an amputation site is not fully understood. Recent reports have indicated that organ regeneration is closely related to epigenetic regulation. For example, the methylation status of genomic DNA is related to the expression of regeneration-related genes, and histone-modification enzymes are required to control the chromatin dynamics for regeneration. A proposed mechanism of cellular memory involving an inheritable system of epigenetic modification led us to hypothesize that epigenetic regulation forms the basis for cellular memory in organ regeneration. Here we summarize the current understanding of the role of epigenetic regulation in organ regeneration and discuss the relationship between organ regeneration and epigenetic memory.

    更新日期:2019-12-11
  • Spotlight on epigenetic reprogramming in cardiac regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-26
    Carolina Soler-Botija, Sonia Vanina Forcales, Antoni Bayés Genís

    Heart failure of ischemic origin is caused by the presence of a large scar resulting from an acute myocardial infarction. Acute myocardial infarction generally occurs when blood supply to the heart is blocked. Regenerative strategies that limit infarct injury would be able to prevent adverse post-ischemic remodelling and maintain the structural support necessary for effective cardiomyocyte contraction. Our understanding of endogenous cardiac regeneration and its biology has exposed a variety of targets for therapeutic approaches, such as non-coding RNAs, DNA methylation, histone modifications, direct cardiac reprogramming, cell transplantation, stimulation of resident cardiomyocytes, proliferation, and inhibition of cardiomyocyte death. In this review, we address the epigenetic mechanisms underlying these strategies and the use of therapeutic epigenetic molecules or epidrugs.

    更新日期:2019-12-11
  • Chromatin dynamics during liver regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-09
    Maria Arechederra, Carmen Berasain, Matias A. Avila, Maite G. Fernández-Barrena
    更新日期:2019-12-11
  • Regeneration enhancers: Starting a journey to unravel regulatory events in tissue regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-08
    Anjelica M. Rodriguez, Junsu Kang

    Regeneration, an ability to replace lost body parts, is widespread across animal species. While mammals poorly regenerate most tissues, teleost fish and urodele amphibians possess remarkable regenerative capacity. Earlier work demonstrated that genes driving regeneration are evolutionarily conserved, indicating that a key factor in diverse tissue regeneration is not the presence or absence of regeneration-driving genes but the mechanisms controlling activation of these genes after injury. Thus, understanding the regulatory events of tissue regeneration could provide the means for unlocking latent capacities for tissue regeneration. After injury, cells undergo extensive epigenetic changes to establish new transcriptional programs for tissue regeneration. Gene transcription in eukaryotes is a complicated process that requires specific interactions between trans-acting regulators and cis-regulatory DNA elements. Among cis-regulatory elements, enhancers are essential to control precise gene expression. Recently, multiple regeneration/injury-associated enhancers have been identified in several model organisms. In this review, we highlight recently discovered regeneration/injury enhancers and their specific characteristics. We also discuss how abnormal regulation of regeneration enhancers influences animal development and physiology. Investigation of regeneration enhancers potentially allows us to begin understanding the fundamental biology of tissue regeneration and inspires new solutions for manipulating regenerative ability.

    更新日期:2019-12-11
  • Chromatin dynamics in regeneration epithelia: Lessons from Drosophila imaginal discs
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-16
    Elena Vizcaya-Molina, Cecilia C. Klein, Florenci Serras, Montserrat Corominas

    During the process of regeneration, a switch in the transcription program occurs in cells that contribute to the reconstruction of the missing tissue. Early signals released upon damage are integrated into the chromatin of responding cells to change its activity and function. Changes in chromatin dynamics result in transcriptional reprogramming, this is the coordinated regulation of expression of a specific subset of genes required for the regeneration process. Here we summarize changes in gene expression and chromatin dynamics that occurs during the process of regeneration of Drosophila imaginal discs.

    更新日期:2019-12-11
  • Epigenetics in neuronal regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-09
    Leah S. VandenBosch, Thomas A. Reh

    Damage to neuronal tissues in mammals leads to permanent loss of tissue function that can have major health consequences. While mammals have no inherent regenerative capacity to functionally repair neuronal tissue, other species such as amphibians and teleost fish readily replace damaged tissue. The exploration of development and native regeneration can thus inform the process of inducing regeneration in non-regenerative systems, which can be used to develop new therapeutics. Increasing evidence points to an epigenetic component in the regulation of the changes in cellular gene expression necessary for regeneration. In this review, we compare evidence of epigenetic roles in development and regeneration of neuronal tissue. We have focused on three key systems of important clinical significance: the neural retina, the inner ear, and the spinal cord in regenerative and non-regenerative species. While evidence for epigenetic regulation of regeneration is still limited, changes in DNA accessibility, histone acetylation and DNA methylation have all emerged as key elements in this process. To date, most studies have used broadly acting experimental manipulations to establish a role for epigenetics in regeneration, but the advent of more targeted approaches to modify the epigenome will be critical to dissecting the relative contributions of these regulatory factors in this process and the development of methods to stimulate the regeneration in those organisms like ourselves where only limited regeneration occurs in these neural systems.

    更新日期:2019-12-11
  • Clustered cell migration: Modeling the model system of Drosophila border cells
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-11
    Bradford E. Peercy, Michelle Starz-Gaiano

    In diverse developmental contexts, certain cells must migrate to fulfill their roles. Many questions remain unanswered about the genetic and physical properties that govern cell migration. While the simplest case of a single cell moving alone has been well-studied, additional complexities arise in considering how cohorts of cells move together. Significant differences exist between models of collectively migrating cells. We explore the experimental model of migratory border cell clusters in Drosophila melanogaster egg chambers, which are amenable to direct observation and precise genetic manipulations. This system involves two special characteristics that are worthy of attention: border cell clusters contain a limited number of both migratory and non-migratory cells that require coordination, and they navigate through a heterogeneous three-dimensional microenvironment. First, we review how clusters of motile border cells are specified and guided in their migration by chemical signals and the physical impact of adjacent tissue interactions. In the second part, we examine questions around the 3D structure of the motile cluster and surrounding microenvironment in understanding the limits to cluster size and speed of movement through the egg chamber. Mathematical models have identified sufficient gene regulatory networks for specification, the key forces that capture emergent behaviors observed in vivo, the minimal regulatory topologies for signaling, and the distribution of key signaling cues that direct cell behaviors. This interdisciplinary approach to studying border cells is likely to reveal governing principles that apply to different types of cell migration events.

    更新日期:2019-12-11
  • Metabolic pathways regulating colorectal cancer initiation and progression
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-28
    Sofia La Vecchia, Carlos Sebastián

    Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Despite recent advances in the molecular genetics of CRC, poor treatment outcomes highlight the need for a better understanding of the underlying mechanisms accounting for tumor initiation and progression. Recently, deregulation of cellular metabolism has emerged as a key hallmark of cancer. Reprogramming of core cellular metabolic pathways by cancer cells provides energy, anaplerotic precursors and reducing equivalents required to support tumor growth. Here, we review key findings implicating cancer metabolism as a major contributor of tumor initiation, growth and metastatic dissemination in CRC. We summarize the metabolic pathways governing stem cell fate in the intestine, the metabolic adaptations of proliferating colon cancer cells and their crosstalk with oncogenic signaling, and how they fulfill the energetic demands imposed by the metastatic cascade. Lastly, we discuss how some of these metabolic pathways could represent new vulnerabilities of CRC cells with the potential to be targeted.

    更新日期:2019-12-11
  • Glia-specific autophagy dysfunction in ALS
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-28
    Laura Strohm, Christian Behrends

    Neuronal cell death is the main pathological feature of chronic neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As age is strongly linked to NDs, these diseases are one of the leading medical and societal challenges faced by the rapidly aging western societies. Despite the increasing prevalence, the causes and mechanisms behind most NDs are still vague. A common hallmark of several NDs is the accumulation and aggregation of proteins. Prominent examples are amyloid beta and tau in Alzheimer’s disease, α−synuclein in Parkinson’s disease and transactive response DNA binding protein 43 kDa (TDP-43) in ALS and FTD. Under physiological conditions, protein quality control systems, namely the ubiquitin proteasome system and the autophagy machinery, eliminate such aberrant protein forms and thereby prevent proteotoxic stress. However, as proteins must unfold to undergo proteasomal degradation, aggregated proteins are poor substrates for the proteasome. Such proteins are thought to be primarily turned over by autophagy. Therefore, autophagy is considered a critical ND-protective pathway, which opens up potential new therapeutic interventions. One drawback is that the majority of research in NDs has been focused on elucidating the underlying pathomechanisms in neurons. However, neurons make up only about half of the brain cells with neuroglia being the other major central nervous system (CNS) cell type. Due to the ubiquitous presence of disease-causing mutations in all cells of the CNS, it is likely that non-neuronal cells contribute to the disease onset and/or progression. While our understanding of the roles of autophagy and its contribution to neurodegeneration in neurons deepened considerably over the last years, still comparatively little is known about the functions and disease contribution of the autophagy machinery in glia cells.

    更新日期:2019-12-11
  • 3D gastrointestinal models and organoids to study metabolism in human colon cancer
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-25
    Catarina Silva-Almeida, Marie-Ann Ewart, Colin Wilde

    Recent advances in the field of cancer metabolism raised awareness for the importance of the tumour microenvironment in tumour growth and progression. The initial theory by Heinrich Warburg was that cancer cells had a deficient oxidative respiration and thus had to perform aerobic glycolysis to produce energy. However, further research suggested that there is a metabolic reprogramming within the tumour microenvironment, controlled by communication between tumour and stromal cells. The importance of this communication exposes the need to use complex models in cancer research. Until recently, classic cell models included immortalized 2D cell lines or patient-derived tumour xenografts. Despite having contributed to many discoveries, these models present many limitations. Improved models are now being developed using 3D cell culture technology. These models are more physiologically relevant allowing the co-culture of different cells types and establishing a gradient concentration of solutes. Recent developments in organoid technology contributed largely to the expansion of 3D cell technology. Organoids can be developed from different tissues including tumours, representing the cell population and spatial organization of the tissue of origin. In the field of cancer metabolism, the interaction of different cell types, the stroma, and the different solutes and oxygen concentrations are crucial parameters. Current models to study metabolism either include only one cell population or are unable to represent solute/oxygen gradients or to collect samples in a proficient manner. The characteristics of organoid culture thus makes them a potent model to use in metabolic studies, drug development, disease model or even personalized medicine.

    更新日期:2019-12-11
  • Excitable networks controlling cell migration during development and disease
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-10
    Xiaoguang Li, Yuchuan Miao, Dhiman Sankar Pal, Peter N. Devreotes

    The directed movements of individual, groups, or sheets of cells at specific times in particular locations bring about form and complexity to developing organisms. Cells move by extending protrusions, such as macropinosomes, pseudopods, lamellipods, filopods, or blebs. Although many of the cytoskeletal components within these structures are known, less is known about the mechanisms that determine their location, number, and characteristics. Recent evidence suggests that control may be exerted by a signal transduction excitable network whose components and activities, including Ras, PI3K, TorC2, and phosphoinositides, self-organize on the plasma membrane and propagate in waves. The waves drive the various types of protrusions, which in turn, determine the modes of cell migration. Acute perturbations at specific points in the network produce abrupt shifts in protrusion type, including transitions from pseudopods to filopods or lamellipods. These observations have also contributed to a delineation of the signal transduction network, including candidate fast positive and delayed negative feedback loops. The network contains many oncogenes and tumor suppressors, and other molecules which have recently been implicated in developmental and metabolic abnormalities. Thus, the concept of signal transduction network excitability in cell migration can be used to understand disease states and morphological changes occurring in development.

    更新日期:2019-12-11
  • Towards a structural understanding of the remodeling of the actin cytoskeleton
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-10
    Felipe Merino, Sabrina Pospich, Stefan Raunser

    Actin filaments (F-actin) are a key component of eukaryotic cells. Whether serving as a scaffold for myosin or using their polymerization to push onto cellular components, their function is always related to force generation. To control and fine-tune force production, cells have a large array of actin-binding proteins (ABPs) dedicated to control every aspect of actin polymerization, filament localization, and their overall mechanical properties. Although great advances have been made in our biochemical understanding of the remodeling of the actin cytoskeleton, the structural basis of this process is still being deciphered. In this review, we summarize our current understanding of this process. We outline how ABPs control the nucleation and disassembly, and how these processes are affected by the nucleotide state of the filaments. In addition, we highlight recent advances in the understanding of actomyosin force generation, and describe recent advances brought forward by the developments of electron cryomicroscopy.

    更新日期:2019-12-11
  • Insights regarding skin regeneration in non-amniote vertebrates: Skin regeneration without scar formation and potential step-up to a higher level of regeneration
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-09
    Gembu Abe, Toshinori Hayashi, Keigo Yoshida, Takafumi Yoshida, Hidehiro Kudoh, Joe Sakamoto, Ayumi Konishi, Yasuhiro Kamei, Takashi Takeuchi, Koji Tamura, Hitoshi Yokoyama

    Skin wounds are among the most common injuries in animals and humans. Vertebrate skin is composed of an epidermis and dermis. After a deep skin injury in mammals, the wound heals, but the dermis cannot regenerate. Instead, collagenous scar tissue forms to fill the gap in the dermis, but the scar does not function like the dermis and often causes disfiguration. In contrast, in non-amniote vertebrates, including fish and amphibians, the dermis and skin derivatives are regenerated after a deep skin injury, without a recognizable scar remaining. Furthermore, skin regeneration can be compared with a higher level of organ regeneration represented by limb regeneration in these non-amniotes, as fish, anuran amphibians (frogs and toads), and urodele amphibians (newts and salamanders) have a high capacity for organ regeneration. Comparative studies of skin regeneration together with limb or other organ regeneration could reveal how skin regeneration is stepped up to a higher level of regeneration. The long history of regenerative biology research has revealed that fish, anurans, and urodeles have their own strengths as models for regeneration studies, and excellent model organisms of these non-amniote vertebrates that are suitable for molecular genetic studies are now available. Here, we summarize the advantages of fish, anurans, and urodeles for skin regeneration studies with special reference to three model organisms: zebrafish (Danio rerio), African clawed frog (Xenopus laevis), and Iberian ribbed newt (Pleurodele waltl). All three of these animals quickly cover skin wounds with the epidermis (wound epidermis formation) and regenerate the dermis and skin derivatives as adults. The availability of whole genome sequences, transgenesis, and genome editing with these models enables cell lineage tracing and the use of human disease models in skin regeneration phenomena, for example. Zebrafish present particular advantages in genetics research (e.g., human disease model and Cre-loxP system). Amphibians (X. laevis and P. waltl) have a skin structure (keratinized epidermis) common with humans, and skin regeneration in these animals can be stepped up to limb regeneration, a higher level of regeneration.

    更新日期:2019-12-11
  • Death versus dedifferentiation: The molecular bases of beta cell mass reduction in type 2 diabetes
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-09
    Tong Sun, Xiao Han

    Diabetes Mellitus is currently affecting more than 425 million people worldwide, among which over 90 % of the cases belong to type 2 diabetes. The number is growing quickly every year. Together with its many complications, the disease is causing tremendous social and economic burden and is classified as one of the leading causes of high morbidity and mortality rate. Residing in the islets of Langerhans, pancreatic beta cell serves as a central mediator in glucose homeostasis through secreting insulin, the only hormone that could reduce glucose level in the body, into the blood. Abnormality in pancreatic beta cell is generally considered as the fundamental reason which is responsible for the development of diabetes. Evidence shows that beta cell mass is greatly reduced in the biopsy of type 2 diabetic patients. Since then, large amount of research was conducted in order to decipher the molecular mechanisms behind the phenotype above and enormous progression has been made. The aim of this review is to summarize and provide a rudimentary molecular road map for beta cell mass reduction from the aspects of apoptosis and dedifferentiation based on recent research advances. Hopefully, this review could give the community some enlightenment for the next-step research and, more importantly, could provide avenues for developing novel and effective therapies to restrain or reverse beta cell loss in type 2 diabetes in the clinic.

    更新日期:2019-12-09
  • Prions and Prion-like assemblies in neurodegeneration and immunity: The emergence of universal mechanisms across health and disease
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-06
    Ailis O’Carroll, Joanne Coyle, Yann Gambin

    Prion-like behaviour is an abrupt process, an “all-or-nothing” transition between a monomeric species and an “infinite” fibrillated form. Once a nucleation point is formed, the process is unstoppable as fibrils self-propagate by recruiting and converting all monomers into the amyloid fold. After the “mad cow” episode, prion diseases have made the headlines, but more and more prion-like behaviours have emerged in neurodegenerative diseases, where formation of fibrils and large conglomerates of proteins deeply disrupt the cell homeostasis. More interestingly, in the last decade, examples emerged to suggest that prion-like conversion can be used as a positive gain of function, for memory storage or structural scaffolding. More recent experiments show that we are only seeing the tip of the iceberg and that, for example, prion-like amplification is found in many pathways of the immune response. In innate immunity, receptors on the cellular surface or within the cells ‘sense’ danger and propagate this information as signal, through protein-protein interactions (PPIs) between ‘receptor’, ‘adaptor’ and ‘effector’ proteins. In innate immunity, the smallest signal of a foreign element or pathogen needs to trigger a macroscopic signal output, and it was found that adaptor polymerize to create an extreme signal amplification. Interestingly, our body uses multiple structural motifs to create large signalling platform; a few innate proteins use amyloid scaffolds but most of the polymers discovered are composed by self-assembly in helical filaments. Some of these helical assemblies even have intercellular “contamination” in a “true” prion action, as demonstrated for ASC specks and MyD88 filaments. Here, we will describe the current knowledge in neurodegenerative diseases and innate immunity and show how these two very different fields can cross-seed discoveries.

    更新日期:2019-12-06
  • Mechanical regulation of formin-dependent actin polymerization
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-05
    Shimin Le, Miao Yu, Alexander Bershadsky, Jie Yan

    The actomyosin cytoskeleton network plays a key role in a variety of fundamental cellular processes such as cell division, migration, and cell adhesion. The functions of cytoskeleton rely on its capability to receive, generate, respond to and transmit mechanical signals throughout the cytoskeleton network within the cells and throughout the tissue via cell-extracellular matrix and cell-cell adhesions. Crucial to the cytoskeleton’s functions is actin polymerization that is regulated by many cellular factors. Among these factors, the formin family proteins, which bind the barbed end of an actin filament (F-actin), are known to be a major actin polymerization promoting factor. Mounting evidence from single-molecule mechanical manipulation experiments have suggested that formin-dependent actin polymerization is sensitively regulated by the force and torque applied to the F-actin, making the formin family an emerging mechanosensing factor that selectively promotes elongation of the F-actin under tensile forces. In this review, we will focus on the current understanding of the mechanical regulation of formin-mediated actin polymerization, the key technologies that have enabled quantification of formin-mediated actin polymerization under mechanical constraints, and future perspectives and studies on molecular mechanisms involved in the mechanosensing of actin dynamics.

    更新日期:2019-12-05
  • Cell migration by swimming: Drosophila adipocytes as a new in vivo model of adhesion-independent motility
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-12-04
    Paul Martin, Will Wood, Anna Franz

    Several cell lineages migrate through the developing and adult tissues of our bodies utilising a variety of modes of motility to suit the different substrates and environments they encounter en route to their destinations. Here we describe a novel adhesion-independent mode of single cell locomotion utilised by Drosophila fat body cells – the equivalent of vertebrate adipocytes. Like their human counterpart, these large cells were previously presumed to be immotile. However, in the Drosophila pupa fat body cells appear to be motile and migrate in a directed way towards wounds by peristaltic swimming through the hemolymph. The propulsive force is generated from a wave of cortical actomyosin that travels rearwards along the length of the cell. We discuss how this swimming mode of motility overcomes the physical constraints of microscopic objects moving in fluids, how fat body cells switch on other “motility machinery” to plug the wound on arrival, and whether other cell lineages in Drosophila and other organisms may, under certain circumstances, also adopt swimming as an effective mode of migration.

    更新日期:2019-12-04
  • Endothelium-mediated contributions to fibrosis
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-29
    Xuetao Sun, Blessing Nkennor, Olya Mastikhina, Kayla Soon, Sara S. Nunes

    Fibrosis, characterized by abnormal and excessive deposition of extracellular matrix, results in compromised tissue and organ structure. This can lead to reduced organ function and eventual failure. Although activated fibroblasts, called myofibroblasts, are considered the central players in fibrosis, the contribution of endothelial cells to the inception and progression of fibrosis has become increasingly recognized. Endothelial cells can contribute to fibrosis by acting as a source of myofibroblasts via endothelial-mesenchymal transition (EndoMT), or by becoming senescent, by secretion of profibrotic mediators and pro-inflammatory cytokines, chemokines and exosomes, promoting the recruitment of immune cells, and by participating in vascular rarefaction and decreased angiogenesis. In this review, we provide an overview of the different aspects of fibrosis in which endothelial cells have been implicated.

    更新日期:2019-11-30
  • CRISPR-Cas9: A multifaceted therapeutic strategy for cancer treatment
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-04
    Itishree Kaushik, Sharavan Ramachandran, Sanjay K. Srivastava

    CRISPR-Cas9 is an RNA guided endonuclease that has revolutionized the ability to edit genome and introduce desired manipulations in the target genomic sequence. It is a flexible methodology and is capable of targeting multiple loci simultaneously. Owing to the fact that cancer is an amalgamation of several genetic mutations, application of CRISPR-Cas9 technology is considered as a novel strategy to combat cancer. Genetic and epigenetic modulations in cancer leads to development of resistance to conventional therapy options. Given the abundance of transcriptomic and genomic alterations in cancer, developing a strategy to decipher these alterations is critical. CRISPR-Cas9 system has proven to be a promising tool in generating cellular and animal models to mimic the mutations and understand their role in tumorigenesis. CRISPR-Cas9 is an upheaval in the field of cancer immunotherapy. Furthermore, CRISPR-Cas9 plays an important role in the development of whole genome libraries for cancer patients. This approach will help understand the diversity in genome variation among the patients and also, will provide multiple variables to scientists to investigate and improvise cancer therapy. This review will focus on the discovery of CRISPR-Cas9 system, mechanisms behind CRISPR technique and its current status as a potential tool for investigating the genomic mutations associated with all cancer types.

    更新日期:2019-11-29
  • A CRISPR/Cas9 based polymeric nanoparticles to treat/inhibit microbial infections
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-23
    Richa Verma, Rajnish Sahu, Desh Deepak Singh, Timothy E. Egbo

    The latest breakthrough towards the adequate and decisive methods of gene editing tools provided by CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR Associated System), has been repurposed into a tool for genetically engineering eukaryotic cells and now considered as the major innovation in gene-related disorders. Nanotechnology has provided an alternate way to overcome the conventional problems where methods to deliver therapeutic agents have failed. The use of nanotechnology has the potential to safe-side the CRISPR/Cas9 components delivery by using customized polymeric nanoparticles for safety and efficacy. The pairing of two (CRISPR/Cas9 and nanotechnology) has the potential for opening new avenues in therapeutic use. In this review, we will discuss the most recent advances in developing nanoparticle-based CRISPR/Cas9 gene editing cargo delivery with a focus on several polymeric nanoparticles including fabrication proposals to combat microbial infections.

    更新日期:2019-11-29
  • CRISPR-Cas based targeting of host and viral genes as an antiviral strategy
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-08
    Lulia Koujah, Deepak Shukla, Afsar R. Naqvi

    Viral infections in human are leading cause of mortality and morbidity across the globe. Several viruses (including HIV and Herpesvirus), have evolved ingenious strategies to evade host-immune system and persist life-long. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) is an ancient antiviral system recently discovered in bacteria that has shown tremendous potential as a precise, invariant genome editing tool. Using CRISPR-Cas based system to activate host defenses or genetic modification of viral genome can provide novel, exciting and successful antiviral mechanisms and treatment modalities. In this review, we will provide progress on the CRISPR-Cas based antiviral approaches that facilitate clearance of virus-infected cells and/or prohibit virus infection or replication. We will discuss on the possibilities of CRIPSR-Cas as prophylaxis and therapy in viral infections and review the challenges of this potent gene editing technology.

    更新日期:2019-11-29
  • Improving plant-resistance to insect-pests and pathogens: The new opportunities through targeted genome editing
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-08
    Deepak Singh Bisht, Varnika Bhatia, Ramcharan Bhattacharya

    The advantages of high input agriculture are fading away due to degenerating soil health and adverse effects of climate change. Safeguarding crop yields in the changing environment and dynamics of pest and pathogens, has posed new challenges to global agriculture. Thus, integration of new technologies in crop improvement has been imperative for achieving the breeding objectives in faster ways. Recently, enormous potential of genome editing through engineered nucleases has been demonstrated in plants. Continuous refinements of the genome editing tools have increased depth and breadth of their applications. So far, genome editing has been demonstrated in more than fifty plant species. These include model species like Arabidopsis, as well as important crops like rice, wheat, maize etc. Particularly, CRISPR/Cas9 based two component genome editing system has been facile with wider applicability. Potential of genome editing has unfurled enormous possibilities for engineering diverse agronomic traits including durable resistance against insect-pests and pathogens. Novel propositions of developing insect and pathogen resistant crops by genome editing include altering the effector-target interaction, knocking out of host-susceptibility genes, engineering synthetic immune receptor eliciting broad spectrum resistance, uncoupling of antagonistic action of defense hormones etc. Alternatively, modification of insect genomes has been used either to create gene drive or to counteract resistance to various insecticides. The distinct advantage of genome editing system is that it can knock out specific target region in the genome without leaving the unwanted vector backbone. In this article, we have reviewed the novel opportunities offered by the genome editing technologies for developing insect and pathogen resistant crop-types, their future prospects and anticipated challenges.

    更新日期:2019-11-29
  • The potential application of genome editing by using CRISPR/Cas9, and its engineered and ortholog variants for studying the transcription factors involved in the maintenance of phosphate homeostasis in model plants
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-07
    Anupam Jyoti, Sanket Kaushik, Vijay Kumar Srivastava, Manali Datta, Shailesh Kumar, Poli Yugandhar, Shanker L. Kothari, Vandna Rai, Ajay Jain

    Phosphorus (P), an essential macronutrient, is pivotal for growth and development of plants. Availability of phosphate (Pi), the only assimilable P, is often suboptimal in rhizospheres. Pi deficiency triggers an array of spatiotemporal adaptive responses including the differential regulation of several transcription factors (TFs). Studies on MYB TF PHR1 in Arabidopsis thaliana (Arabidopsis) and its orthologs OsPHRs in Oryza sativa (rice) have provided empirical evidence of their significant roles in the maintenance of Pi homeostasis. Since the functional characterization of PHR1 in 2001, several other TFs have now been identified in these model plants. This raised a pertinent question whether there are any likely interactions across these TFs. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system has provided an attractive paradigm for editing genome in plants. Here, we review the applications and challenges of this technique for genome editing of the TFs for deciphering the function and plausible interactions across them. This technology could thus provide a much-needed fillip towards engineering TFs for generating Pi use efficient plants for sustainable agriculture. Furthermore, we contemplate whether this technology could be a viable alternative to the controversial genetically modified (GM) rice or it may also eventually embroil into a limbo.

    更新日期:2019-11-29
  • CRISPR-Cas9 directed genome engineering for enhancing salt stress tolerance in rice
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-21
    Sufia Farhat, Neha Jain, Nisha Singh, Rohini Sreevathsa, Prasanta K. Dash, Rhitu Rai, Sandeep Yadav, Pramod Kumar, Ananda K. Sarkar, Ajay Jain, Nagendra K Singh, Vandna Rai

    Crop productivity in rice is harshly limited due to high concentration of salt in the soil. To understand the intricacies of the mechanism it is important to unravel the key pathways operating inside the plant cell. Emerging state-of-the art technologies have provided the tools to discover the key components inside the plant cell for salt tolerance. Among the molecular entities, transcription factors and/or other important components of sensing and signaling cascades have been the attractive targets and the role of NHX and SOS1 transporters amply described. Not only marker assisted programs but also transgenic approaches by using reverse genetic strategies (knockout or knockdown) or overexpression have been extensively used to engineer rice crop. CRISPR/Cas is an attractive paradigm and provides the feasibility for manipulating several genes simultaneously. Here, in this review we highlight some of the molecular entities that could be potentially targeted for generating rice amenable to sustain growth under high salinity conditions by employing CRISPR/Cas. We also try to address key questions for rice salt stress tolerance other than what is already known.

    更新日期:2019-11-29
  • CRISPR mediated genome engineering to develop climate smart rice: Challenges and opportunities
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-05-10
    Akshaya K. Biswal, Satendra K. Mangrauthia, M. Raghurami Reddy, Poli Yugandhar

    Rice is a staple food crop, which ensures the calorie requirement of half of the world’s population. With the continued increase in population, rice will play a key role in achieving the food security. However, in the constantly shrinking scenario of rice fields, the necessity of these extra grains of rice must be met by reducing the yield loss due to various abiotic and biotic stresses. The adverse effects of climate impact both quality and quantity of rice production. One of the most desirable applications of CRISPR/Cas technology would be to develop climate smart rice crop to sustain and enhance its productivity in the changing environment. In this review, we analyze the desirable phenotypes and responsible genetic factors, which can be utilized to develop tolerance against major abiotic stresses imposed by climate change through genome engineering. The possibility of utilizing the information from wild resources to engineer the corresponding alleles of cultivated rice has been presented. We have also shed light on available resources for generating genome edited rice lines. The CRISPR/Cas mediated genome editing strategies for engineering of novel genes were proposed to create a plant phenotype, which can face the adversities of climate change. Further, challenges of off-targets and undesirable phenotype were discussed.

    更新日期:2019-11-29
  • Versatile and multifaceted CRISPR/Cas gene editing tool for plant research
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-24
    Prashant K. Pandey, Teagen D. Quilichini, Neha Vaid, Peng Gao, Daoquan Xiang, Raju Datla

    The ability to create desirable gene variants through targeted changes offers tremendous opportunities for the advancement of basic and applied plant research. Gene editing technologies have opened new avenues to perform such precise gene modifications in diverse biological systems. These technologies use sequence-specific nucleases, such as homing endonucleases, zinc-finger nucleases, transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (CRISPR/Cas) complexes to enable targeted genetic manipulations. Among these, the CRISPR/Cas system has emerged as a broadly applicable and valued gene editing system for its ease of use and versatility. The adaptability of the CRISPR/Cas system has facilitated rapid and continuous innovative developments to the precision and applications of this technology, since its introduction less than a decade ago. Although developed in animal systems, the simple and elegant CRISPR/Cas gene editing technology has quickly been embraced by plant researchers. From early demonstration in model plants, the CRISPR/Cas system has been successfully adapted for various crop species and enabled targeting of agronomically important traits. Although the approach faces several efficiency and delivery related challenges, especially in recalcitrant crop species, continuous advances in the CRISPR/Cas system to address these limitations are being made. In this review, we discuss the CRISPR/Cas technology, its myriad applications and their prospects for crop improvement.

    更新日期:2019-11-29
  • Precise editing of plant genomes – Prospects and challenges
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-04-19
    Viswanathan Satheesh, Hui Zhang, Xianting Wang, Mingguang Lei

    The past decade has witnessed unprecedented development in genome engineering, a process that enables targeted modification of genomes. The identification of sequence-specific nucleases such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the CRISPR/Cas system, in particular, has led to precise and efficient introduction of genetic variations into genomes of various organisms. Since the CRISPR/Cas system is highly versatile, cost-effective and much superior to ZFNs and TALENs, its widespread adoption by the research community has been inevitable. In plants, a number of studies have shown that CRISPR/Cas could be a potential tool in basic research where insertion, deletion and/or substitution in the genetic sequence could help answer fundamental questions about plant processes, and in applied research these technologies could help build or reverse-engineer plant systems to make them more useful. In this review article, we summarize technologies for precise editing of genomes with a special focus on the CRISPR/Cas system, highlight the latest developments in the CRISPR/Cas system and discuss the challenges and prospects in using the system for plant biology research.

    更新日期:2019-11-29
  • Subarachnoid cerebrospinal fluid is essential for normal development of the cerebral cortex
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-28
    Jaleel Miyan, Sarah Cains, Stephanie Larcombe, Naila Naz, Alicia Requena Jimenez, David Bueno, Angel Gato

    The central nervous system develops around a fluid filled space which persists in the adult within the ventricles, spinal canal and around the outside of the brain and spinal cord. Ventricular fluid is known to act as a growth medium and stimulator of proliferation and differentiation to neural stem cells but the role of CSF in the subarachnoid space has not been fully investigated except for its role in the recently described “glymphatic” system. Fundamental changes occur in the control and coordination of CNS development upon completion of brain stem and spinal cord development and initiation of cortical development. These include changes in gene expression, changes in fluid and fluid source from neural tube fluid to cerebrospinal fluid (CSF), changes in fluid volume, composition and fluid flow pathway, with exit of high volume CSF into the subarachnoid space and the critical need for fluid drainage. We used a number of experimental approaches to test a predicted critical role for CSF in development of the cerebral cortex in rodents and humans. Data from fetuses affected by spina bifida and/or hydrocephalus are correlated with experimental evidence on proliferation and migration of cortical cells from the germinal epithelium in rodent neural tube defects, as well as embryonic brain slice experiments demonstrating a requirement for CSF to contact both ventricular and pial surfaces of the developing cortex for normal proliferation and migration. We discuss the possibility that complications with the fluid system are likely to underlie developmental disorders affecting the cerebral cortex as well as function and integrity of the cortex throughout life.

    更新日期:2019-11-29
  • Neurogenesis: A process ontogenically linked to brain cavities and their content, CSF
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-27
    A. Gato, M.I. Alonso, F. Lamus, J. Miyan

    Neurogenesis is the process underlying the development of the highly evolved central nervous system (CNS) in vertebrates. Neurogenesis takes place by differentiation of specific Neural Precursor Cells in the neurogenic niche. The main objective of this review is to highlight the specific relationship between the brain cavities, and neurogenesis from neural precursors. Brain cavities and their content, Cerebrospinal Fluid (CSF), establish a key relation with the neurogenic “niche” because of the presence in this fluid of neurogenic signals able to control neural precursor cell behaviour, inducing precursor proliferation and neuronal differentiation. This influence seems to be ontogenically preserved, despite the temporal and spatial variations that occur throughout life. In order to better understand this concept, we consider three main life periods in the CSF-Neurogenesis interaction: The “Embryonic” period, which take place at the Neural Tube stage and extends from the isolation of the neural tube at the end of “neurulation” to the beginning of Choroid Plexus activity; the “Fetal” period, which includes the remaining developmental and the early postnatal stages; and the “Adult” period, which continues for the rest of adult life. Each period has specific characteristics in respect of CSF synthesis and composition, and the location, extension and neurogenic activity of the neurogenic niche. However, CSF interaction with the neurogenic niche is a common factor, which should be taken into account to better understand the ontogeny of neuron formation and replacement, as well as its potential role in the success or failure of therapies for the ageing, injured or diseased brain.

    更新日期:2019-11-28
  • Viscoelastic voyages – Biophysical perspectives on cell intercalation during Drosophila gastrulation
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-26
    Dinah Loerke, J. Todd Blankenship

    Developmental processes are driven by a combination of cytoplasmic, cortical, and surface-associated forces. However, teasing apart the contributions of these forces and how a viscoelastic cell responds has long been a key question in developmental biology. Recent advances in applying biophysical approaches to these questions is leading to a fundamentally new understanding of morphogenesis. In this review, we discuss how computational analysis of experimental findings and in silico modeling of Drosophila gastrulation processes has led to a deeper comprehension of the physical principles at work in the early embryo. We also summarize many of the emerging methodologies that permit biophysical analysis as well as those that provide direct and indirect measurements of force directions and magnitudes. Finally, we examine the multiple frameworks that have been used to model tissue and cellular behaviors.

    更新日期:2019-11-27
  • Under pressure: Cerebrospinal fluid contribution to the physiological homeostasis of the eye
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-21
    Serena Mirra, Gemma Marfany, Jordi Garcia-Fernàndez

    The cerebrospinal fluid (CSF) is a waterly, colorless fluid contained within the brain ventricles and the cranial and spinal subarachnoid spaces. CSF physiological functions range from hydromechanical protection of the central nervous system (CNS) to CNS modulation of developmental processes and regulation of interstitial fluid homeostasis. Optic nerve (ON) is surrounded by CSF circulating in the subarachnoid spaces and is exposed to both CSF (CSFP) and intra ocular (IOP) pressures, which converge at the lamina cribrosa (LC) as two opposite forces. The trans–lamina cribrosa pressure gradient (TLPG) is defined as IOP - CSFP and its alterations (due either to an elevation in IOP or a reduction in ICP) could result in structural damaging of the ON, including glaucomatous changes. The purpose of this review is to update the readers on the CSF contribution in controlling the functions/dysfunctions of ON by regulating homeostasis at LC. We also highlight emerging parallelisms regarding the expression of cilia-related genes in the regulation of common functions of body fluids in both brain and eye structures.

    更新日期:2019-11-21
  • Lung regeneration: a tale of mice and men
    Semin. Cell Dev. Biol. (IF 5.460) Pub Date : 2019-11-21
    Maria C. Basil, Edward E. Morrisey

    The respiratory system is the main site of gas exchange with the external environment in complex terrestrial animals. Within the trachea and lungs are multiple different tissue niches each consisting of a myriad of cells types with critical roles in air conduction, gas exchange, providing important niche specific cell-cell interactions, connection to the cardiovascular system, and immune surveillance. How the respiratory system responds to external insults and executes the appropriate regenerative response remains challenging to study given the plethora of cell and tissue interactions for this to occur properly. This review will examine the various cell types and tissue niches found within the respiratory system and provide a comparison between mouse and human lungs and trachea to highlight important similarities and differences. Defining the critical gaps in knowledge in human lung and tracheal regeneration is critical for future development of therapies directed towards respiratory diseases.

    更新日期:2019-11-21
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