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Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation.

Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity.

The formation of red blood cells begins with the differentiation of multipotent haematopoietic progenitors. Reconstructing the steps of this differentiation represents a general challenge in stem-cell biology. Here we used single-cell transcriptomics, fate assays and a theory that allows the prediction of cell fates from population snapshots to demonstrate that mouse haematopoietic progenitors differentiate through a continuous, hierarchical structure into seven blood lineages. We uncovered coupling between the erythroid and the basophil or mast cell fates, a global haematopoietic response to erythroid stress and novel growth factor receptors that regulate erythropoiesis. We defined a flow cytometry sorting strategy to purify early stages of erythroid differentiation, completely isolating classically defined burst-forming and colony-forming progenitors. We also found that the cell cycle is progressively remodelled during erythroid development and during a sharp transcriptional switch that ends the colony-forming progenitor stage and activates terminal differentiation. Our work showcases the utility of linking transcriptomic data to predictive fate models, and provides insights into lineage development in vivo . Single-cell transcriptomics, fate assays and a computational theory enable prediction of cell fates during haematopoiesis, discovery of regulators of erythropoiesis and reveal coupling between the erythroid, basophil and mast cell fates. The hierarchy of blood cell lineages Allon Klein, Merav Socolovsky and colleagues examine the emergence of distinct blood cell lineages from mouse haematopoietic progenitors. Their approach combines single-cell transcriptomics, cell fate potential assays and population balance analysis—a computational method for predicting cell fate probabilities from population snapshots. They use a new flow-cytometry strategy to sort cells with newly defined markers of erythroid differentiation and validate the findings at the single-cell level. The results show that differentiation is a continuous, albeit hierarchical, process. They also reveal that erythroid and mast cell fates are coupled, and that remodelling the expression of cell cycle regulators is very important as erythroid cells proceed to terminal differentiation.

Key Points Mast cells and basophils are phenotypically and functionally related cell types that promote protective immunity to helminths, but that can also cause pathology during allergic inflammation. Mast cells and basophils might have evolved from a common precursor cell, such as the mast cell/basophil-like (MCBL) cell or the test cell, which were identified in the urochordate Styela plicata . A basophil/mast cell progenitor (BMCP) cell population was isolated from the spleen of adult mice, and the timed expression of the transcription factors GATA-binding protein 2 and CCAAT/enhancer-binding protein-α in these progenitor cells might determine whether they eventually mature into basophils or mast cells. New mouse models have been developed in which mast cells or basophils can be constitutively or conditionally depleted. These models allow more specific targeting of mast cells and basophils, compared with the Kit -mutant mouse strains and depleting antibody strategies which were previously used to assess mast cell and basophil functions in vivo . Therefore, these new mouse models will help to further clarify the true biological roles of basophils and mast cells. Although mast cells and basophils can express interleukin-4, CD40 ligand and low levels of MHC class II under certain conditions, they seem to have no major role in driving the induction of adaptive type 2 immune responses. Mast cells and basophils cooperate to provide protection during secondary infestation with ticks. In addition, both cell types contribute, to various degrees, to protective immunity during gastrointestinal helminth infections in mice. IgE-mediated anaphylaxis is strictly mast cell-dependent, whereas IgG1-mediated anaphylaxis in mice results from the activation of monocytes, neutrophils or basophils. Basophils are recruited to the skin in a mouse model of atopic dermatitis and they induce IgE-mediated chronic allergic inflammation of the skin in the absence of mast cells. Mast cells and basophils are associated with protective immunity to helminths, but can also drive pathological immune responses in asthma and allergy. This Review covers the recent advances that have improved our understanding of the origins of these cells and of their biological functions in both health and disease. Mast cells and basophils are potent effector cells of the innate immune system, and they have both beneficial and detrimental functions for the host. They are mainly implicated in pro-inflammatory responses to allergens but can also contribute to protection against pathogens. Although both cell types were identified more than 130 years ago by Paul Ehrlich, their in vivo functions remain poorly understood. The precursor cell populations that give rise to mast cells and basophils have recently been characterized and isolated. Furthermore, new genetically modified mouse strains have been developed, which enable more specific targeting of mast cells and basophils. Such advances offer new opportunities to uncover the true in vivo activities of these cells and to revisit their previously proposed effector functions.

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.

The regeneration of injured tissues by exogenous and endogenous stem cells relies on the local microenvironment being conducive to repair. Chronic diseases confer tissue and organ damage that reduce quality of life and are largely refractory to therapy. Although stem cells hold promise for treating degenerative diseases by 'seeding' injured tissues, the regenerative capacity of stem cells is influenced by regulatory networks orchestrated by local immune responses to tissue damage, with macrophages being a central component of the injury response and coordinator of tissue repair. Recent research has turned to how cellular and signaling components of the local stromal microenvironment (the 'soil' to the stem cells' seed), such as local inflammatory reactions, contribute to successful tissue regeneration. This Review discusses the basic principles of tissue regeneration and the central role locally acting components may play in the process. Application of seed-and-soil concepts to regenerative medicine strengthens prospects for developing cell-based therapies or for promotion of endogenous repair.

Mast cells are critical for allergic and inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. SP (0.01–1 μM) administered together with IL-33 (30 ng/mL) to human cultured LAD2 mast cells stimulates a marked increase (P < 0.0001) in secretion of the proinflammatory cytokine IL-1β. Preincubation of LAD2 (30 min) with the SP receptor (NK-1) antagonists L-733,060 (10 μM) or CP-96345 (10 μM) inhibits (P < 0.001) secretion of IL-1β stimulated by either SP (1 μM) or SP together with IL-33 (30 ng/mL). Surprisingly, secretion of IL-1β stimulated by IL-33 is inhibited (P < 0.001) by each NK-1 antagonist. Preincubation with an antibody against the IL-33 receptor ST2 inhibits (P < 0.0001) secretion of IL-1β stimulated either by IL-33 or together with SP. The combination of SP (1 μM) with IL-33 (30 ng/mL) increases IL-1β gene expression by 90-fold in LAD2 cells and by 200-fold in primary cultured mast cells from human umbilical cord blood. The combination of SP and IL-33 increases intracellular levels of IL-1β in LAD2 by 100-fold and gene expression of IL-1β and procaspase-1 by fivefold and pro-IL-1β by twofold. Active caspase-1 is present even in unstimulated cells and is detected extracellularly. Preincubation of LAD2 cells with the natural flavonoid methoxyluteolin (1–100 mM) inhibits (P < 0.0001) secretion and gene expression of IL-1β, procaspase-1, and pro-IL-1β. Mast cell secretion of IL-1β in response to SP and IL-33 reveals targets for the development of antiinflammatory therapies.

Ex vivo expansion of hematopoietic stem cells (HSC) requires the maintenance of a stemness state while cells are proliferating. This can be achieved via exposure to UM171 which leads to the degradation of chromatin modifiers and prevents the loss of key epigenetic marks. However, the chromatin landscape varies across populations within the hematopoietic system and the effect of UM171 on self-renewal and differentiation potential of different hematopoietic progenitor cells is less characterized. To address this, we use the CellTag barcoding approach to track the fate of individual stem and progenitor cells during in vitro expansion. We show that, in addition to its HSC self-renewing property, UM171 specifically modulates cell fate of a precursor common to erythroid, megakaryocytic, and mast cells in favor of self-renewal and a mast-bias differentiation trajectory. This differentiation bias can be driven by pro-inflammatory signaling pathways that are activated downstream of UM171 and results in an abundant mast cell population that can be transplanted as part of the graft to populate mice tissues in xenotransplantation studies. UM171 is being used to promote self-renewal and expansion of human hematopoietic stem cells in vitro. Here, authors show through clonal analysis that UM171 also biases the differentiation trajectories of hematopoietic progenitor cells in culture.

Key Points Although widely associated with various inflammatory diseases, mast cells have an evolutionarily conserved role in host defence and have been shown to make functional contributions to immunity to a broad range of pathogens including bacteria, parasites and possibly viruses. Functioning as sentinels, mast cells quickly recognize pathogens during primary and subsequent infections through various direct and indirect receptors, including Toll-like receptors, receptors for endogenous host by-products of inflammation and Fc receptors, which can bind pathogens through high-affinity antibody-mediated interactions. Mast cells have the potential to be the first responding cell type at a site of infection owing to their ability to degranulate in response to many signs of inflammation and infection and release preformed mediators within seconds of activation. A key function of mast cells during infection is to communicate with many cell types, such as dendritic cells, lymphocytes, neutrophils, macrophages, epithelial cells, endothelial cells and neural cells, both locally at a site of infection and in distant tissues such as lymph nodes. Mast cells act as catalysts for immune responses to pathogens, enhancing the speed and magnitude of both innate and adaptive immune responses, and they can also influence the character of responses by producing unique factors depending on the type of pathogen challenge. These qualities also make them effective targets to enhance immune responses to vaccine antigens. Unique attributes of mast cells, including their abilities to survive after activation, replenish their granules, replicate at sites of inflammation and bind pathogen-specific antibodies after a primary response, highlight their potential to contribute to immunological memory, which may influence host responses to chronic or secondary infections. In this Review the authors describe the key attributes of mast cells that make them well suited to initiate and coordinate innate and adaptive immune responses to pathogens, by acting as pathogen sensors, immune effectors and immune modulators. Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the recognition of pathogens and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at the host–environment interface, mast cells have been shown to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection and to draining lymph nodes. Interestingly, the character and timing of these responses can vary depending on the type of pathogen stimulus, location of pathogen recognition and sensitization state of the responding mast cells. Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.

The formation of mature spermatozoa originates from spermatogonial stem cells (SSCs) located near the basement membrane of the seminiferous tubules. This developmental process, known as spermatogenesis, is tightly regulated to ensure continuous sperm production. A critical aspect of this regulation is the balance between SSC differentiation and self-renewal, which is directed by various factors guiding SSCs in either of these two directions. The SSC niche, defined functionally rather than anatomically, includes all factors necessary for SSC maintenance. These factors are produced by cells surrounding the SSC niche, collectively creating the microenvironment of the seminiferous tubules. Coordination between the cells in this microenvironment is essential for the proper function of the SSC niche and successful spermatogenesis. Testicular mast cells (MCs) significantly influence the regulation of this niche, as they contain various biologically active substances that regulate a wide range of physiological processes and contribute to different pathological conditions affecting fertility. This review explores the effects of testicular MCs on SSCs, their role in regulating spermatogenesis under normal and pathological conditions, and their interactions with other components of the testicular microenvironment, with a focus on their potentially critical impact on spermatogenesis and male fertility.