scholarly journals Induction of different human enteroendocrine cells in intestinal organoids

2020 ◽  
Author(s):  
Hans Clevers ◽  
Joep Beumer
Keyword(s):  
Cell Types ◽  
Bmp Signaling ◽  
Enteroendocrine Cells ◽  
Model Systems ◽  
Endocrine Organ ◽  
Intestinal Organoids ◽  
Novel Approach ◽  
Key Players ◽  
And Function ◽  
Diabetes And Obesity

Abstract Intestinal enteroendocrine cells \(EECs) are key players in mammalian physiology as largest endocrine organ, and regulate metabolic processes such as insulin secretion and induction of satiety. EECs are rare cell types \(less than 1% of the epithelium) and produce a large number of different hormones making these challenging to study. Model systems to assess the differentiation and function of these essential cell types have been lacking. In a novel approach, we describe the induction of human EECs in intestinal organoids. Moreover, in the manuscript linked to this protocol, we describe that manipulating the BMP signaling pathway allows to induce expression of specific sets of hormones that correspond to the EEC state in the crypt-villus axis. This differentiation platform can be used to study the function of EECs and could contribute to the development of drugs for diabetes and obesity.

scholarly journals Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

2018 ◽  
Author(s):  
Caroline Fecher ◽  
Laura Trovò ◽  
Stephan A. Müller ◽  
Nicolas Snaidero ◽  
Jennifer Wettmarshausen ◽  
...  
Keyword(s):  
Molecular Diversity ◽  
Molecular Level ◽  
Cell Types ◽  
Long Chain Fatty Acids ◽  
Cell Type ◽  
Mitochondrial Proteome ◽  
Novel Approach ◽  
Cell Type Specific ◽  
And Function

AbstractMitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts.

scholarly journals BMP signaling inhibition in Drosophila secondary cells remodels the seminal proteome and self and rival ejaculate functions

2019 ◽  
Vol 116 (49) ◽  
pp. 24719-24728 ◽  
Author(s):  
Ben R. Hopkins ◽  
Irem Sepil ◽  
Sarah Bonham ◽  
Thomas Miller ◽  
Philip D. Charles ◽  
...  
Keyword(s):  
Seminal Fluid ◽  
Cell Types ◽  
Bmp Signaling ◽  
Secretory Cells ◽  
Normal Female ◽  
Seminal Fluid Proteins ◽  
Accessory Glands ◽  
Offspring Production ◽  
Morphogenetic Protein ◽  
And Function

Seminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. In Drosophila melanogaster, most SFPs are produced in the accessory glands, which are composed of ∼1,000 fertility-enhancing “main cells” and ∼40 more functionally cryptic “secondary cells.” Inhibition of bone morphogenetic protein (BMP) signaling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female postmating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary-cell secretions might therefore make highly specific contributions to the seminal proteome and ejaculate function; alternatively, they might regulate more global—but hitherto undiscovered—SFP functions and proteome composition. Here, we present data that support the latter model. We show that in addition to previously reported phenotypes, secondary-cell-specific BMP signaling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal changes to the seminal proteome that surprisingly encompass alterations to main-cell–derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell types, suggesting that modification to the cellular make-up of seminal-fluid-producing tissues is an important factor in ejaculate evolution.

scholarly journals Natural variation in the regulation of neurodevelopmental genes modifies flight performance in Drosophila

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1008887
Author(s):  
Adam N. Spierer ◽  
Jim A. Mossman ◽  
Samuel Pattillo Smith ◽  
Lorin Crawford ◽  
Sohini Ramachandran ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
System Development ◽  
Nervous System Development ◽  
Bmp Signaling ◽  
Flight Performance ◽  
Genetic Modifiers ◽  
Epistatic Interactions ◽  
Novel Approach ◽  
A Genome ◽  
And Function

The winged insects of the order Diptera are colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, such as dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of flight performance. Accordingly, we sought to uncover the genetic modifiers of flight using a measure of flies’ reaction and response to an abrupt drop in a vertical flight column. We conducted a genome wide association study (GWAS) using 197 of the Drosophila Genetic Reference Panel (DGRP) lines, and identified a combination of additive and marginal variants, epistatic interactions, whole genes, and enrichment across interaction networks. Egfr, a highly pleiotropic developmental gene, was among the most significant additive variants identified. We functionally validated 13 of the additive candidate genes’ (Adgf-A/Adgf-A2/CG32181, bru1, CadN, flapper (CG11073), CG15236, flippy (CG9766), CREG, Dscam4, form3, fry, Lasp/CG9692, Pde6, Snoo), and introduce a novel approach to whole gene significance screens: PEGASUS_flies. Additionally, we identified ppk23, an Acid Sensing Ion Channel (ASIC) homolog, as an important hub for epistatic interactions. We propose a model that suggests genetic modifiers of wing and muscle morphology, nervous system development and function, BMP signaling, sexually dimorphic neural wiring, and gene regulation are all important for the observed differences flight performance in a natural population. Additionally, these results represent a snapshot of the genetic modifiers affecting drop-response flight performance in Drosophila, with implications for other insects.

scholarly journals Regulation of the Immune System in Health and Disease by Members of the Bone Morphogenetic Protein Family

2021 ◽  
Vol 12 ◽  
Author(s):  
Tommaso Sconocchia ◽  
Giuseppe Sconocchia
Keyword(s):  
Immune System ◽  
Bone Morphogenetic Proteins ◽  
Adaptive Immune Response ◽  
Cell Types ◽  
Bmp Signaling ◽  
Adaptive Immune ◽  
Main Cell ◽  
Morphogenetic Protein ◽  
Health And Disease ◽  
And Function

Bone morphogenetic proteins (BMPs) are potent signaling molecules initially described as osteopromoting proteins. BMPs represent one of the members of the larger TGFβ family and today are recognized for their important role in numerous processes. Among the wide array of functions recently attributed to them, BMPs were also described to be involved in the regulation of components of the innate and adaptive immune response. This review focuses on the signaling pathway of BMPs and highlights the effects of BMP signaling on the differentiation, activation, and function of the main cell types of the immune system.

scholarly journals Human primitive mesenchymal stem cell-derived retinal progenitor cells promoted neuroprotection and neurogenesis in rd12 mice

2021 ◽  
Author(s):  
Christina Brown ◽  
Patrina Agosta ◽  
Christina McKee ◽  
Keegan Walker ◽  
Matteo Mazzella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Retinal Thickness ◽  
Bmp Signaling ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor ◽  
Novel Approach ◽  
Retinal Degenerative Diseases ◽  
Retinal Structure ◽  
And Function

Retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP) have no treatment. Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. We investigated a novel approach in which human retinal progenitor cells (RPCs) derived from primitive mesenchymal stem cells (pMSCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Intravitreally transplanted cells improved retinal function and significantly increased retinal thickness. Transplanted cells homed, survived, and integrated to various retinal layers. They also induced anti-inflammatory and neuroprotective responses and upregulated neurogenesis genes. We found that RPCs were more efficacious than pMSCs in improving the retinal structure and function. RNA analyses suggest that RPCs promote neuroprotection and neuronal differentiation by activating JAK/STAT and MAPK, and inhibiting BMP signaling pathways. These promising results provide the basis for clinical studies to treat RDD using RPCs derived from pMSCs.

Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

1999 ◽  
Vol 81 (06) ◽  
pp. 951-956 ◽  
Author(s):  
J. Corral ◽  
R. González-Conejero ◽  
J. Rivera ◽  
F. Ortuño ◽  
P. Aparicio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cell Types ◽  
Receptor Expression ◽  
Case Control Studies ◽  
Platelet Surface ◽  
Vitro Analysis ◽  
And Function ◽  
In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

Role of inflammation in the development of colorectal cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
R. Ileng Kumaran ◽  
Kokelavani Nampalli Babu ◽  
Sneha Krishnamoorthy ◽  
Akash Guruswamy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chronic Inflammation ◽  
Interleukin 1 ◽  
Cell Types ◽  
Model Systems ◽  
Cytokine Gene Expression ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

scholarly journals Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 149
Author(s):  
Sreekumar Othumpangat ◽  
William G. Lindsley ◽  
Donald H. Beezhold ◽  
Michael L. Kashon ◽  
Carmen N. Burrell ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Influenza Infection ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Differentially Expressed ◽  
Influenza B ◽  
Airway Epithelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Approach

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

scholarly journals Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amitava Basu ◽  
Vijay K. Tiwari
Keyword(s):  
Regenerative Medicine ◽  
Cell Types ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Cell Type ◽  
Pathological Conditions ◽  
Gene Regulatory ◽  
Induced Pluripotent ◽  
And Function

AbstractEpigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes.

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