scholarly journals Cell-Specific Regulation of Intestinal Immunity

2019 ◽  
Author(s):  
Minjeong Shin ◽  
Reegan J. Willms ◽  
Lena Ocampo Jones ◽  
Kristina Petkau ◽  
Andrew Panteluk ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Types ◽  
Host Responses ◽  
Intestinal Immunity ◽  
Intestinal Homeostasis ◽  
Immune Activity ◽  
Bacterial Microbiome ◽  
Specific Regulation ◽  
Immune Pathway ◽  
Epithelial Immunity

ABSTRACTThe intestinal epithelium contains secretory and absorptive cell lineages that develop from undifferentiated progenitor cells. Despite the collective importance of these cells to host responses against microbial invaders, little is known about the contributions of immune responses in individual cell types to the maintenance of intestinal homeostasis. In this study, we asked how inhibition of immune pathway activity exclusively in progenitor cells, or in differentiated enterocytes, affects midgut homeostasis in adult Drosophila. We found that blocking immune activity in enterocytes rendered flies more tolerant of Vibrio cholerae infection, had negligible effects on the gut bacterial microbiome, and significantly affected metabolism. In contrast, inhibition of immune activity in progenitors rendered flies less tolerant of Vibrio infections, modified host association with Lactobacillus symbionts, and blocked growth and renewal in the midgut epithelium. Together, these data uncover substantial cell type-specific contributions of epithelial immunity to adult intestinal homeostasis.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

2011 ◽  
Vol 11 ◽  
pp. 2037-2050 ◽  
Author(s):  
Manoranjan Sahoo ◽  
Ivonne Ceballos-Olvera ◽  
Laura del Barrio ◽  
Fabio Re
Keyword(s):  
Bacterial Infections ◽  
Innate Immune ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Different Types ◽  
Molecular Aspects ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Receptor Family

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

scholarly journals A54 THE CIRCADIAN CLOCK INFLUENCES JAK/STAT SIGNALING AND GUT PERMEABILITY

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 11-12
Author(s):  
K Parasram ◽  
D Bachetti ◽  
P Karpowicz
Keyword(s):  
Circadian Clock ◽  
Clock Cycle ◽  
Intestinal Barrier ◽  
Fruit Fly ◽  
Cell Types ◽  
Time Of Day ◽  
Acute Injury ◽  
Intestinal Barrier Function ◽  
Intestinal Immunity ◽  
Stat Signaling

Abstract Background The circadian clock is a 24-hour feedback loop that drives rhythms in behaviours and physiological processes. This molecular timekeeper consists of the transcription factors, Clock-Cycle, that drive expression of thousands of clock-controlled genes, with two of these, Period and Timeless, acting as negative regulators of Clock-Cycle. This fundamental mechanism was initially characterized in the fruit fly, Drosophila melanogaster (Nobel Prize in Physiology & Medicine, 2017), and is highly conserved in humans. The intestine, or midgut, of Drosophila, is also similar to the human small intestine consisting of similar cellular lineage, signaling pathways, and physiological functions. The lineage of the Drosophila intestine contains the same four cell types as humans: intestinal stem cells (ISCs), progenitors called enteroblasts, enterocytes and enteroendocrine cells. This simplified lineage as well as the genetic tools available, make Drosophila an ideal model for intestinal regeneration in health and disease. We have previously shown that the circadian clock is active in ISCs, EBs and ECs during both homeostatic and regenerating conditions. Furthermore, the circadian clock regulates the mitosis of ISCs under regenerating conditions. Aims We sought to uncover if Jak/STAT signaling, one of the key pathways involved in ISC proliferation in the Drosophila intestine, shows a circadian rhythm and if there is a time-of-day difference in the regenerative response. Methods To test whether the clock regulates Jak/STAT during acute injury, we developed an irradiation assay that does not affect survival but acutely disrupts intestinal barrier function. Results Using a dynamic reporter of Jak/STAT activity we show that Period circadian clock mutants have low Jak/STAT signaling and a leaky gut phenotype. Wildtype controls show time-dependent gut leakiness upon irradiation, which is higher and time-independent in Period mutants. The level of Jak/STAT response differs depending on the time of irradiation in the controls, but is higher at all times in the mutants. Conclusions The Jak/Stat pathway regulates intestinal immunity and epithelial cell proliferation in humans, thus playing a role in colorectal cancer and inflammatory bowel disease. Our results suggest Jak/Stat is controlled by the circadian clock, which has implications for intestinal recovery following medical treatments, including radiation therapy. Funding Agencies NRC

scholarly journals Human leukemia mutations corrupt but do not abrogate GATA-2 function

2018 ◽  
Vol 115 (43) ◽  
pp. E10109-E10118 ◽  
Author(s):  
Koichi R. Katsumura ◽  
Charu Mehta ◽  
Kyle J. Hewitt ◽  
Alexandra A. Soukup ◽  
Isabela Fraga de Andrade ◽  
...  
Keyword(s):  
Dna Binding ◽  
Progenitor Cells ◽  
Zinc Finger ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Myeloid Differentiation ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Amino Terminal ◽  
Disease Mutations

By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA-2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the amino-terminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 −77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin−Kit+ myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2–linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA-2–dependent pathologies.

scholarly journals Neural stemness contributes to cell tumorigenicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liyang Xu ◽  
Min Zhang ◽  
Lihua Shi ◽  
Xiaoli Yang ◽  
Lu Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Progenitor Cells ◽  
Neural Development ◽  
Ground State ◽  
Cell Types ◽  
Bioinformatic Analysis ◽  
Neural Cells ◽  
Differentiation Potential ◽  
Neural Genes ◽  
Neural Stem Progenitor Cells

Abstract Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. By contrast, loss of neural stemness via differentiation results in the loss of tumorigenicity. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

scholarly journals Neural stemness contributes to cell tumorigenicity

2020 ◽  
Author(s):  
Liyang Xu ◽  
Min Zhang ◽  
Lihua Shi ◽  
Xiaoli Yang ◽  
Lu Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Progenitor Cells ◽  
Neural Development ◽  
Ground State ◽  
Cell Types ◽  
Bioinformatic Analysis ◽  
Neural Cells ◽  
Differentiation Potential ◽  
Neural Genes ◽  
Neural Stem Progenitor Cells

Abstract Background: Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown.Results: We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. By contrast, loss of neural stemness via differentiation results in the loss of tumorigenicity. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells.Conclusions: We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

scholarly journals A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine

2020 ◽  
Author(s):  
Reegan J. Willms ◽  
Jennifer C. Hocking ◽  
Edan Foley
Keyword(s):  
Transcriptional Activity ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Host Responses ◽  
Cellular Specificity ◽  
Direct Growth ◽  
A Cell ◽  
Microbe Interactions ◽  
Regulatory Effects ◽  
Host Microbe Interactions

ABSTRACTGut microbial products direct growth, differentiation and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence, or absence, of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome, that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered transduction of vascular endothelial growth factor-dependent signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type.

scholarly journals Evidence for a novel antioxidant function and isoform-specific regulation of the human p66Shc gene

2014 ◽  
Vol 25 (13) ◽  
pp. 2116-2127 ◽  
Author(s):  
Masaki Miyazawa ◽  
Yoshiaki Tsuji
Keyword(s):  
Stress Response ◽  
Adaptor Protein ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Antioxidant Response ◽  
Related Factor ◽  
Antioxidant Genes ◽  
Specific Regulation ◽  
And Function ◽  
Species Production

The mammalian Shc family, composed of p46, p52, and p66 isoforms, serves as an adaptor protein in cell growth and stress response. p66Shc was shown to be a negative lifespan regulator by acting as a prooxidant protein in mitochondria; however, the regulatory mechanisms of p66Shc expression and function are incompletely understood. This study provides evidence for new features of p66Shc serving as an antioxidant and critical protein in cell differentiation. Unique among the Shc family, transcription of p66Shc is activated through the antioxidant response element (ARE)–nuclear factor erythroid 2–related factor 2 (Nrf2) pathway in K562 human erythroleukemia and other cell types after treatment with hemin, an iron-containing porphyrin. Phosphorylated p66Shc at Ser-36, previously reported to be prone to mitochondrial localization, is increased by hemin treatment, but p66Shc remains exclusively in the cytoplasm. p66Shc knockdown inhibits hemin-induced erythroid differentiation, in which reactive oxygen species production and apoptosis are significantly enhanced in conjunction with suppression of other ARE-dependent antioxidant genes. Conversely, p66Shc overexpression is sufficient for inducing erythroid differentiation. Collectively these results demonstrate the isoform-specific regulation of the Shc gene by the Nrf2-ARE pathway and a new antioxidant role of p66Shc in the cytoplasm. Thus p66Shc is a bifunctional protein involved in cellular oxidative stress response and differentiation.

Fibroblast progenitor cells of the embryonic chick limb

Development ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 191-200
Author(s):  
Stuart A. Newman
Keyword(s):  
Progenitor Cells ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
The Other ◽  
Embryonic Chick ◽  
Similar Morphology ◽  
Level Characteristic ◽  
Fibroblast Progenitor Cells ◽  
Wing Tip ◽  
Mesodermal Lineage

A population of mesenchymal cells derived from the stage-25 chick wing tip gives rise to progeny of a similar morphology and to authentic fibroblasts when grown in low densityculture. Mixed clones containing both cell types are often observed. As the more rapidly proliferating fibroblasts begin to predominate in these cultures, collagen biosynthesisrises from the basal mesenchymal level to a level characteristic of mature fibroblasts. Thefibroblast progenitor is discussed relative to the other cell types of the mesodermal lineage of the developing limb.

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