Showing papers in "Results and problems in cell differentiation in 2017"
TL;DR: Although F4/80 surface expression continues to be the best method to identify tissue macrophages, additional molecules must also be examined to distinguish these cells from other immune cells.
Abstract: Tissue macrophages are a heterogeneous cell population residing in all body tissues that contribute to the maintenance of homeostasis and trigger immune activation in response to injurious stimuli. This heterogeneity may be associated with tissue-specific functions; however, the presence of distinct macrophage populations within the same microenvironment indicates that macrophage heterogeneity may also be influenced outside of tissue specialization. The F4/80 molecule was established as a unique marker of murine macrophages when a monoclonal antibody was found to recognize an antigen exclusively expressed by these cells. However, recent research has shown that F4/80 is expressed by other immune cells and is not equivalently expressed across tissue-specific macrophage lineages, including those residing in the same microenvironment, such as the peritoneum and spleen. In this context, two murine macrophage subtypes with distinct F4/80 expression patterns were recently found to coexist in the peritoneum, termed large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs). However, the presence of phenotypic and functional heterogeneous macrophage subpopulations in the spleen was already known. Thus, although F4/80 surface expression continues to be the best method to identify tissue macrophages, additional molecules must also be examined to distinguish these cells from other immune cells.
123 citations
TL;DR: This work has shown that the natural wound-healing process can be accelerated by the intracellular delivery of ATP to wound tissue, and this novel ATP-mediated acceleration arises due to an alternative activation of the M1 to M2 transition (macrophage polarization).
Abstract: Chronic wounds pose considerable public health challenges and burden. Wound healing is known to require the participation of macrophages, but mechanisms remain unclear. The M1 phenotype macrophages have a known scavenger function, but they also play multiple roles in tissue repair and regeneration when they transition to an M2 phenotype. Macrophage precursors (mononuclear cells/monocytes) follow the influx of PMN neutrophils into a wound during the natural wound-healing process, to become the major cells in the wound. Natural wound-healing process is a four-phase progression consisting of hemostasis, inflammation, proliferation, and remodeling. A lag phase of 3–6 days precedes the remodeling phase, which is characterized by fibroblast activation and finally collagen production. This normal wound-healing process can be accelerated by the intracellular delivery of ATP to wound tissue. This novel ATP-mediated acceleration arises due to an alternative activation of the M1 to M2 transition (macrophage polarization), a central and critical feature of the wound-healing process. This response is also characterized by an early increased release of pro-inflammatory cytokines (TNF, IL-1 beta, IL-6), a chemokine (MCP-1), an activation of purinergic receptors (a family of plasma membrane receptors found in almost all mammalian cells), and an increased production of platelets and platelet microparticles. These factors trigger a massive influx of macrophages, as well as in situ proliferation of the resident macrophages and increased synthesis of VEGFs. These responses are followed, in turn, by rapid neovascularization and collagen production by the macrophages, resulting in wound covering with granulation tissue within 24 h.
111 citations
TL;DR: The aim of this chapter is to provide an overview of the concepts and profibrotic pathways and to present the evidence that has been published in favor and against EMT and EndMT.
Abstract: Tubulointerstitial injury is one of the hallmarks of renal disease. In particular, interstitial fibrosis has a prominent role in the development and progression of kidney injury. Collagen-producing fibroblasts are responsible for the ECM deposition. However, the origin of those activated fibroblasts is not clear. This chapter will discuss in detail the concept of epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) in the context of fibrosis and kidney disease. In short, EMT and EndMT involve a change in cell shape, loss of polarity and increased motility associated with increased collagen production. Thus, providing a new source of fibroblasts. However, many controversies exist regarding the existence of EMT and EndMT in kidney disease, as well as its burden and role in disease development. The aim of this chapter is to provide an overview of the concepts and profibrotic pathways and to present the evidence that has been published in favor and against EMT and EndMT.
86 citations
TL;DR: The role of NO and iNOS in inflammatory and immune responses are summarized and the regulatory mechanisms that control inducible nitric oxide synthase expression and activity are discussed.
Abstract: Nitric oxide (NO) is a bioactive gas that has multiple roles in innate and adaptive immune responses. In macrophages, nitric oxide is produced by inducible nitric oxide synthase upon microbial and cytokine stimulation. It is needed for host defense against pathogens and for immune regulation. This review will summarize the role of NO and iNOS in inflammatory and immune responses and will discuss the regulatory mechanisms that control inducible nitric oxide synthase expression and activity.
79 citations
TL;DR: In this chapter, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis.
Abstract: Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151–164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443–448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518–526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477–1485, 2008; Zeier et al., Kidney Int 42:1259–1265, 1992; Ibrahim, Sci World J 7:1757–1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317–330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129–144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980–989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522–534, 1993, Kidney Int 60:2087–2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809–1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863–868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis (Ta et al., Nephrology 18:317–330, 2013). These cytokines are produced by interstitial fibroblasts, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309–1318, 2012; Park et al., Am J Nephrol 32:169–178, 2010; Bhunia et al., Cell 109:157–168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic growth factors observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32–36, 2000; Wilson et al., J Cell Physiol 150:360–369, 1992; Song et al., Hum Mol Genet 18:2328–2343, 2009; Schieren et al., Nephrol Dial Transplant 21:1816–1824, 2006). These growth factors trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.
67 citations
TL;DR: The goal of this chapter is to provide an overview of what is known about Hofbauer cell origins and their potential roles in normal and complicated pregnancy and to review established and emerging methodologies available for the study of Hofb Bauer cells during in vitro and in vivo conditions.
Abstract: Pregnancy complications such as preterm birth, miscarriage, maternal and/or neonatal morbidities, and mortality can be manifestations of underlying placental pathology. Hofbauer cells refer to a heterogeneous population of fetal macrophages that reside within the functional unit of the placenta known as the chorionic villus. Hofbauer cells can be detected within the connective tissue matrix of the placenta as early as 4 weeks post-conception and are present throughout pregnancy. These cells are implicated in a wide array of functions important for a successful pregnancy including placental morphogenesis, immune regulation, control of stromal water content, and the transfer of ions and serum proteins across the maternal–fetal barrier. Derangements in Hofbauer cell homeostasis are associated with placental pathologies involving infection, inflammation, and inadequate placental development. Despite a growing body of evidence that these cells are important, our knowledge about Hofbauer cell function in both normal and dysfunctional pregnancy is rudimentary. The goal of this chapter is to provide an overview of what is known about Hofbauer cell origins and their potential roles in normal and complicated pregnancy. We also review established and emerging methodologies available for the study of Hofbauer cells during in vitro and in vivo conditions.
65 citations
TL;DR: This chapter focuses on recent advances in the understanding of the evolution of macrophage polarization and functional heterogeneity with a focus on ectothermic vertebrates.
Abstract: Macrophages constitute a heterogeneous population of myeloid cells that are essential for maintaining homeostasis and as a first line of innate responders controlling and organizing host defenses against pathogens. Monocyte–macrophage lineage cells are among the most functionally diverse and plastic cells of the immune system. They undergo specific activation into functionally distinct phenotypes in response to immune signals and microbial products. In mammals, macrophage functional heterogeneity is defined by two activation states, M1 and M2, which represent two polar ends of a continuum exhibiting pro-inflammatory and tissue repair activities, respectively. While the ancient evolutionary origin of macrophages as phagocytic defenders is well established, the evolutionary roots of the specialized division of macrophages into subsets with polarized activation phenotypes is less well defined. Accordingly, this chapter focuses on recent advances in the understanding of the evolution of macrophage polarization and functional heterogeneity with a focus on ectothermic vertebrates.
64 citations
TL;DR: The mechanisms behind defective macrophages function in lung diseases are not currently understood, but potential mechanisms include alterations in phagocytic receptor expression levels, oxidative stress, but also the possibility that specific diseases are associated with a specific, altered, macrophage phenotype that displays reduced function.
Abstract: In the healthy lung, macrophages maintain homeostasis by clearing inhaled particles, bacteria, and removing apoptotic cells from the local pulmonary environment. However, in respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis, macrophages appear to be dysfunctional and may contribute to disease pathogenesis. In COPD, phagocytosis of bacterial species and apoptotic cells by both alveolar macrophages and monocyte-derived macrophages is significantly reduced, leading to colonization of the lung with pathogenic bacteria. COPD macrophages also release high levels of pro-inflammatory cytokines and chemokines, including CXCL8, TGFβ, and CCL2, driving recruitment of other inflammatory cells including neutrophils and monocytes to the lungs and promoting disease progression.In asthma, defective phagocytosis and efferocytosis have also been reported, and macrophages appear to have altered cell surface receptor expression; however, it is as yet unclear how this contributes to disease progression but may be important in driving Th2-mediated inflammation. In cystic fibrosis, macrophages also display defective phagocytosis, and reduced bacterial killing, which may be driven by the pro-inflammatory environment present in the lungs of these patients.The mechanisms behind defective macrophage function in lung diseases are not currently understood, but potential mechanisms include alterations in phagocytic receptor expression levels, oxidative stress, but also the possibility that specific diseases are associated with a specific, altered, macrophage phenotype that displays reduced function. Identification of the mechanisms responsible may present novel therapeutic opportunities for treatment.
62 citations
TL;DR: An overview of various approaches to model kidney disease using the zebrafish is provided, with methods spanning the use of antisense morpholino oligonucleotides to genome editing approaches such as the CRISPR/Cas9 system to see if they produce kidney phenotypes.
Abstract: Animal models have been an invaluable means to advance biomedical research as they provide experimental avenues for cellular and molecular investigations of disease pathology. The zebrafish (Danio rerio) is a good alternative to mammalian models that can be used to apply powerful genetic experimental methods normally used in invertebrates to answer questions about vertebrate development and disease. In the case of the kidney, the zebrafish has proven itself to be an applicable and versatile experimental system, mainly due to the simplicity of its pronephros, which contains two nephrons that possess conserved structural and physiological aspects with mammalian nephrons. Numerous genes that were not previously related to kidney conditions have now been linked to renal diseases by applying genetic screening with the zebrafish. In fact, a large collection of mutations that affect nephron formation and function were generated through phenotype-based forward screens. Complementary reverse genetic approaches have also been insightful, with methods spanning the use of antisense morpholino oligonucleotides to genome editing approaches such as the CRISPR/Cas9 system, to selectively knock down or knock out genes of interest to see if they produce kidney phenotypes. Acute kidney injury (AKI) has also been easily modeled in the zebrafish by injecting nephrotoxins, directly inducing damage through surgical intervention, or by generating transgenic lines that express compounds in a tissue-specific manner that when exposed to certain drugs promote an apoptotic response within cells. In this chapter, we provide an overview of these various approaches as well as discuss many of the contributions that have been achieved through the use of zebrafish to model kidney disease.
51 citations
TL;DR: The roles of the Wnt/β-catenin pathway in specifying cell fate throughout evolution are discussed, how its function in patterning during development is often reactivated during regeneration and how perturbation of this pathway has negative consequences for the control of cell fate.
Abstract: The Wnt/β-catenin pathway is an ancient and highly conserved signalling pathway that plays fundamental roles in the regulation of embryonic development and adult homeostasis. This pathway has been implicated in numerous cellular processes, including cell proliferation, differentiation, migration, morphological changes and apoptosis. In this chapter, we aim to illustrate with specific examples the involvement of Wnt/β-catenin signalling in cell fate determination. We discuss the roles of the Wnt/β-catenin pathway in specifying cell fate throughout evolution, how its function in patterning during development is often reactivated during regeneration and how perturbation of this pathway has negative consequences for the control of cell fate.
43 citations
TL;DR: This review will focus on what has been learned about the basic mechanisms underlying ACD in fly neuroblasts, and its usefulness to study basic aspects of stem cell biology and tumor formation.
Abstract: Asymmetric cell division (ACD) is a fundamental mechanism to generate cell diversity, giving rise to daughter cells with different developmental potentials. ACD is manifested in the asymmetric segregation of proteins or mRNAs, when the two daughter cells differ in size or are endowed with different potentials to differentiate into a particular cell type (Horvitz and Herskowitz, Cell 68:237–255, 1992). Drosophila neuroblasts, the neural stem cells of the developing fly brain, are an ideal system to study ACD since this system encompasses all of these characteristics. Neuroblasts are intrinsically polarized cells, utilizing polarity cues to orient the mitotic spindle, segregate cell fate determinants asymmetrically, and regulate spindle geometry and physical asymmetry. The neuroblast system has contributed significantly to the elucidation of the basic molecular mechanisms underlying ACD. Recent findings also highlight its usefulness to study basic aspects of stem cell biology and tumor formation. In this review, we will focus on what has been learned about the basic mechanisms underlying ACD in fly neuroblasts.
TL;DR: This chapter gives a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of TCTP, a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes.
Abstract: The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein.
TL;DR: This chapter reviews the modes of transovarial transmission of symbionts between generations in insects and reveals a large diversity of symbiotic microorganisms and different strategies of their transmission from one generation to the next.
Abstract: Many insects, on account of their unbalanced diet, live in obligate symbiotic associations with microorganisms (bacteria or yeast-like symbionts), which provide them with substances missing in the food they consume. In the body of host insect, symbiotic microorganisms may occur intracellularly (e.g., in specialized cells of mesodermal origin termed bacteriocytes, in fat body cells, in midgut epithelium) or extracellularly (e.g., in hemolymph, in midgut lumen). As a rule, symbionts are vertically transmitted to the next generation. In most insects, symbiotic microorganisms are transferred from mother to offspring transovarially within female germ cells. The results of numerous ultrastructural and molecular studies on symbiotic systems in different groups of insects have shown that they have a large diversity of symbiotic microorganisms and different strategies of their transmission from one generation to the next. This chapter reviews the modes of transovarial transmission of symbionts between generations in insects.
TL;DR: Data indicate that Vtg, in addition to being involved in yolk protein formation, also plays non-nutritional roles via functioning as immune-relevant molecules and antioxidant reagents.
Abstract: Our understanding of the functions of vitellogenin (Vtg) in reproduction has undergone an evolutionary transformation over the past decade. Primarily, Vtg was regarded as a female-specific reproductive protein, which is cleaved into yolk proteins including phosvitin (Pv) and lipovitellin (Lv), stored in eggs, providing the nutrients for early embryos. Recently, Vtg has been shown to be an immunocomponent factor capable of protecting the host against the attack by microbes including bacteria and viruses. Moreover, Pv and Lv that both are proteolytically cleaved products of maternal Vtg, as well as Pv-derived small peptides, all display an antibacterial role in developing embryos. In addition, both Vtg and yolk protein Pv possess antioxidant activity capable of protecting cells from damage by free radicals. Collectively, these data indicate that Vtg, in addition to being involved in yolk protein formation, also plays non-nutritional roles via functioning as immune-relevant molecules and antioxidant reagents.
TL;DR: Several parameters have been identified that influence macrophage response to biomaterials, specifically size, geometry, surface topography, hydrophobicity, surface chemistry, material mechanics, and protein adsorption.
Abstract: Macrophages are the initial biologic responders to biomaterials. These highly plastic immune sentinels control and modulate responses to materials, foreign or natural. The responses may vary from immune stimulatory to immune suppressive. Several parameters have been identified that influence macrophage response to biomaterials, specifically size, geometry, surface topography, hydrophobicity, surface chemistry, material mechanics, and protein adsorption. In this review, the influence of these parameters is supported with examples of both synthetic and naturally derived materials and illustrates that a combination of these parameters ultimately influences macrophage responses to the biomaterial. Having an understanding of these properties may lead to highly efficient design of biomaterials with desirable biologic response properties.
TL;DR: This short review will review the current hypotheses on tissue-resident macrophage ontogeny and functions, as compared to blood-derived monocytes, with a particular focus on inflammatory conditions.
Abstract: Mononuclear phagocytes are key cells in tissue integrity and defense. Tissue-resident macrophages are abundantly present in all tissues of the body and have a complex role in ensuring tissue functions and homeostatic balance. Circulating blood monocytes can enter tissue both in steady-state conditions, for helping in replenishing the tissue-resident macrophage pool and, in particular, for acting as potent effector cells during inflammatory events such as infections, traumas, and diseases. The heterogeneity of monocytes and macrophages depends on their ontogeny, their tissue location, and their functional programming, with both monocytes and macrophages able to exert distinct or similar functions depending on the tissue-specific and stimulus-specific microenvironment. In this short review, we will review the current hypotheses on tissue-resident macrophage ontogeny and functions, as compared to blood-derived monocytes, with a particular focus on inflammatory conditions.
TL;DR: The maternal legacy of the follicular microenvironment is witnessed by the fertilization of the ovulated oocyte and subsequent birth of healthy offspring.
Abstract: Development of animal germ cells depends critically on continuous contact and communication with the somatic compartment of the gonad. In females, each oocyte is enclosed within a follicle, whose somatic cells supply nutrients that sustain basal metabolic activity of the oocyte and send signals that regulate its differentiation. This maternal microenvironment thus plays an indispensable role in ensuring the production of fully differentiated oocytes that can give rise to healthy embryos. The granulosa cells send signals, likely membrane-associated Kit ligand, which trigger oocytes within resting-stage primordial follicles to initiate growth. During growth, the granulosa cells feed amino acids, nucleotides, and glycolytic substrates to the oocyte. These factors are necessary for the oocyte to complete its growth and are delivered via gap junctions that couple the granulosa cells to the oocyte. In a complementary manner, growing oocytes also release growth factors, notably growth-differentiation factor 9 and bone morphogenetic protein 15, which are necessary for proper differentiation of the granulosa cells and for these cells to support oocyte growth. During the late stages of oocyte growth, cyclic GMP that is synthesized by the granulosa cells and diffuses into the oocyte is required to prevent its precocious entry into meiotic maturation. Finally, at the early stages of maturation, granulosa cell signals promote the synthesis of a subset of proteins within the oocyte that enhance their ability to develop as embryos. Thus, the maternal legacy of the follicular microenvironment is witnessed by the fertilization of the ovulated oocyte and subsequent birth of healthy offspring.
TL;DR: In vivo studies in genetic model organisms that shed light on how diet-dependent signals control the proliferation, maintenance, and survival of adult germline stem cells and their progeny have implications for fertility during aging or disease states are focused on.
Abstract: Tight coupling of reproduction to environmental factors and physiological status is key to long-term species survival. In particular, highly conserved pathways modulate germline stem cell lineages according to nutrient availability. This chapter focuses on recent in vivo studies in genetic model organisms that shed light on how diet-dependent signals control the proliferation, maintenance, and survival of adult germline stem cells and their progeny. These signaling pathways can operate intrinsically in the germ line, modulate the niche, or act through intermediate organs to influence stem cells and their differentiating progeny. In addition to illustrating the extent of dietary regulation of reproduction, findings from these studies have implications for fertility during aging or disease states.
TL;DR: How the interplay between macrophages and MSC mutually modulates their phenotypes and functions, orchestrates tissue repair, and controls inflammation during autoimmunity and tumor growth is discussed.
Abstract: Mesenchymal stem cells (MSC) are multipotent stem cells with a broad well-described immunosuppressive potential. They are able to modulate both the innate and the adaptive immune response. Particularly, MSC are able to regulate the phenotype and function of macrophages that are critical for different biological processes including wound healing, inflammation, pathogenesis of several autoimmune diseases, and tumor growth. These multifunctional roles of macrophages are due to their high plasticity, which enable them to adopt different phenotypes such as a pro-inflammatory M1 and anti-inflammatory M2 phenotype. MSC promote macrophage differentiation toward an M2-like phenotype with a high tissue remodeling potential and anti-inflammatory activity but also a pro-tumorigenic function. MSC regulatory effect on macrophages is mediated through the secretion of different immunomodulatory molecules such as PGE2, IL1RA, and IL-6. Moreover, the presence of macrophages in damaged tissue and inflammation is essential for MSC to exert their therapeutic function. In this chapter, we discuss how the interplay between macrophages and MSC mutually modulates their phenotypes and functions, orchestrates tissue repair, and controls inflammation during autoimmunity and tumor growth.
TL;DR: Oocyte activation, the fundamental process by which the oocyte is alleviated from metaphase II arrest by a sperm-soluble factor, is focused upon.
Abstract: This chapter intends to summarise the importance of sperm- and oocyte-derived factors in the processes of sperm–oocyte binding and oocyte activation. First, we describe the initial interaction between sperm and the zona pellucida, with particular regard to acrosome exocytosis. We then describe how sperm and oocyte membranes fuse, with special reference to the discovery of the sperm protein IZUMO1 and its interaction with the oocyte membrane receptor JUNO. We then focus specifically upon oocyte activation, the fundamental process by which the oocyte is alleviated from metaphase II arrest by a sperm-soluble factor. The identity of this sperm factor has been the source of much debate recently, although mounting evidence, from several different laboratories, provides strong support for phospholipase C ζ (PLCζ), a sperm-specific phospholipase. Herein, we discuss the evidence in support of PLCζ and evaluate the potential role of other candidate proteins, such as post-acrosomal WW-binding domain protein (PAWP/WBP2NL). Since the cascade of downstream events triggered by the sperm-borne oocyte activation factor heavily relies upon specialised cellular machinery within the oocyte, we also discuss the critical role of oocyte-borne factors, such as the inositol trisphosphate receptor (IP3R), protein kinase C (PKC), store-operated calcium entry (SOCE) and calcium/calmodulin-dependent protein kinase II (CaMKII), during the process of oocyte activation. In order to place the implications of these various factors and processes into a clinical context, we proceed to describe their potential association with oocyte activation failure and discuss how clinical techniques such as the in vitro maturation of oocytes may affect oocyte activation ability. Finally, we contemplate the role of artificial oocyte activating agents in the clinical rescue of oocyte activation deficiency and discuss options for more endogenous alternatives.
TL;DR: The role of macrophages in specific cases of injury and disease is described and enhanced therapeutic treatments can be developed that enhance the normal healing response as well as help the survival of therapeutic cells delivered to the site of injury.
Abstract: Inflammation is an essential component of the normal mammalian host tissue response and plays an important role during cardiovascular and musculoskeletal diseases. Given the important role of inflammation on the host tissue response after injury, understanding this process represents essential aspects of biomedical research, tissue engineering, and regenerative medicine. Macrophages are central players during the inflammatory response with an extensive role during wound healing. These cells exhibit a spectrum of activation states that span from pro-inflammatory to pro-healing phenotypes. The phenotype of the macrophages can have profound influences on the progression of disease or injury. As such, understanding and subsequent modulation of macrophage phenotype represents an exciting target area for regenerative medicine therapies. In this chapter, we describe the role of macrophages in specific cases of injury and disease. After myocardial infarction, a biphasic response of pro- and anti-inflammatory macrophages are involved in the remodeling process. In volumetric muscle loss, there is an intricate communication between inflammatory cells and progenitor cells affecting repair processes. Osteoarthritis is characterized by increased levels of pro-inflammatory macrophages over an extended period of time with significant impact on the progression of the disease. By harnessing the complex role of macrophages, enhanced therapeutic treatments can be developed that enhance the normal healing response as well as help the survival of therapeutic cells delivered to the site of injury.
TL;DR: This chapter presents evidences that Malpighian tubules can be used as a model organ system to address the fundamental questions in developmental and functional disorders of the kidney.
Abstract: The Malpighian tubules of insects are structurally simple but functionally important organs, and their integrity is important for the normal excretory process. They are functional analogs of human kidneys which are important physiological organs as they maintain water and electrolyte balance in the blood and simultaneously help the body to get rid of waste and toxic products after various metabolic activities. In addition, it receives early indications of insults to the body such as immune challenge and other toxic components and is essential for sustaining life. According to National Vital Statistics Reports 2016, renal dysfunction has been ranked as the ninth most abundant cause of death in the USA. This chapter provides detailed descriptions of Drosophila Malpighian tubule development, physiology, immune function and also presents evidences that Malpighian tubules can be used as a model organ system to address the fundamental questions in developmental and functional disorders of the kidney.
TL;DR: This chapter focuses on the recent findings on RNA distribution related to the temporal and spatial translational control of the meiotic cycle progression in mammalian oocytes and the most relevant mechanisms involved in the organization of the oocyte's maternal transcriptome storage and localization, and the regulation of translation.
Abstract: Fully grown oocytes arrest meiosis at prophase I and deposit maternal RNAs. A subset of maternal transcripts is stored in a dormant state in the oocyte, and the timely driven translation of specific mRNAs guides meiotic progression, the oocyte-embryo transition, and early embryo development. In the absence of transcription, the regulation of gene expression in oocytes is controlled almost exclusively at the level of transcriptome and proteome stabilization and at the level of protein synthesis.This chapter focuses on the recent findings on RNA distribution related to the temporal and spatial translational control of the meiotic cycle progression in mammalian oocytes. We discuss the most relevant mechanisms involved in the organization of the oocyte's maternal transcriptome storage and localization, and the regulation of translation, in correlation with the regulation of oocyte meiotic progression.
TL;DR: To better understand ciliary function in the kidney, the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease are highlighted.
Abstract: Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.
TL;DR: The zebrafish pronephric kidney provides a simple, yet powerful, model system to better understand the conserved molecular and cellular progresses that drive nephron formation, structure, and function.
Abstract: The pronephros is the first kidney type to form in vertebrate embryos. The first step of pronephrogenesis in the zebrafish is the formation of the intermediate mesoderm during gastrulation, which occurs in response to secreted morphogens such as BMPs and Nodals. Patterning of the intermediate mesoderm into proximal and distal cell fates is induced by retinoic acid signaling with downstream transcription factors including wt1a, pax2a, pax8, hnf1b, sim1a, mecom, and irx3b. In the anterior intermediate mesoderm, progenitors of the glomerular blood filter migrate and fuse at the midline and recruit a blood supply. More posteriorly localized tubule progenitors undergo epithelialization and fuse with the cloaca. The Notch signaling pathway regulates the formation of multi-ciliated cells in the tubules and these cells help propel the filtrate to the cloaca. The lumenal sheer stress caused by flow down the tubule activates anterior collective migration of the proximal tubules and induces stretching and proliferation of the more distal segments. Ultimately these processes create a simple two-nephron kidney that is capable of reabsorbing and secreting solutes and expelling excess water—processes that are critical to the homeostasis of the body fluids. The zebrafish pronephric kidney provides a simple, yet powerful, model system to better understand the conserved molecular and cellular progresses that drive nephron formation, structure, and function.
TL;DR: This chapter will review how the main objective of asymmetric divisions in size is reached with an emphasis on the role of actin microfilaments in this process in mouse oocytes, the most studied example in mammals.
Abstract: Mammalian oocytes grow periodically after puberty thanks to the dialogue with their niche in the follicle. This communication between somatic and germ cells promotes the accumulation, inside the oocyte, of maternal RNAs, proteins and other molecules that will sustain the two gamete divisions and early embryo development up to its implantation. In order to preserve their stock of maternal products, oocytes from all species divide twice minimizing the volume of their daughter cells to their own benefit. For this, they undergo asymmetric divisions in size where one main objective is to locate the division spindle with its chromosomes off-centred. In this chapter, we will review how this main objective is reached with an emphasis on the role of actin microfilaments in this process in mouse oocytes, the most studied example in mammals. This chapter is subdivided into three parts: I-General features of asymmetric divisions in mouse oocytes, II-Mechanism of chromosome positioning by actin in mouse oocytes and III-Switch from asymmetric to symmetric division at the oocyte-to-embryo transition.
TL;DR: The different types of mechanical signals that cells encounter within the body are described and the current knowledge on the role of Mechanical signals in regulating macrophage, monocyte, and dendritic cell function is reviewed.
Abstract: Tissue homeostasis is not only controlled by biochemical signals but also through mechanical forces that act on cells. Yet, while it has long been known that biochemical signals have profound effects on cell biology, the importance of mechanical forces has only been recognized much more recently. The types of mechanical stress that cells experience include stretch, compression, and shear stress, which are mainly induced by the extracellular matrix, cell-cell contacts, and fluid flow. Importantly, macroscale tissue deformation through stretch or compression also affects cellular function.Immune cells such as macrophages and dendritic cells are present in almost all peripheral tissues, and monocytes populate the vasculature throughout the body. These cells are unique in the sense that they are subject to a large variety of different mechanical environments, and it is therefore not surprising that key immune effector functions are altered by mechanical stimuli. In this chapter, we describe the different types of mechanical signals that cells encounter within the body and review the current knowledge on the role of mechanical signals in regulating macrophage, monocyte, and dendritic cell function.
TL;DR: Recent advances in elucidating the molecular basis for the establishment of oocyte polarity at the level of Balbiani body assembly as well as the formation of RNP assemblies for early and late pathway mRNA localization in the oocyte are outlined.
Abstract: RNA localization is a fundamental mechanism for controlling cell structure and function. Early development in fish and amphibians requires the localization of specific mRNAs to establish the initial differences in cell fates prior to the onset of zygotic genome activation. RNA localization in these oocytes (e.g., Xenopus and zebrafish) requires that animal-vegetal polarity be established early in oogenesis, mediated by formation of the Balbiani body/mitochondrial cloud. This structure serves as a platform for assembly and transport of germline determinants to the future vegetal pole and also sets up the machinery for the localization of non-germline transcripts later in oogenesis. Understanding these polarization and localization mechanisms is critical for understanding the basis for early embryonic development in these organisms and also for understanding the role of RNA compartmentalization in animal gametogenesis. Here we outline recent advances in elucidating the molecular basis for the establishment of oocyte polarity at the level of Balbiani body assembly as well as the formation of RNP assemblies for early and late pathway mRNA localization in the oocyte.
TL;DR: Different types of macrophages and their roles in Atherosclerotic lesion dynamics are discussed and the results of several experiments studying macrophage polarisation in atherosclerosis are described.
Abstract: Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.
TL;DR: The body of evidence underlying a unified model for Wnt-driven asymmetric cell division in C. elegans is reviewed to identify global themes that occur during asymmetrical cell division, as well as highlight tissue-specific variations.
Abstract: Asymmetric cell division is a common mode of cell differentiation during the invariant lineage of the nematode, C. elegans. Beginning at the four-cell stage, and continuing throughout embryogenesis and larval development, mother cells are polarized by Wnt ligands, causing an asymmetric inheritance of key members of a Wnt/β-catenin signal transduction pathway termed the Wnt/β-catenin asymmetry pathway. The resulting daughter cells are distinct at birth with one daughter cell activating Wnt target gene expression via β-catenin activation of TCF, while the other daughter displays transcriptional repression of these target genes. Here, we seek to review the body of evidence underlying a unified model for Wnt-driven asymmetric cell division in C. elegans, identify global themes that occur during asymmetric cell division, as well as highlight tissue-specific variations. We also discuss outstanding questions that remain unanswered regarding this intriguing mode of asymmetric cell division.