scholarly journals Cell type-selective secretome profiling in vivo

2020 ◽  
Author(s):  
Wei Wei ◽  
Nicholas M. Riley ◽  
Andrew C. Yang ◽  
Joon T. Kim ◽  
Stephanie M. Terrell ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Cell Types ◽  
Intercellular Signaling ◽  
Cell Type ◽  
Unconventional Secretion ◽  
Classical Plasma ◽  
A Cell ◽  
Global Understanding ◽  
Secretome Profiling

ABSTRACTSecreted polypeptides are a fundamental biochemical axis of intercellular and endocrine communication. However, a global understanding of composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection, and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte, and myeloid cell secretomes by direct purification of biotinylated secreted polypeptides from blood. Our secretome atlas validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types, and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by increased unconventional secretion of the cytosolic enzyme BHMT. This secretome profiling strategy enables dynamic and cell-type dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

Contact guidance on microfabricated substrata: the response of teleost fin mesenchyme cells to repeating topographical patterns

1988 ◽  
Vol 90 (4) ◽  
pp. 667-681 ◽  
Author(s):  
A. Wood
Keyword(s):  
Cell Types ◽  
Cell Type ◽  
Fibroblastic Cell ◽  
Tissue Component ◽  
Flat Surfaces ◽  
Mesenchymal Tissue ◽  
Computer Aided Analysis ◽  
A Cell ◽  
Mesenchyme Cells

The mesenchymal tissue component of the teleost pectoral fin bud has been explanted onto microfabricated quartz discs containing patterns of regular grooves of dimensions similar to those encountered by contact-guided cells in the intact fin system. Computer-aided analysis of cell migration on five separate patterns, from 1.8 to 7.4 microns repeat spacing, revealed that migration was predominantly aligned parallel to the long axis of the grooves, with individual cells becoming highly polarized, and the highest index of alignment (3.7) produced on the widest repeat spacings. When these cells are cultured on planar quartz, which is both chemically and physically isotropic, they flatten and adopt a morphology similar to that shown by cultured fibroblastic cell types on flat surfaces, suggesting that fin mesenchymal cells are not intrinsically predisposed to adopt an arborized morphology, like that observed in the intact fin bud. These results clearly demonstrate a directional migration in response to substratum topography, from a cell type known to be contact guided in vivo, and in the complete absence of adhesive heterogeneities.

scholarly journals Cell type- and stage-specific expression of Otx2 is regulated by multiple transcription factors and cis-regulatory modules in the retina

Development ◽  
2020 ◽  
Vol 147 (14) ◽  
pp. dev187922 ◽  
Author(s):  
Candace S. Y. Chan ◽  
Nicolas Lonfat ◽  
Rong Zhao ◽  
Alexander E. Davis ◽  
Liang Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Retinal Cell ◽  
Mouse Retina ◽  
Cell Type ◽  
Specific Expression ◽  
Regulatory Modules ◽  
A Cell

ABSTRACTTranscription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is necessary. We analyzed how the expression of the homeobox TF, orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during development in the mouse retina. We identified seven Otx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs, respectively. The chromatin status of these three CRMs was found to be distinct in vivo in different retinal cell types and at different stages. We conclude that retinal cells use a cohort of TFs with different expression patterns and multiple CRMs with different chromatin configurations to regulate the expression of Otx2 precisely.

scholarly journals Cell type- and stage-specific expression of Otx2 is coordinated by a cohort of transcription factors and multiple cis-regulatory modules in the retina

2019 ◽  
Author(s):  
Candace Chan ◽  
Nicolas Lonfat ◽  
Rong Zhao ◽  
Alexander Davis ◽  
Liang Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Retinal Cell ◽  
Cell Type ◽  
Specific Expression ◽  
Regulatory Modules ◽  
Specific Manner ◽  
A Cell

AbstractTranscription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is an advantageous strategy. However, the mechanisms that control the activation of TFs in different cell types and at different stages of development remain unclear. The neural retina serves as a model of the development of a complex tissue. We used this system to analyze how expression of the homeobox TF, Orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during retinogenesis. We identified seven Otx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. These include mature bipolar interneurons, photoreceptors, and retinal progenitor/precursor cells. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs respectively. The chromatin status of these three CRMs was found to be distinct in vivo in different retinal cell types and at different stages, as revealed by ATAC-seq and DNase-seq analyses. We conclude that retinal cells utilize a cohort of TFs with different expression patterns, and multiple CRMs with different chromatin configurations, to precisely regulate the expression of Otx2 in a cell type- and stage-specific manner in the retina.

scholarly journals Heterogeneity of Transcription Factor binding specificity models within and across cell lines

2015 ◽  
Author(s):  
Mahfuza Sharmin ◽  
Hector Corrada Bravo ◽  
Sridhar S. Hannenhalli
Keyword(s):  
Expression Patterns ◽  
Specific Interaction ◽  
Cell Types ◽  
Cell Type ◽  
Binding Interaction ◽  
Interaction Partners ◽  
A Cell ◽  
Cell Type Specific ◽  
Different Cell Types

Complex gene expression patterns are mediated by binding of transcription factors (TF) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TFs DNA binding interaction partners, motivating genomic context based models of TF occupancy. However, the approaches thus far have assumed a uniform binding model to explain genome wide bound sites for a TF in a cell-type and as such heterogeneity of TF occupancy models, and the extent to which binding rules underlying a TFs occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble based approach (TRISECT) to identify heterogeneous binding rules of cell-type specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-Seq data in 4-12 cell-types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy (93%) substantially improving upon previous methods. Importantly, many of the binding rules derived from individual cell-types are shared across cell-types and reveal distinct yet functionally coherent putative target genes in different cell-types. Closer inspection of the predicted cell-type-specific interaction partners provides insights into context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising interaction partners within a cell-type, many of which nevertheless transcend cell-types. Notably, the putative targets of shared binding rules in different cell-types, while distinct, exhibit significant functional coherence.

scholarly journals Sensory coding mechanisms revealed by optical tagging of physiologically defined neuronal types

Science ◽  
2019 ◽  
Vol 366 (6471) ◽  
pp. 1384-1389 ◽  
Author(s):  
Donghoon Lee ◽  
Maiko Kume ◽  
Timothy E. Holy
Keyword(s):  
Neural Circuit ◽  
Ectopic Expression ◽  
Cell Types ◽  
Specific Cell ◽  
Sensory Coding ◽  
Cell Type ◽  
Neuronal Types ◽  
A Cell ◽  
Circuit Function

Neural circuit analysis relies on having molecular markers for specific cell types. However, for a cell type identified only by its circuit function, the process of identifying markers remains laborious. We developed physiological optical tagging sequencing (PhOTseq), a technique for tagging and expression profiling of cells on the basis of their functional properties. PhOTseq was capable of selecting rare cell types and enriching them by nearly 100-fold. We applied PhOTseq to the challenge of mapping receptor-ligand pairings among pheromone-sensing neurons in mice. Together with in vivo ectopic expression of vomeronasal chemoreceptors, PhOTseq identified the complete combinatorial receptor code for a specific set of ligands.

scholarly journals Modulation of the Triggering Receptor Expressed on the Myeloid Cell Type 1 Pathway in Murine Septic Shock

2006 ◽  
Vol 74 (5) ◽  
pp. 2823-2830 ◽  
Author(s):  
Sébastien Gibot ◽  
Cecilia Buonsanti ◽  
Frédéric Massin ◽  
Michele Romano ◽  
Marie-Nathalie Kolopp-Sarda ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Polymorphonuclear Neutrophils ◽  
Cell Type ◽  
Cell Surface Molecule ◽  
Necrosis Factor Alpha ◽  
Initial Stage ◽  
A Cell ◽  
Factor Alpha

ABSTRACT The triggering receptor expressed on myeloid cell type 1 (TREM-1) is a cell surface molecule that has been identified on both human and murine polymorphonuclear neutrophils and mature monocytes. The activation of TREM-1 in the presence of microbial components amplifies the inflammatory response and may be responsible for the hyperresponsiveness observed during the initial stage of sepsis. To investigate the effect of the modulation of the TREM-1 pathway during experimental murine sepsis, we used analogue synthetic peptides derived from the extracellular moiety of TREM-1. The TREM-1 ligand was expressed on both peritoneal and peripheral neutrophils during experimental peritonitis in mice. The TREM-1 peptides inhibited the recognition by TREM-1 of its ligand and protected endotoxinic mice from death. In septic rats, the TREM-1 peptides improved the hemodynamic status, attenuated the development of lactic acidosis, modulated the production of such proinflammatory cytokines as tumor necrosis factor alpha and interleukin-1β, and improved survival. The protective effect of these peptides on arterial pressure could partly be explained by a decreased production of nitric oxide. These data suggest that in vivo modulation of TREM-1 might be a suitable therapeutic tool for the treatment of sepsis.

Dendritic cells of the human epidermis: immuno-electron microscopic studies of la antigen reactivity

1978 ◽  
Vol 36 (2) ◽  
pp. 644-645
Author(s):  
G. Rowden ◽  
M. G. Lewis ◽  
T. M. Phillips
Keyword(s):  
Dendritic Cells ◽  
Langerhans Cells ◽  
Cell Types ◽  
Cell Type ◽  
Electron Microscopic ◽  
La Antigen ◽  
Microscopic Studies ◽  
A Cell ◽  
C3 Receptors ◽  
Antigen Reactivity

Langerhans cells of mammalian stratified squamous epithelial have proven to be an enigma since their discovery in 1868. These dendritic suprabasal cells have been considered as related to melanocytes either as effete cells, or as post divisional products. Although grafting experiments seemed to demonstrate the independence of the cell types, much confusion still exists. The presence in the epidermis of a cell type with morphological features seemingly shared by melanocytes and Langerhans cells has been especially troublesome. This so called "indeterminate", or " -dendritic cell" lacks both Langerhans cells granules and melanosomes, yet it is clearly not a keratinocyte. Suggestions have been made that it is related to either Langerhans cells or melanocyte. Recent studies have unequivocally demonstrated that Langerhans cells are independent cells with immune function. They display Fc and C3 receptors on their surface as well as la (immune region associated) antigens.

scholarly journals EMeth: An EM algorithm for cell type decomposition based on DNA methylation data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hanyu Zhang ◽  
Ruoyi Cai ◽  
James Dai ◽  
Wei Sun
Keyword(s):  
Dna Methylation ◽  
Tumor Cells ◽  
T Regulatory Cells ◽  
Simulated Data ◽  
Cell Types ◽  
Computational Method ◽  
Methylation Data ◽  
Cell Type ◽  
A Cell ◽  
Type Decomposition

AbstractWe introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.

Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Signaling Pathways ◽  
Chemotherapy Resistance ◽  
Effective Strategy ◽  
Cell Type ◽  
Normal Cells ◽  
A Cell ◽  
Cell Type Specific ◽  
Catabolic Process ◽  
Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

scholarly journals Cell-type specific analysis of physiological action of estrogen in mouse oviducts

2020 ◽  
Author(s):  
Emily A. McGlade ◽  
Gerardo G. Herrera ◽  
Kalli K. Stephens ◽  
Sierra L. W. Olsen ◽  
Sarayut Winuthayanon ◽  
...  
Keyword(s):  
Hormone Replacement ◽  
Cell Types ◽  
Normal Embryo ◽  
Developmental Defect ◽  
Cell Type ◽  
Specific Analysis ◽  
Cell Type Specific ◽  
17Β Estradiol ◽  
Oviductal Cell

AbstractOne of the endogenous estrogens, 17β-estradiol (E2) is a female steroid hormone secreted from the ovary. It is well established that E2 causes biochemical and histological changes in the uterus. The oviduct response to E2 is virtually unknown in an in vivo environment. In this study, we assessed the effect of E2 on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single cell RNA-sequencing (scRNA-seq), in situ hybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2 distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2 did not drastically alter the transcriptomic profile from that of endogenous E2 produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2-target gene in the mouse oviduct and was also expressed in human Fallopian tubes. Deletion of Igf1 in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types are differentially regulated by E2 and support gene expression changes that are required for normal embryo development and transport in mouse models.

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