Journal Description
Cells
Cells
is an international, peer-reviewed, open access journal on cell biology, molecular biology, and biophysics, published semimonthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH) and Society for Regenerative Medicine (Russian Federation) (RPO) are affiliated with Cells and their members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Cell Biology) / CiteScore - Q1 (General Biochemistry, Genetics and Molecular Biology)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16.6 days after submission; acceptance to publication is undertaken in 2.8 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Sections: published in 21 topical sections.
- Companion journal: Organoids.
Impact Factor:
6.0 (2022);
5-Year Impact Factor:
6.7 (2022)
Latest Articles
CBFA2T3 Is PPARA Sensitive and Attenuates Fasting-Induced Lipid Accumulation in Mouse Liver
Cells 2024, 13(10), 831; https://doi.org/10.3390/cells13100831 (registering DOI) - 13 May 2024
Abstract
Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in the liver. Accumulating evidence shows that PPARA regulates the expression of various protein coding and non-coding genes that modulate metabolic stress
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Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in the liver. Accumulating evidence shows that PPARA regulates the expression of various protein coding and non-coding genes that modulate metabolic stress in the liver. CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3) is a DNA-binding transcription factor that belongs to the myeloid translocation gene family. Many studies have shown that CBFA2T3 is associated with acute myeloid leukemia. Especially, CBFA2T3–GLIS2 fusion is a chimeric oncogene associated with a poor survival rate in pediatric acute megakaryocytic leukemia. A previous study identified that PPARA activation promoted Cbfa2t3 induction in liver and that Cbfa2t3 may have a modulatory role in metabolic stress. However, the effect of CBFA2T3 gene expression on metabolic stress is not understood. In this study, the PPARA ligand WY14643 activated Cbfa2t3 expression in mouse liver. Glucose tolerance test and insulin tolerance test data showed that insulin resistance is increased in Cbfa2t3−/− mice compared to Cbfa2t3+/+ mice. Hepatic CBFA2T3 modulates heat shock protein family A member 1b and carbonic anhydrase 5a expression. Histology analysis revealed lipid droplet and lipid accumulation in the liver of fasting Cbfa2t3−/− mice but not Cbfa2t3+/+ mice. The expression of lipid accumulation-related genes, such as Cd36, Cidea, and Fabp1, was increased in the liver of fasting Cbfa2t3−/− mice. Especially, basal expression levels of Cidea mRNA were elevated in the liver of Cbfa2t3−/− mice compared to Cbfa2t3+/+ mice. Much higher induction of Cidea mRNA was seen in the liver of Cbfa2t3−/− mice after WY14643 administration. These results indicate that hepatic CBFA2T3 is a PPARA-sensitive gene that may modulate metabolic stress in mouse liver.
Full article
(This article belongs to the Special Issue The Role of PPARs in Disease - Volume III)
Open AccessArticle
Effects of the Dual FAAH/MAGL Inhibitor AKU-005 on Trigeminal Hyperalgesia in Male Rats
by
Rosaria Greco, Chiara Demartini, Miriam Francavilla, Anna Maria Zanaboni, Sara Facchetti, Michela Palmisani, Valentina Franco and Cristina Tassorelli
Cells 2024, 13(10), 830; https://doi.org/10.3390/cells13100830 (registering DOI) - 13 May 2024
Abstract
The inhibition of endocannabinoid hydrolysis by enzymatic inhibitors may interfere with mechanisms underlying migraine-related pain. The dual FAAH/MAGL inhibitor AKU-005 shows potent inhibitory activity in vitro. Here, we assessed the effect of AKU-005 in a migraine animal model based on nitroglycerin (NTG) administration.
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The inhibition of endocannabinoid hydrolysis by enzymatic inhibitors may interfere with mechanisms underlying migraine-related pain. The dual FAAH/MAGL inhibitor AKU-005 shows potent inhibitory activity in vitro. Here, we assessed the effect of AKU-005 in a migraine animal model based on nitroglycerin (NTG) administration. Male rats were treated with AKU-005 (0.5 mg/kg, i.p.) or vehicle 3 h after receiving NTG (10 mg/kg, i.p.) or NTG vehicle. One hour later, rats were subjected to the open field test followed by the orofacial formalin test. At the end of the test, we collected serum samples for assessing calcitonin gene-related peptide (CGRP) levels as well as meninges, trigeminal ganglia, and brain areas to assess mRNA levels of CGRP and pro-inflammatory cytokines, and endocannabinoid and related lipid levels. AKU-005 reduced NTG-induced hyperalgesia during the orofacial formalin test but did not influence NTG-induced changes in the open field test. It significantly reduced serum levels of CGRP, CGRP, and pro-inflammatory cytokine mRNA levels in the meninges, trigeminal ganglia, and central areas. Surprisingly, AKU-005 caused no change in endocannabinoids and related lipids in the regions evaluated. The present findings suggest that AKU-005 may have anti-migraine effects by reducing CGRP synthesis and release and the associated inflammatory events. This effect, however, does not seem mediated via an interference with the endocannabinoid pathway.
Full article
(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)
Open AccessArticle
Generation of Rhesus Macaque Embryos with Expanded CAG Trinucleotide Repeats in the Huntingtin Gene
by
Junghyun Ryu, John P. Statz, William Chan, Kiana Oyama, Maggie Custer, Martin Wienisch, Richard Chen, Carol B. Hanna and Jon D. Hennebold
Cells 2024, 13(10), 829; https://doi.org/10.3390/cells13100829 (registering DOI) - 13 May 2024
Abstract
Huntington’s disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development
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Huntington’s disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide important insight into disease development and the generation of novel therapies due to their genetic and physiological similarity to humans. For this purpose, we tested CRISPR/Cas9 and a single-stranded DNA (ssDNA) containing expanded CAG repeats in introducing an expanded CAG repeat into the HTT gene in rhesus macaque embryos. Analyses were conducted on arrested embryos and trophectoderm (TE) cells biopsied from blastocysts to assess the insertion of the ssDNA into the HTT gene. Genotyping results demonstrated that 15% of the embryos carried an expanded CAG repeat. The integration of an expanded CAG repeat region was successfully identified in five blastocysts, which were cryopreserved for NHP HD animal production. Some off-target events were observed in biopsies from the cryopreserved blastocysts. NHP embryos were successfully produced, which will help to establish an NHP HD model and, ultimately, may serve as a vital tool for better understanding HD’s pathology and developing novel treatments.
Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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Open AccessReview
Clinical Islet Xenotransplantation: Development of Isolation Protocol, Anti-Rejection Strategies, and Clinical Outcomes
by
Shinichi Matsumoto and Kyohei Matsumoto
Cells 2024, 13(10), 828; https://doi.org/10.3390/cells13100828 (registering DOI) - 13 May 2024
Abstract
Allogeneic islet transplantation has become a standard therapy for unstable type 1 diabetes. However, considering the large number of type 1 diabetic patients, the shortage of donors is a serious issue. To address this issue, clinical islet xenotransplantation is conducted. The first clinical
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Allogeneic islet transplantation has become a standard therapy for unstable type 1 diabetes. However, considering the large number of type 1 diabetic patients, the shortage of donors is a serious issue. To address this issue, clinical islet xenotransplantation is conducted. The first clinical islet xenotransplantation was performed by a Swedish team using fetal pancreatic tissue. Thereafter, clinical trials of islet xenotransplantation were conducted in New Zealand, Russia, Mexico, Argentina, and China using neonatal pig islets. In clinical trials, fetal or neonatal pancreata are used because of the established reliable islet isolation methods. These trials demonstrate the method’s safety and efficacy. Currently, the limited number of source animal facilities is a problem in terms of promoting islet xenotransplantation. This limitation is due to the high cost of source animal facilities and the uncertain future of xenotransplantation. In the United States, the first xenogeneic heart transplantation has been performed, which could promote xenotransplantation. In Japan, to enhance xenotransplantation, the ‘Medical Porcine Development Association’ has been established. We hope that xenogeneic transplantation will become a clinical reality, serving to address the shortage of donors.
Full article
(This article belongs to the Special Issue Islet Transplantation)
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Open AccessArticle
Transcriptome and Metabolome Reveal Key Genes from the Plant Hormone Signal Transduction Pathway Regulating Plant Height and Leaf Size in Capsicum baccatum
by
Na Xing, Xiaoqi Li, Shuhua Wu and Zhiwei Wang
Cells 2024, 13(10), 827; https://doi.org/10.3390/cells13100827 (registering DOI) - 13 May 2024
Abstract
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Plant structure-related agronomic traits like plant height and leaf size are critical for growth, development, and crop yield. Defining the types of genes involved in regulating plant structure size is essential for the molecular-assisted breeding of peppers. This research conducted comparative transcriptome analyses
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Plant structure-related agronomic traits like plant height and leaf size are critical for growth, development, and crop yield. Defining the types of genes involved in regulating plant structure size is essential for the molecular-assisted breeding of peppers. This research conducted comparative transcriptome analyses using Capsicum baccatum germplasm HNUCB0112 and HNUCB0222 and their F2 generation as materials. A total of 6574 differentially expressed genes (DEGs) were detected, which contain 379 differentially expressed transcription factors, mainly including transcription factor families such as TCP, WRKY, AUX/IAA, and MYB. Seven classes of DEGs were annotated in the plant hormone signal transduction pathway, including indole acetic acid (IAA), gibberellin (GA), cytokinin (CK), abscisic acid (ABA), jasmonic acid (JA), ethylene (ET), and salicylic acid (SA). The 26 modules were obtained by WGCNA analysis, and the MEpink module was positively correlated with plant height and leaf size, and hub genes associated with plant height and leaf size were anticipated. Differential genes were verified by qRT-PCR, which was consistent with the RNA-Seq results, demonstrating the accuracy of the sequencing results. These results enhance our understanding of the developmental regulatory networks governing pepper key traits like plant height and leaf size and offer new information for future research on the pepper plant architecture system.
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Open AccessArticle
Ectopic MYBL2-Mediated Regulation of Androglobin Gene Expression
by
Antonia Herwig, Carina Osterhof, Anna Keppner, Darko Maric, Teng Wei Koay, Ambre Mbemba-Nsungi and David Hoogewijs
Cells 2024, 13(10), 826; https://doi.org/10.3390/cells13100826 (registering DOI) - 11 May 2024
Abstract
Androglobin (ADGB) is a highly conserved and recently identified member of the globin superfamily. Although previous studies revealed a link to ciliogenesis and an involvement in murine spermatogenesis, its physiological function remains mostly unknown. Apart from FOXJ1-dependent regulation, the transcriptional landscape of the
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Androglobin (ADGB) is a highly conserved and recently identified member of the globin superfamily. Although previous studies revealed a link to ciliogenesis and an involvement in murine spermatogenesis, its physiological function remains mostly unknown. Apart from FOXJ1-dependent regulation, the transcriptional landscape of the ADGB gene remains unexplored. We, therefore, aimed to obtain further insights into regulatory mechanisms governing ADGB expression. To this end, changes in ADGB promoter activity were examined using luciferase reporter gene assays in the presence of a set of more than 475 different exogenous transcription factors. MYBL2 and PITX2 resulted in the most pronounced increase in ADGB promoter-dependent luciferase activity. Subsequent truncation strategies of the ADGB promoter fragment narrowed down the potential MYBL2 and PITX2 binding sites within the proximal ADGB promoter. Furthermore, MYBL2 binding sites on the ADGB promoter were further validated via a guide RNA-mediated interference strategy using reporter assays. Chromatin immunoprecipitation (ChIP)-qPCR experiments illustrated enrichment of the endogenous ADGB promoter region upon MYBL2 and PITX2 overexpression. Consistently, ectopic MYBL2 expression induced endogenous ADGB mRNA levels. Collectively, our data indicate that ADGB is strongly regulated at the transcriptional level and might have functions beyond ciliogenesis.
Full article
(This article belongs to the Special Issue Hemoglobin and Other Globin Types: Structure, Function and Evolution)
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Open AccessReview
The Role of Autophagy in Vascular Endothelial Cell Health and Physiology
by
Meghan Hu, Joseph M. Ladowski and He Xu
Cells 2024, 13(10), 825; https://doi.org/10.3390/cells13100825 (registering DOI) - 11 May 2024
Abstract
Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells
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Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
Full article
(This article belongs to the Special Issue Autophagy and Inflammasome)
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Open AccessArticle
Assessing the Impact of Novel BRCA1 Exon 11 Variants on Pre-mRNA Splicing
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Halla Elshwekh, Inas M. Alhudiri, Adam Elzagheid, Nabil Enattah, Yasmine Abbassi, Lubna Abou Assali, Ilenia Marino, Cristiana Stuani, Emanuele Buratti and Maurizio Romano
Cells 2024, 13(10), 824; https://doi.org/10.3390/cells13100824 (registering DOI) - 11 May 2024
Abstract
Our study focused on assessing the effects of three newly identified BRCA1 exon 11 variants (c.1019T>C, c.2363T>G, and c.3192T>C) on breast cancer susceptibility. Using computational predictions and experimental splicing assays, we evaluated their potential as pathogenic mutations. Our in silico analyses suggested that
[...] Read more.
Our study focused on assessing the effects of three newly identified BRCA1 exon 11 variants (c.1019T>C, c.2363T>G, and c.3192T>C) on breast cancer susceptibility. Using computational predictions and experimental splicing assays, we evaluated their potential as pathogenic mutations. Our in silico analyses suggested that the c.2363T>G and c.3192T>C variants could impact both splicing and protein function, resulting in the V340A and V788G mutations, respectively. We further examined their splicing effects using minigene assays in MCF7 and SKBR3 breast cancer cell lines. Interestingly, we found that the c.2363T>G variant significantly altered splicing patterns in MCF7 cells but not in SKBR3 cells. This finding suggests a potential influence of cellular context on the variant’s effects. While attempts to correlate in silico predictions with RNA binding factors were inconclusive, this observation underscores the complexity of splicing regulation. Splicing is governed by various factors, including cellular contexts and protein interactions, making it challenging to predict outcomes accurately. Further research is needed to fully understand the functional consequences of the c.2363T>G variant in breast cancer pathogenesis. Integrating computational predictions with experimental data will provide valuable insights into the role of alternative splicing regulation in different breast cancer types and stages.
Full article
Open AccessReview
Glioblastoma Phagocytic Cell Death: Balancing the Opportunities for Therapeutic Manipulation
by
Ruochen Du, Shashwat Tripathi, Hinda Najem, Daniel J. Brat, Rimas V. Lukas, Peng Zhang and Amy B. Heimberger
Cells 2024, 13(10), 823; https://doi.org/10.3390/cells13100823 (registering DOI) - 11 May 2024
Abstract
Macrophages and microglia are professional phagocytes that sense and migrate toward “eat-me” signals. The role of phagocytic cells is to maintain homeostasis by engulfing senescent or apoptotic cells, debris, and abnormally aggregated macromolecules. Usually, dying cells send out “find-me” signals, facilitating the recruitment
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Macrophages and microglia are professional phagocytes that sense and migrate toward “eat-me” signals. The role of phagocytic cells is to maintain homeostasis by engulfing senescent or apoptotic cells, debris, and abnormally aggregated macromolecules. Usually, dying cells send out “find-me” signals, facilitating the recruitment of phagocytes. Healthy cells can also promote or inhibit the phagocytosis phenomenon of macrophages and microglia by tuning the balance between “eat-me” and “don’t-eat-me” signals at different stages in their lifespan, while the “don’t-eat-me” signals are often hijacked by tumor cells as a mechanism of immune evasion. Using a combination of bioinformatic analysis and spatial profiling, we delineate the balance of the “don’t-eat-me” CD47/SIRPα and “eat-me” CALR/STC1 ligand–receptor interactions to guide therapeutic strategies that are being developed for glioblastoma sequestered in the central nervous system (CNS).
Full article
(This article belongs to the Special Issue Cell Death Mechanisms and Therapeutic Opportunities in Glioblastoma)
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Open AccessArticle
Effects of Garlic on Breast Tumor Cells with a Triple Negative Phenotype: Peculiar Subtype-Dependent Down-Modulation of Akt Signaling
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Federica Brugnoli, Marcello Dell’Aira, Paola Tedeschi, Silvia Grassilli, Marina Pierantoni, Rebecca Foschi and Valeria Bertagnolo
Cells 2024, 13(10), 822; https://doi.org/10.3390/cells13100822 (registering DOI) - 11 May 2024
Abstract
Breast cancer includes tumor subgroups with morphological, molecular, and clinical differences. Intrinsic heterogeneity especially characterizes breast tumors with a triple negative phenotype, often leading to the failure of even the most advanced therapeutic strategies. To improve breast cancer treatment, the use of natural
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Breast cancer includes tumor subgroups with morphological, molecular, and clinical differences. Intrinsic heterogeneity especially characterizes breast tumors with a triple negative phenotype, often leading to the failure of even the most advanced therapeutic strategies. To improve breast cancer treatment, the use of natural agents to integrate conventional therapies is the subject of ever-increasing attention. In this context, garlic (Allium sativum) shows anti-cancerous potential, interfering with the proliferation, motility, and malignant progression of both non-invasive and invasive breast tumor cells. As heterogeneity could be at the basis of variable effects, the main objective of our study was to evaluate the anti-tumoral activity of a garlic extract in breast cancer cells with a triple negative phenotype. Established triple negative breast cancer (TNBC) cell lines from patient-derived xenografts (PDXs) were used, revealing subtype-dependent effects on morphology, cell cycle, and invasive potential, correlated with the peculiar down-modulation of Akt signaling, a crucial regulator in solid tumors. Our results first demonstrate that the effects of garlic on TNBC breast cancer are not unique and suggest that only more precise knowledge of the mechanisms activated by this natural compound in each tumor will allow for the inclusion of garlic in personalized therapeutic approaches to breast cancer.
Full article
(This article belongs to the Section Cell Microenvironment)
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Open AccessArticle
Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial–Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer
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Madhumathy G. Nair, Apoorva D. Mavatkar, Chandrakala M. Naidu, Snijesh V. P., Anupama C. E., Savitha Rajarajan, Sarthak Sahoo, Gayathri Mohan, Vishnu Sunil Jaikumar, Rakesh S. Ramesh, Srinath B. S., Mohit Kumar Jolly, Tessy Thomas Maliekal and Jyothi S. Prabhu
Cells 2024, 13(10), 821; https://doi.org/10.3390/cells13100821 (registering DOI) - 10 May 2024
Abstract
Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial–mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state
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Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial–mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures.
Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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Open AccessReview
The Imperative for Innovative Enteric Nervous System–Intestinal Organoid Co-Culture Models: Transforming GI Disease Modeling and Treatment
by
Cristina Llorente
Cells 2024, 13(10), 820; https://doi.org/10.3390/cells13100820 (registering DOI) - 10 May 2024
Abstract
This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves
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This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves as an introduction to the companion protocol paper featured in this journal. The protocol outlines the isolation and co-culture of myenteric and submucosal neurons with small intestinal organoids. This review provides an overview of the intestinal organoid culture field to establish a solid foundation for effective protocol application. Remarkably, the ENS surpasses the number of neurons in the spinal cord. Referred to as the “second brain”, the ENS orchestrates pivotal roles in GI functions, including motility, blood flow, and secretion. The ENS is organized into myenteric and submucosal plexuses. These plexuses house diverse subtypes of neurons. Due to its proximity to the gut musculature and its cell type complexity, there are methodological intricacies in studying the ENS. Diverse approaches such as primary cell cultures, three-dimensional (3D) neurospheres, and induced ENS cells offer diverse insights into the multifaceted functionality of the ENS. The ENS exhibits dynamic interactions with the intestinal epithelium, the muscle layer, and the immune system, influencing epithelial physiology, motility, immune responses, and the microbiome. Neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), and vasoactive intestinal peptide (VIP), play pivotal roles in these intricate interactions. Understanding these dynamics is imperative, as the ENS is implicated in various diseases, ranging from neuropathies to GI disorders and neurodegenerative diseases. The emergence of organoid technology presents an unprecedented opportunity to study ENS interactions within the complex milieu of the small and large intestines. This manuscript underscores the urgent need for standardized protocols and advanced techniques to unravel the complexities of the ENS and its dynamic relationship with the gut ecosystem. The insights gleaned from such endeavors hold the potential to revolutionize GI disease modeling and treatment paradigms.
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(This article belongs to the Collection Advances in 3D Cell Culture)
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Open AccessArticle
Discrepant Phenotyping of Monocytes Based on CX3CR1 and CCR2 Using Fluorescent Reporters and Antibodies
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Katrin Sommer, Hilal Garibagaoglu, Eva-Maria Paap, Maximilian Wiendl, Tanja M. Müller, Imke Atreya, Gerhard Krönke, Markus F. Neurath and Sebastian Zundler
Cells 2024, 13(10), 819; https://doi.org/10.3390/cells13100819 (registering DOI) - 10 May 2024
Abstract
Monocytes, as well as downstream macrophages and dendritic cells, are essential players in the immune system, fulfilling key roles in homeostasis as well as in inflammatory conditions. Conventionally, driven by studies on reporter models, mouse monocytes are categorized into a classical and a
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Monocytes, as well as downstream macrophages and dendritic cells, are essential players in the immune system, fulfilling key roles in homeostasis as well as in inflammatory conditions. Conventionally, driven by studies on reporter models, mouse monocytes are categorized into a classical and a non-classical subset based on their inversely correlated surface expression of Ly6C/CCR2 and CX3CR1. Here, we aimed to challenge this concept by antibody staining and reporter mouse models. Therefore, we took advantage of Cx3cr1GFP and Ccr2RFP reporter mice, in which the respective gene was replaced by a fluorescent reporter protein gene. We analyzed the expression of CX3CR1 and CCR2 by flow cytometry using several validated fluorochrome-coupled antibodies and compared them with the reporter gene signal in these reporter mouse strains. Although we were able to validate the specificity of the fluorochrome-coupled flow cytometry antibodies, mouse Ly6Chigh classical and Ly6Clow non-classical monocytes showed no differences in CX3CR1 expression levels in the peripheral blood and spleen when stained with these antibodies. On the contrary, in Cx3cr1GFP reporter mice, we were able to reproduce the inverse correlation of the CX3CR1 reporter gene signal and Ly6C surface expression. Furthermore, differential CCR2 surface expression correlating with the expression of Ly6C was observed by antibody staining, but not in Ccr2RFP reporter mice. In conclusion, our data suggest that phenotyping strategies for mouse monocyte subsets should be carefully selected. In accordance with the literature, the suitability of CX3CR1 antibody staining is limited, whereas for CCR2, caution should be applied when using reporter mice.
Full article
(This article belongs to the Section Cell Microenvironment)
Open AccessReview
Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation
by
Kamel Laghmani
Cells 2024, 13(10), 818; https://doi.org/10.3390/cells13100818 (registering DOI) - 10 May 2024
Abstract
Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension.
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Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter’s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.
Full article
(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)
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Open AccessReview
Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells
by
Sandra Jenkner, Jillian Mary Clark, Stan Gronthos and Ryan Louis O’Hare Doig
Cells 2024, 13(10), 817; https://doi.org/10.3390/cells13100817 (registering DOI) - 10 May 2024
Abstract
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a
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Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.
Full article
(This article belongs to the Special Issue Understanding Spinal Cord Injury and Repair: From Molecules to Neurocircuits and Multimodal Prostheses)
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Open AccessCorrection
Correction: Zhao et al. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020, 9, 559
by
Yin Zhao, Yuan Lei, Shi-Wei He, Ying-Qin Li, Ya-Qin Wang, Xiao-Hong Hong, Ye-Lin Liang, Jun-Yan Li, Yang Chen, Wei-Jie Luo, Pan-Pan Zhang, Xiao-Jing Yang, Qing-Mei He, Jun Ma, Na Liu and Ling-Long Tang
Cells 2024, 13(10), 816; https://doi.org/10.3390/cells13100816 - 10 May 2024
Abstract
In the original publication [...]
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(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)
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Open AccessProtocol
Isolation of Myenteric and Submucosal Plexus from Mouse Gastrointestinal Tract and Subsequent Co-Culture with Small Intestinal Organoids
by
Cristina Llorente
Cells 2024, 13(10), 815; https://doi.org/10.3390/cells13100815 - 10 May 2024
Abstract
Intestinal homeostasis results from the proper interplay among epithelial cells, the enteric nervous system (ENS), interstitial cells of Cajal (ICCs), smooth muscle cells, the immune system, and the microbiota. The disruption of this balance underpins the onset of gastrointestinal-related diseases. The scarcity of
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Intestinal homeostasis results from the proper interplay among epithelial cells, the enteric nervous system (ENS), interstitial cells of Cajal (ICCs), smooth muscle cells, the immune system, and the microbiota. The disruption of this balance underpins the onset of gastrointestinal-related diseases. The scarcity of models replicating the intricate interplay between the ENS and the intestinal epithelium highlights the imperative for developing novel methods. We have pioneered a sophisticated tridimensional in vitro technique, coculturing small intestinal organoids with myenteric and submucosal neurons. Notably, we have made significant advances in (1) refining the isolation technique for culturing the myenteric plexus, (2) enhancing the isolation of the submucosal plexus—both yielding mixed cultures of enteric neurons and glial cells from both plexuses, and (3) subsequently co-culturing myenteric and submucosal neurons with small intestinal organoids. This co-culture system establishes neural innervations with intestinal organoids, allowing for the investigation of regulatory interactions in the context of gastrointestinal diseases. Furthermore, we have developed a method for microinjecting the luminal space of small intestinal organoids with fluorescently labeled compounds. This technique possesses broad applicability such as the assessment of intestinal permeability, transcytosis, and immunocytochemical and immunofluorescence applications. This microinjection method could be extended to alternative experimental setups, incorporating bacterial species, or applying treatments to study ENS-small intestinal epithelium interactions. Therefore, this technique serves as a valuable tool for evaluating the intricate interplay between neuronal and intestinal epithelial cells (IECs) and shows great potential for drug screening, gene editing, the development of novel therapies, the modeling of infectious diseases, and significant advances in regenerative medicine. The co-culture establishment process spans twelve days, making it a powerful asset for comprehensive research in this critical field.
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(This article belongs to the Collection Advances in 3D Cell Culture)
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Immuno-Hematologic Complexity of ABO-Incompatible Allogeneic HSC Transplantation
by
Antonella Matteocci and Luca Pierelli
Cells 2024, 13(10), 814; https://doi.org/10.3390/cells13100814 - 10 May 2024
Abstract
ABO incompatibility is not considered a contraindication for hematopoietic stem cell transplantation (HSCT). Approximately 30% of transplants from related donors and up to 50% of transplants from unrelated donors are ABO incompatible. Immuno-hematologic investigations allow to estimate donor/recipient ABO mismatch and anti-A/B isohemagglutinin
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ABO incompatibility is not considered a contraindication for hematopoietic stem cell transplantation (HSCT). Approximately 30% of transplants from related donors and up to 50% of transplants from unrelated donors are ABO incompatible. Immuno-hematologic investigations allow to estimate donor/recipient ABO mismatch and anti-A/B isohemagglutinin (IHA) titration in the pre-HSCT phase. Immediate hemolysis or delayed complications (passenger lymphocyte syndrome and pure red cell aplasia) can occur post HSCT. Some preventive measures take into consideration either decision-making algorithms based on the recipient’s IHA titration or clinical protocols for the removal/reduction of IHAs through plasma exchange or immunoadsorption procedures. Product manipulation through red blood cell (RBC) and/or plasma depletion can also be taken into account. Currently, the best approach in the management of ABO-incompatible transplant is not defined in expert consensus documents or with solid evidence. In addition, the methods for IHA titration are not standardized. A transfusion strategy must consider both the donor’s and recipient’s blood group systems until the RBC engraftment catches on and ABO conversion (forward and reverse typing) is confirmed on two consecutive and independent samples. Therefore, ABO incompatibility in HSCT represents a demanding immuno-hematologic challenge and requires all necessary preventive measures, including the appropriate selection of ABO blood components for transfusion.
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(This article belongs to the Special Issue Clinical and Methodological Aspects of HSC Transplantation in Hematological Malignancies)
Open AccessArticle
Senotherapeutic Peptide 14 Suppresses Th1 and M1 Human T Cell and Monocyte Subsets In Vitro
by
Thuany Alencar-Silva, Stefhani Martins de Barcelos, Amandda Silva-Carvalho, Mauricio Gonçalves da Costa Sousa, Taia Maria Berto Rezende, Robert Pogue, Felipe Saldanha-Araújo, Octávio Luiz Franco, Mariana Boroni, Alessandra Zonari and Juliana Lott Carvalho
Cells 2024, 13(10), 813; https://doi.org/10.3390/cells13100813 - 10 May 2024
Abstract
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Inflammation contributes to the onset and exacerbation of numerous age-related diseases, often manifesting as a chronic condition during aging. Given that cellular senescence fosters local and systemic inflammation, senotherapeutic interventions could potentially aid in managing or even reducing inflammation. Here, we investigated the
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Inflammation contributes to the onset and exacerbation of numerous age-related diseases, often manifesting as a chronic condition during aging. Given that cellular senescence fosters local and systemic inflammation, senotherapeutic interventions could potentially aid in managing or even reducing inflammation. Here, we investigated the immunomodulatory effects of the senotherapeutic Peptide 14 (Pep 14) in human peripheral blood mononuclear cells (PBMCs), monocytes, and macrophages. We found that, despite failing to significantly influence T cell activation and proliferation, the peptide promoted a Th2/Treg gene expression and cytokine signature in PBMCs, characterized by increased expression of the transcription factors GATA3 and FOXP3, as well as the cytokines IL-4 and IL-10. These observations were partially confirmed through ELISA, in which we observed increased IL-10 release by resting and PHA-stimulated PBMCs. In monocytes from the U-937 cell line, Pep 14 induced apoptosis in lipopolysaccharide (LPS)-stimulated cells and upregulated IL-10 expression. Furthermore, Pep 14 prevented LPS-induced activation and promoted an M2-like polarization in U-937-derived macrophages, evidenced by decreased expression of M1 markers and increased expression of M2 markers. We also showed that the conditioned media from Pep 14-treated macrophages enhanced fibroblast migration, indicative of a functional M2 phenotype. Taken together, our findings suggest that Pep 14 modulates immune cell function towards an anti-inflammatory and regenerative phenotype, highlighting its potential as a therapeutic intervention to alleviate immunosenescence-associated dysregulation.
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Open AccessCorrection
Correction: Kolesar et al. Role of Nse1 Subunit of SMC5/6 Complex as a Ubiquitin Ligase. Cells 2022, 11, 165
by
Peter Kolesar, Karel Stejskal, David Potesil, Johanne M. Murray and Jan J. Palecek
Cells 2024, 13(10), 812; https://doi.org/10.3390/cells13100812 - 10 May 2024
Abstract
In the original publication [...]
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