scholarly journals Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors

2021 ◽  
Author(s):  
Chenyan Wu ◽  
Daryl Boey ◽  
Oscar Bril ◽  
Jennine Grootens ◽  
M. S. Vijayabaskar ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Differentiation ◽  
Mast Cells ◽  
Single Cell ◽  
Expression Patterns ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Mast Cell Progenitor

AbstractMast cell accumulation is a hallmark of a number of diseases including allergic asthma and systemic mastocytosis. IgE-mediated crosslinking of the FcεRI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages and there are still controversies about the identity of the mast cell progenitor, i.e., whether FcεRI expression appears during the hematopoietic progenitor stage or in maturing mast cells. Here, we used single-cell transcriptomics to reveal a temporal association between the appearance of FcεRI and the mast cell gene signature in CD34+ hematopoietic progenitors. In agreement with these data, the FcεRI+ hematopoietic progenitors formed morphologically, phenotypically and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating mast cell progenitor development. Culture assays showed that IL-3 and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust FcεRI downregulation. Taken together, we have demonstrated that FcεRI appears during the hematopoietic progenitor stage of mast cell differentiation and that external stimuli may regulate the FcεRI expression. Thus, the results resolve the controversy regarding the appearance of FcεRI during mast cell development.One-sentence summarySingle-cell analysis of human hematopoiesis uncovers the stage at which FcεRI appears during mast cell differentiation and reveals disparate effects of IL-3, IL-5 and IL-33 on mast cell progenitor proliferation, survival, and suppression of FcεRI expression.

scholarly journals Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction

2018 ◽  
Vol 19 (12) ◽  
pp. 4092 ◽  
Author(s):  
Chen Shao ◽  
Bingjie Fu ◽  
Ning Ji ◽  
Shunli Pan ◽  
Xiaoxia Zhao ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Allergic Reaction ◽  
Nuclear Factor Kappa B ◽  
Immunoglobulin E ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

Ectopic Expression of Lin28 Biases Myeloid Differentiation to Promote an Immature Mast Cell State and Is Implicated in Aggressive Mastocytosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5571-5571
Author(s):  
Leo D. Wang ◽  
Phi Nguyen ◽  
Robert G Rowe ◽  
Tata Nageswara Rao ◽  
George Q. Daley ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
In Vitro Assays ◽  
Human Mast Cell ◽  
Adult Mice

Abstract Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Lin28 is a heterochronic gene and pluripotency factor implicated in many types of malignancy, and prior studies suggest that Lin28 expression can restore a fetal hematopoietic program in adult mice. However, the role of Lin28 in hematologic malignancy remains controversial. In our study, we induced expression of Lin28 in adult mice using a doxycycline-responsive transgenic system. Lin28 induction caused marked mast cell accumulation in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in Lin28-expressing hematopoietic progenitors, with increased levels of Lin28 in common myeloid progenitors and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhance mast cell specification. In addition, Lin28-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of Lin28 upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28 in abnormal mast cells from patients with aggressive systemic mastocytosis (ASM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Essential roles of sphingosine-1–phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema

2010 ◽  
Vol 207 (3) ◽  
pp. 465-474 ◽  
Author(s):  
Carole A. Oskeritzian ◽  
Megan M. Price ◽  
Nitai C. Hait ◽  
Dmitri Kapitonov ◽  
Yves T. Falanga ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Pulmonary Edema ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Critical Role ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Cell Functions ◽  
Sphingosine 1 Phosphate

Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1–phosphate (S1P), a ligand for a family of G protein–coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P2 receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E–triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P2 antagonist JTE-013 and in S1P2-deficient mice, in contrast to anaphylaxis induced by administration of histamine or platelet-activating factor. Hence, S1P and S1P2 on mast cells are determinants of systemic anaphylaxis and associated pulmonary edema and might be beneficial targets for anaphylaxis attenuation and prophylaxis.

scholarly journals Influence of IL-6, IL-33, and TNF-α on human mast cell activation: Lessons from single cell analysis by flow cytometry

2017 ◽  
Vol 94 (3) ◽  
pp. 405-411 ◽  
Author(s):  
Nathalie Cop ◽  
Didier G. Ebo ◽  
Chris H. Bridts ◽  
Jessy Elst ◽  
Margo M. Hagendorens ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mast Cell ◽  
Single Cell ◽  
Cell Activation ◽  
Single Cell Analysis ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Cell Analysis ◽  
Tnf Α

MMP dependence of fibroblast contraction and collagen production induced by human mast cell activation in a three-dimensional collagen lattice

2009 ◽  
Vol 296 (2) ◽  
pp. L236-L247 ◽  
Author(s):  
Alexander Margulis ◽  
Karl H. Nocka ◽  
Nancy L. Wood ◽  
Stanley F. Wolf ◽  
Samuel J. Goldman ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Three Dimensional ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Proteolytic Activation ◽  
Collagen Production ◽  
Collagen Lattice

Mast cell-fibroblast interactions may contribute to fibrosis in asthma and other disease states. Fibroblast contraction is known to be stimulated by coculture with the human mast cell line, HMC-1, or by mast cell-derived agents. Matrix metalloproteinases (MMPs) can also mediate contraction, but the MMP-dependence of mast cell-induced fibroblast contractility is not established, and the consequences of mast cell activation within the coculture system have not been fully explored. We demonstrate that activation of primary human mast cells (pHMC) with IgE receptor cross-linking, or activation of HMC-1 with C5a, enhanced contractility of human lung fibroblasts in a three-dimensional collagen lattice system. This enhanced contractility was inhibited by the pan-MMP antagonist, batimastat, and was transferrable in the conditioned medium of activated mast cells. Exogenously added MMPs promoted gel contraction by mediating the proteolytic activation of latent transforming growth factor-β (TGF-β). Consistent with this, fibroblast contraction induced by mast cell activation was enhanced by addition of excess latent TGF-β to the cultures. Batimastat inhibited this response, suggesting that MMPs capable of activating latent TGF-β were released following mast cell activation in coculture with fibroblasts. Collagen production was also stimulated by activated mast cells in an MMP-dependent manner. MMP-2 and MMP-3 content of the gels increased in the presence of activated mast cells, and inhibition of these enzymes blocked the contractile response. These findings demonstrate the MMP dependence of mast cell-induced fibroblast contraction and collagen production.

scholarly journals Brain mast cells link the immune system to anxiety-like behavior

2008 ◽  
Vol 105 (46) ◽  
pp. 18053-18057 ◽  
Author(s):  
Katherine M. Nautiyal ◽  
Ana C. Ribeiro ◽  
Donald W. Pfaff ◽  
Rae Silver
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Neural Systems ◽  
Loss Of Function ◽  
Littermate Control ◽  
Cytokines And Chemokines ◽  
Function Models ◽  
The Brain

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

Association of Mast Cell Burden and TIM-3 Expression with Recalcitrant Chronic Rhinosinusitis with Nasal Polyps

2021 ◽  
pp. 000348942199503
Author(s):  
Michael A. Belsky ◽  
Erica Corredera ◽  
Hridesh Banerjee ◽  
John Moore ◽  
Li Wang ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Cell Activation ◽  
Enzymatic Digestion ◽  
Sinus Surgery ◽  
Mast Cell Activation ◽  
Need For Treatment ◽  
Inflammatory State

Objectives: Previous work showed that higher polyp mast cell load correlated with worse postoperative endoscopic appearance in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Polyp epithelial mast cells showed increased expression of T-cell/transmembrane immunoglobulin and mucin domain protein 3 (TIM-3), a receptor that promotes mast cell activation and cytokine production. In this study, CRSwNP patients were followed post-operatively to investigate whether mast cell burden or TIM-3 expression among mast cells can predict recalcitrant disease. Methods: Nasal polyp specimens were obtained via functional endoscopic sinus surgery (FESS) and separated into epithelial and stromal layers via enzymatic digestion. Mast cells and TIM-3-expressing mast cells were identified via flow cytometry. Mann-Whitney U tests and Cox proportional hazard models assessed whether mast cell burden and TIM-3 expression were associated with clinical outcomes, including earlier recurrence of polypoid edema and need for treatment with steroids. Results: Twenty-three patients with CRSwNP were studied and followed for 6 months after undergoing FESS. Higher mast cell levels were associated with earlier recurrence of polypoid edema: epithelial HR = 1.283 ( P = .02), stromal HR = 1.103 ( P = .02). Percent of mast cells expressing TIM-3 in epithelial or stromal layers was not significantly associated with earlier recurrence of polypoid edema. Mast cell burden and TIM-3+ expression were not significantly associated with need for future treatment with steroids post-FESS. Conclusions: Mast cell load in polyp epithelium and stroma may predict a more refractory postoperative course for CRSwNP patients. The role of TIM-3 in the chronic inflammatory state seen in CRSwNP remains unclear.

scholarly journals Human mast cell activation through Fc receptors and Toll-like receptors

2004 ◽  
Vol 53 (3) ◽  
pp. 227-233 ◽  
Author(s):  
Yoshimichi Okayama ◽  
Shigeru Okumura ◽  
Hisashi Tomita ◽  
Hiroko Katayama ◽  
Keisuke Yuki ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Activation ◽  
Fc Receptors ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Toll Like Receptors

Development of hematopoietic cells lacking transcription factor GATA-1

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 163-172 ◽  
Author(s):  
L. Pevny ◽  
C.S. Lin ◽  
V. D'Agati ◽  
M.C. Simon ◽  
S.H. Orkin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mast Cell ◽  
Cell Differentiation ◽  
Mast Cells ◽  
Blood Cell ◽  
Embryonic Stem ◽  
Sequence Motif ◽  
Erythroid Cells ◽  
Gata Factor

GATA-1 is a zinc-finger transcription factor believed to play an important role in gene regulation during the development of erythroid cells, megakaryocytes and mast cells. Other members of the GATA family, which can bind to the same DNA sequence motif, are co-expressed in several of these hemopoietic lineages, raising the possibility of overlap in function. To examine the specific roles of GATA-1 in hematopoietic cell differentiation, we have tested the ability of embryonic stem cells, carrying a targeted mutation in the X-linked GATA-1 gene, to contribute to various blood cell types when used to produce chimeric embryos or mice. Previously, we reported that GATA-1- mutant cells failed to contribute to the mature red blood cell population, indicating a requirement for this factor at some point in the erythroid lineage (L. Pevny et al., (1991) Nature 349, 257–260). In this study, we have used in vitro colony assays to identify the stage at which mutant erythroid cells are affected, and to examine the requirement for GATA-1 in other lineages. We found that the development of erythroid progenitors in embryonic yolk sacs was unaffected by the mutation, but that the cells failed to mature beyond the proerythroblast stage, an early point in terminal differentiation. GATA-1- colonies contained phenotypically normal macrophages, neutrophils and megakaryocytes, indicating that GATA-1 is not required for the in vitro differentiation of cells in these lineages. GATA-1- megakaryocytes were abnormally abundant in chimeric fetal livers, suggesting an alteration in the kinetics of their formation or turnover. The lack of a block in terminal megakaryocyte differentiation was shown by the in vivo production of platelets expressing the ES cell-derived GPI-1C isozyme. The role of GATA-1 in mast cell differentiation was examined by the isolation of clonal mast cell cultures from chimeric fetal livers. Mutant and wild-type mast cells displayed similar growth and histochemical staining properties after culture under conditions that promote the differentiation of cells resembling mucosal or serosal mast cells. Thus, the mast and megakaryocyte lineages, in which GATA-1 and GATA-2 are co-expressed, can complete their maturation in the absence of GATA-1, while erythroid cells, in which GATA-1 is the predominant GATA factor, are blocked at a relatively early stage of maturation.

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