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Zhang Q, Zheng J, Wang Y, Xu S, Wang W, Xu J, Zhang JR, Li F, Zhu JJ. A Diffusion-Based Synthetic Cell Communication Network Enabled by a Multitasking Deoxyribonucleic Acid Nanomachine. J Am Chem Soc 2025; 147:15806-15813. [PMID: 40275484 DOI: 10.1021/jacs.5c03726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
DNA-mediated synthetic cell communication enabling non-natural signaling and regulatory pathways is highly attractive but relies on direct cell contacts. Here, we report a diffusion-based synthetic cell communication capable of regulating migration behaviors of epithelial cell adhesion molecule (EpCAM)-overexpressed cancer cells in response to apoptosis events at distal sites. This synthetic cell communication network is enabled by a multitasking DNA nanomachine that not only mediates signal production, transmission, and regulation of cell migration but also amplifies signaling ligands in situ in response to specific receiver cells to overcome the signal attenuation during diffusion. Leveraging this diffusion-based synthetic cell communication network, we demonstrate the inhibition of cancer cell migrations in response to distal apoptosis events induced by an anticancer drug. Our system enriches current DNA nanotechnological tools for manipulating cellular interactions and function. It also directs a possible intervening strategy to reduce the invasiveness of cancer cells.
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Affiliation(s)
- Qianying Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Jingyi Zheng
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Yihan Wang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Shengshi Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Wenjing Wang
- State Key Laboratory of Agricultural Microbiology, College of Science, Huazhong Agricultural University, Wuhan 430070, China
| | - Junpeng Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing 210093, China
| | - Jian-Rong Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Feng Li
- Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
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Ouyang J, Chai H, Sun C, Wang S, She C, Geng D, Xu W. Titanium Particles Activate Osteocytic Connexin 43 to Induce Oxidative Stress and Osteoclastogenesis Through the JAK-STAT Pathway. Antioxid Redox Signal 2025. [PMID: 40207369 DOI: 10.1089/ars.2024.0894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Aims: Periprosthetic osteolysis (PPO), a leading cause of aseptic loosening in joint replacement, arose from complex interactions among osteoblasts, osteoclasts, and osteocytes. Given the pivotal role of connexin 43 (Cx43) in osteocyte communication and bone remodeling, investigating its function was essential for understanding the mechanisms of osteolysis. Our previous studies showed that titanium (Ti) particles increased Cx43 expression in osteocytes. However, the role of Cx43 in osteolysis remained unclear. This study investigated the role of Cx43-mediated regulation of osteocytes on osteoclastogenesis in wear debris-induced osteolysis. Results: Using Dmp1-cre conditional Cx43 knockout mice and the MLO-Y4 osteocyte cell line, we demonstrated that Cx43 deficiency reduced bone resorption and osteoclastogenesis, thereby improving bone remodeling in a Ti particle-induced osteolysis model. Sequencing analysis revealed that Cx43 gene expression changes might be linked to oxidative stress and the Janus Kinase (JAK)-STAT pathway. Elevated Cx43 expression in osteocytes stimulated by Ti particles increased STAT1 protein phosphorylation, induced oxidative stress, elevated the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL)/Osteoprotegerin (OPG) ratio, and promoted osteoclast activation and bone resorption. Conversely, Cx43 gene knockout decreased STAT1 protein phosphorylation and enhanced Nuclear Factor Erythroid 2-Related Factor 2 (NrF2) protein expression. Blocking the JAK-STAT signaling pathway activated by Cx43 increased NrF2 expression, reduced reactive oxygen species levels, and subsequently decreased the RANKL/OPG ratio. Innovation and Conclusions: This study identified a novel mechanism where Cx43 in osteocytes promoted osteoclastogenesis through JAK-STAT pathway activation and oxidative stress in wear debris-induced osteolysis. These findings highlighted the critical role of Cx43 in bone resorption and suggested targeting Cx43 or the JAK-STAT pathway as potential therapeutic strategies to mitigate osteolysis and improve implant longevity. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Jiawei Ouyang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Shanxi, China
| | - Chunguang Sun
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Shendong Wang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chang She
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Blackiston D, Dromiack H, Grasso C, Varley TF, Moore DG, Srinivasan KK, Sporns O, Bongard J, Levin M, Walker SI. Revealing non-trivial information structures in aneural biological tissues via functional connectivity. PLoS Comput Biol 2025; 21:e1012149. [PMID: 40228211 PMCID: PMC11996219 DOI: 10.1371/journal.pcbi.1012149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 02/19/2025] [Indexed: 04/16/2025] Open
Abstract
A central challenge in the progression of a variety of open questions in biology, such as morphogenesis, wound healing, and development, is learning from empirical data how information is integrated to support tissue-level function and behavior. Information-theoretic approaches provide a quantitative framework for extracting patterns from data, but so far have been predominantly applied to neuronal systems at the tissue-level. Here, we demonstrate how time series of Ca2+ dynamics can be used to identify the structure and information dynamics of other biological tissues. To this end, we expressed the calcium reporter GCaMP6s in an organoid system of explanted amphibian epidermis derived from the African clawed frog Xenopus laevis, and imaged calcium activity pre- and post- a puncture injury, for six replicate organoids. We constructed functional connectivity networks by computing mutual information between cells from time series derived using medical imaging techniques to track intracellular Ca2+. We analyzed network properties including degree distribution, spatial embedding, and modular structure. We find organoid networks exhibit potential evidence for more connectivity than null models, with our models displaying high degree hubs and mesoscale community structure with spatial clustering. Utilizing functional connectivity networks, our model suggests the tissue retains non-random features after injury, displays long range correlations and structure, and non-trivial clustering that is not necessarily spatially dependent. In the context of this reconstruction method our results suggest increased integration after injury, possible cellular coordination in response to injury, and some type of generative structure of the anatomy. While we study Ca2+ in Xenopus epidermal cells, our computational approach and analyses highlight how methods developed to analyze functional connectivity in neuronal tissues can be generalized to any tissue and fluorescent signal type. We discuss expanded methods of analyses to improve models of non-neuronal information processing highlighting the potential of our framework to provide a bridge between neuroscience and more basal modes of information processing.
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Affiliation(s)
- Douglas Blackiston
- Allen Discovery Center, Tufts University, Medford, Massachusetts, United States of America
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America
- Institute for Computationally-Designed Organisms, UVM, Burlington, Vermont and Tufts, Medford, Massachusetts, United States of America
- Department of Biology, Tufts University, Medford, Massachusetts, United States of America
| | - Hannah Dromiack
- Department of Physics, Arizona State University, Tempe, Arizona, United States of America
- BEYOND Center for Fundamental Concepts in Science, Arizona State University, Tempe, Arizona, United States of America
| | - Caitlin Grasso
- Department of Computer Science, University of Vermont, Burlington, Vermont, United States of America
| | - Thomas F Varley
- Department of Computer Science, University of Vermont, Burlington, Vermont, United States of America
- Department of Complex Systems and Data Science, University of Vermont, Burlington, Vermont, United States of America
- School of Informatics, Computing, and Engineering, Indiana University, Bloomington, Indiana, United States of America
| | - Douglas G Moore
- BEYOND Center for Fundamental Concepts in Science, Arizona State University, Tempe, Arizona, United States of America
- Alpha 39 Research, Tempe, Arizona, United States of America
| | - Krishna Kannan Srinivasan
- Department of Computer Science, University of Vermont, Burlington, Vermont, United States of America
- Department of Complex Systems and Data Science, University of Vermont, Burlington, Vermont, United States of America
| | - Olaf Sporns
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States of America
| | - Joshua Bongard
- Institute for Computationally-Designed Organisms, UVM, Burlington, Vermont and Tufts, Medford, Massachusetts, United States of America
- Department of Computer Science, University of Vermont, Burlington, Vermont, United States of America
| | - Michael Levin
- Allen Discovery Center, Tufts University, Medford, Massachusetts, United States of America
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America
- Institute for Computationally-Designed Organisms, UVM, Burlington, Vermont and Tufts, Medford, Massachusetts, United States of America
- Department of Biology, Tufts University, Medford, Massachusetts, United States of America
| | - Sara I Walker
- BEYOND Center for Fundamental Concepts in Science, Arizona State University, Tempe, Arizona, United States of America
- School of Earth and Space Exploration, Arizona State University, Tempe, Arizona, United States of America
- Santa Fe Institute, Santa Fe, New Mexico, United States of America
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Iaculli D, Montgomery J, Lamouroux A, Caufriez A, Gozalbes R, Vinken M, Molica F, Kwak BR, Ballet S. Design and synthesis of cyclic lipidated peptides derived from the C-terminus of Cx43 for hemichannel inhibition and cardiac endothelium targeting. RSC Med Chem 2025; 16:1289-1303. [PMID: 39829973 PMCID: PMC11740094 DOI: 10.1039/d4md00850b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Abstract
A peptide segment that is 10 residues long at the C-terminal (CT) region of Cx43 is known to be involved in interactions, both with the Cx43 protein itself and with other proteins, that result in hemichannel (HC) activity regulation. Previously reported mimetic peptides based on this region (e.g., αCT1, CT10) have been revealed to be promising therapeutic agents in the context of cardiovascular diseases. In this work, novel approaches, such as C- and N-terminal modification and cyclization, to improve the proteolytic stability and bioavailability of the CT10 peptide are presented. These efforts resulted in a set of unprecedented potent cyclic inhibitors of HC-mediated ATP release with a half-life largely exceeding 24 hours. Additionally, the introduction of a lipophilic moiety with different solubilizing linkers led to the generation of a novel series of water-soluble and lipidated peptides that exhibited high inhibitory capacity in in vitro assays at submicromolar concentrations. A cardiac endothelium targeting strategy was also adopted, exploiting the ability of the CRPPR peptide to selectively deliver the peptides to endothelial cells.
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Affiliation(s)
- Debora Iaculli
- Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel Brussels Belgium
| | - Jade Montgomery
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva Geneva Switzerland
- Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva Geneva Switzerland
| | - Arthur Lamouroux
- Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel Brussels Belgium
| | - Anne Caufriez
- Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel Brussels Belgium
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel Brussels Belgium
| | - Rafael Gozalbes
- ProtoQSAR SL, Parque Tecnológico de Valencia Paterna Valencia Spain
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel Brussels Belgium
| | - Filippo Molica
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva Geneva Switzerland
- Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva Geneva Switzerland
| | - Brenda R Kwak
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva Geneva Switzerland
- Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva Geneva Switzerland
| | - Steven Ballet
- Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel Brussels Belgium
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Maimaitijiang G, Kira J, Nakamura Y, Watanabe M, Takase EO, Nagata S, Sakoda A, Zhang X, Masaki K, Yamasaki R, Isobe N, Yamaguchi H, Imamura T. Blood exosome connexins and small RNAs related to demyelinating disease activity. Ann Clin Transl Neurol 2025; 12:538-555. [PMID: 39901658 PMCID: PMC11920735 DOI: 10.1002/acn3.52307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/23/2024] [Accepted: 01/03/2025] [Indexed: 02/05/2025] Open
Abstract
OBJECTIVES To assess blood exosome (Ex)-connexin (Cx)43 (encoded by GJA1) and its truncated isoforms in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which show distinct alterations in astroglial Cx43. METHODS Serum Exs from 48 patients with MS (34 relapsing-remitting, 14 secondary-progressive), 35 with NMOSD, 20 with other inflammatory neurologic diseases (OIND), and 17 healthy controls (HC) were subjected to quantitative Western blotting for Cx43, single-molecule array for neurofilament-L, and quantitative polymerase chain reaction for non-coding RNAs detected by RNA sequencing. Sera from control and astroglia-specific Cx43 inducible conditional knockout (Cx43-icKO) mice with experimental autoimmune encephalomyelitis (EAE) were also tested. RESULTS Ex-GJA1-29k was markedly higher in MS than in NMOSD, OIND, and HC; it successively increased at relapse, remission, and secondary progression, and positively correlated with disability scores. Ex-hsa-miR-133b and other hsa-miRs that bind to full-length Cx43 were significantly lower in secondary-progressive MS than in HC, and Ex-hsa-miR-133b was negatively correlated with disability scores. Ex-GJA1-11k expression was lower in NMOSD at relapse than in HC and OIND, and was negatively correlated with disability score worsening and Ex-neurofilament-L levels. NMOSD at relapse had significantly higher expression of small nucleolar RNA (SNORD37, SNORD95, and SNORD97) than HC, and SNORD37 and SNORD95 showed strong negative correlations with disability scores. Control mice showed increased Ex-GJA1-43k and -29k during EAE; this effect was markedly reduced in Cx43-icKO mice with attenuated EAE. INTERPRETATION Blood Ex-Cx43-truncated isoforms and small non-coding RNAs, which partially come from brain astroglia, are distinctly dysregulated in MS and NMSOD.
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Affiliation(s)
- Guzailiayi Maimaitijiang
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
| | - Jun‐ichi Kira
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
- Department of Neurology, Brain and Nerve CenterFukuoka Central Hospital, International University of Health and WelfareFukuokaJapan
- School of Pharmacy at FukuokaInternational University of Health and WelfareOkawaJapan
| | - Yuri Nakamura
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
- Department of Neurology, Brain and Nerve CenterFukuoka Central Hospital, International University of Health and WelfareFukuokaJapan
- School of Pharmacy at FukuokaInternational University of Health and WelfareOkawaJapan
| | - Mitsuru Watanabe
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Ezgi Ozdemir Takase
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Satoshi Nagata
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Ayako Sakoda
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
- Department of Neurology, Brain and Nerve CenterFukuoka Central Hospital, International University of Health and WelfareFukuokaJapan
| | - Xu Zhang
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Noriko Isobe
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Hiroo Yamaguchi
- Department of Neurology, Neurological Institute, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- School of Physical Therapy, Faculty of RehabilitationReiwa Health Sciences UniversityFukuokaJapan
| | - Tomohiro Imamura
- Translational Neuroscience Research Center, Graduate School of MedicineInternational University of Health and WelfareOkawaJapan
- School of Pharmacy at FukuokaInternational University of Health and WelfareOkawaJapan
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Tishchenko A, Romero N, Van Waesberghe C, Delva JL, Vickman O, Smith GA, Mettenleiter TC, Fuchs W, Klupp BG, Favoreel HW. Pseudorabies virus infection triggers pUL46-mediated phosphorylation of connexin-43 and closure of gap junctions to promote intercellular virus spread. PLoS Pathog 2025; 21:e1012895. [PMID: 39836710 PMCID: PMC11774492 DOI: 10.1371/journal.ppat.1012895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/28/2025] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
Gap junctions (GJs) play a pivotal role in intercellular communication between eukaryotic cells, including transfer of biomolecules that contribute to the innate and adaptive immune response. However, if, how and why viruses affect gap junction intercellular communication (GJIC) remains largely unexplored. Here, we describe how the alphaherpesvirus pseudorabies virus (PRV) triggers ERK1/2-mediated phosphorylation of the main gap junction component connexin 43 (Cx43) and closure of GJIC, which depends on the viral protein pUL46. Consequently, a UL46null PRV mutant is unable to phosphorylate Cx43 or inhibit GJIC and displays reduced intercellular spread, which is effectively rescued by pharmacological inhibition of GJIC. Intercellular spread of UL46null PRV is also rescued by inhibition of the stimulator of interferon genes (STING), suggesting that pUL46-mediated suppression of GJIC contributes to intercellular virus spread by hindering intercellular communication that activates STING. The current study identifies key viral and cellular proteins involved in alphaherpesvirus-mediated suppression of GJIC and reveals that GJIC inhibition enhances virus intercellular spread, thereby opening new avenues for the design of targeted antiviral therapies.
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Affiliation(s)
- Alexander Tishchenko
- Department of Translational Physiology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Nicolás Romero
- Department of Translational Physiology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Cliff Van Waesberghe
- Department of Translational Physiology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Jonas L. Delva
- Department of Translational Physiology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Oliver Vickman
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Gregory A. Smith
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Thomas C. Mettenleiter
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institute, Insel Riems, Germany
| | - Walter Fuchs
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institute, Insel Riems, Germany
| | - Barbara G. Klupp
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institute, Insel Riems, Germany
| | - Herman W. Favoreel
- Department of Translational Physiology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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Liao L, Kim J, Cho K, Kim J, Lim BK, Won KJ. DeepDoublet identifies neighboring cell-dependent gene expression. Genomics Inform 2024; 22:30. [PMID: 39695909 DOI: 10.1186/s44342-024-00031-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
Cells interact with each other for proper function and homeostasis. Often, co-expression of ligand-receptor pairs from the single-cell RNAseq (scRNAseq) has been used to identify interacting cell types. Recently, RNA sequencing of physically interacting multi-cells has been used to identify interacting cell types without relying on co-expression of ligand-receptor pairs. This opens a new avenue to study the expression of interacting cell types. We present DeepDoublet, a deep-learning-based tool to decompose the transcriptome of physically interacting two cells (or doublet) into two sets of transcriptome. Applying DeepDoublet to the doublets of hepatocyte and liver endothelial cells (LECs), we successfully decomposed into the transcriptome of each cell type. Especially, DeepDoublet identified specific expression of hepatocytes when they are interacting with LECs. Among them was Angptl3 which has a role in blood vessel formation. DeepDoublet is a tool to identify neighboring cell-dependent gene expression.
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Affiliation(s)
- Linbu Liao
- Cancer Institution, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Junyoung Kim
- Department of Bioinformatics, Soongsil University, Seoul, Korea
| | - Kanghee Cho
- Department of Bioinformatics, Soongsil University, Seoul, Korea
| | - Junil Kim
- Department of Bioinformatics, Soongsil University, Seoul, Korea
- School of Systems Biomedical Science, Soongsil University, Seoul, Korea
| | - Byung-Kwan Lim
- Department of Biomedical Science, Jungwon University, Goesan-Gun, Chungbuk, Korea.
| | - Kyoung Jae Won
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Wang C, Xie C. Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer. J Ovarian Res 2024; 17:233. [PMID: 39580453 PMCID: PMC11585251 DOI: 10.1186/s13048-024-01560-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/15/2024] [Indexed: 11/25/2024] Open
Abstract
Mitochondria are dynamic organelles integral to metabolic processes, coordination of essential biological pathways, and oncogenesis and tumor progression. Recent studies have revealed that mitochondria can be transferred between cells via multiple mechanisms, implicating their involvement in the pathogenesis and progression of ovarian cancer. This review provides a comprehensive analysis of intercellular mitochondrial transfer within the context of ovarian cancer and its tumor microenvironment. We also propose targeted pathways and therapeutic strategies that could be utilized to modulate diseases associated with mitochondrial transfer therapy. Finally, we examine recent advancements in this field and identify several unresolved questions.
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Affiliation(s)
- Caixia Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan Province, China
| | - Chuan Xie
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan Province, China.
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Shaaban A, Scott SS, Greenlee AN, Binda N, Noor A, Webb A, Guo S, Purdy N, Pennza N, Habib A, Mohammad SJ, Smith SA. Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms. J Mol Cell Cardiol 2024; 194:118-132. [PMID: 38897563 PMCID: PMC11500699 DOI: 10.1016/j.yjmcc.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024]
Abstract
Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF.
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Affiliation(s)
- Adnan Shaaban
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA
| | - Shane S Scott
- Medical Scientist Training Program, Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Ashley N Greenlee
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Nkongho Binda
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA
| | - Ali Noor
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Averie Webb
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Shuliang Guo
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Najhee Purdy
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Nicholas Pennza
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701, USA
| | - Alma Habib
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA
| | - Somayya J Mohammad
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Sakima A Smith
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
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10
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Xu C, Wu X, Qiu J, Ye J, Lin Q, Deng J, Zeng Y, Wang W, Zhang H, Zheng H. Genome-wide identification of gap junction gene family and their expression profiles under low temperature stress in noble scallop Chlamys nobilis. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 52:101310. [PMID: 39137603 DOI: 10.1016/j.cbd.2024.101310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/13/2024] [Accepted: 08/08/2024] [Indexed: 08/15/2024]
Abstract
Gap junctions, formed by gap junction proteins (GJ), play crucial roles in cell signaling and immune responses. The structure and function of the GJ from vertebrates (called connexins) have been extensively studied. However, little is known about the proteins forming gap junctions in invertebrates (called innexins). In this study, 14 GJ genes of Chlamys nobilis were identified. GJ proteins are mainly distributed on the plasma membrane, and all proteins are hydrophilic Phylogenetic tree analysis showed that the GJ proteins in C. nobilis were distantly related to those in vertebrates but closely related to those in invertebrates. Conserved motifs analysis of these GJ proteins in C. nobilis identified to have 10 conserved motifs, similar to gap junction proteins in other bivalves. Moreover, expression profiles of CnGJ genes under chronic and acute low temperature stress were also investigated. Results showed that chronic low temperature stress had a significant effect on the expression levels of CnGJ genes, and the expression profiles of CnGJ genes showed significantly variation under acute low temperature stress. All these results indicated that CnGJ genes play important roles in environmental adaptation in scallops. The present study initially elucidated the function of gap junction genes in noble scallop C. nobilis, which provides new insights into the GJ genes in mollusks and will help us better understand their roles in environmental stress in scallops.
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Affiliation(s)
- Changping Xu
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Xuanbing Wu
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Jiale Qiu
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Jianming Ye
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Qing Lin
- Shantou Fruit Tree and Aquatic Technology Promotion Station, Shantou 515063, China
| | - Jingwen Deng
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Yetao Zeng
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Weili Wang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Hongkuan Zhang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China.
| | - Huaiping Zheng
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; Research Center of Engineering Technology for Subtropical Mariculture of Guangdong Province, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China.
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11
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Li JP, Liu YJ, Li Y, Yin Y, Ye QW, Lu ZH, Dong YW, Zhou JY, Zou X, Chen YG. Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer. J Transl Med 2024; 22:549. [PMID: 38849852 PMCID: PMC11161970 DOI: 10.1186/s12967-024-05369-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 05/30/2024] [Indexed: 06/09/2024] Open
Abstract
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.
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Affiliation(s)
- Jie-Pin Li
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yuan-Jie Liu
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yang Li
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yi Yin
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Qian-Wen Ye
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Zhi-Hua Lu
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yu-Wei Dong
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jin-Yong Zhou
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Xi Zou
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China.
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Nanjing, 210029, Jiangsu, China.
- Institute of Chinese & Western Medicine and Oncology Clinical Research, Nanjing, 210029, Jiangsu, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210029, Jiangsu, China.
| | - Yu-Gen Chen
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road No.155, Nanjing, 210029, Jiangsu, China.
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Nanjing, 210029, Jiangsu, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210029, Jiangsu, China.
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12
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Wang Y, Xiong Y, Shi K, Effah CY, Song L, He L, Liu J. DNA nanostructures for exploring cell-cell communication. Chem Soc Rev 2024; 53:4020-4044. [PMID: 38444346 DOI: 10.1039/d3cs00944k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
The process of coordinating between the same or multiple types of cells to jointly execute various instructions in a controlled and carefully regulated environment is a very appealing field. In order to provide clearer insight into the role of cell-cell interactions and the cellular communication of this process in their local communities, several interdisciplinary approaches have been employed to enhance the core understanding of this phenomenon. DNA nanostructures have emerged in recent years as one of the most promising tools in exploring cell-cell communication and interactions due to their programmability and addressability. Herein, this review is dedicated to offering a new perspective on using DNA nanostructures to explore the progress of cell-cell communication. After briefly outlining the anchoring strategy of DNA nanostructures on cell membranes and the subsequent dynamic regulation of DNA nanostructures, this paper highlights the significant contribution of DNA nanostructures in monitoring cell-cell communication and regulating its interactions. Finally, we provide a quick overview of the current challenges and potential directions for the application of DNA nanostructures in cellular communication and interactions.
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Affiliation(s)
- Ya Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Yamin Xiong
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Kangqi Shi
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Clement Yaw Effah
- The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou 450003, China
| | - Lulu Song
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Leiliang He
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Jianbo Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha 410082, China.
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13
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Xing C, Wang M, Chen Z, Li Y, Zhou X, Wang L, Zhong Y, Li W, Shen X, Gao H, Wang P. Morphological and Molecular Changes during Limb Regeneration of the Exopalaemon carinicauda. Animals (Basel) 2024; 14:685. [PMID: 38473070 DOI: 10.3390/ani14050685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
With the increase in breeding density of Exopalaemon carinicauda, appendage breakage may occur, which seriously affects survival and economic benefits. To study the limb regeneration process of E. carinicauda, we induced autotomy of the pereopods. After a period of time, wound swelling disappeared, the pigment gradually accumulated, and a tawny film subsequently formed in the wound. The healing period of the wound occurred 24 h after autotomy, and the blastema formation stage occurred 48 h after autotomy. After 4 days of cutting, the limb buds began to differentiate, grow, and expand rapidly, and this process lasted approximately 15 days. Microscopic observations revealed significant changes in the type and number of associated cells including outer epithelial cells, granulocytes, embryonic cells, columnar epidermal cells, elongated cells, and blastoma cells, during the process from limb fracture to regeneration. A comparative transcriptome analysis identified 1415 genes differentially expressed between the J0h (0 h post autotomy) and J18h (18 h post autotomy), and 3952 and 4366 differentially expressed genes for J0 and J14d (14 days post autotomy) and J18h and J14d, respectively. Some of these genes may be related to muscle growth or molting, as indicated by the presence of troponin C, chitinase, actin, innexin, and cathepsin L. As a functional gene involved in epidermal formation, the mRNA expression level of the innexin inx2 in the pereopod of E. carinicauda changed significantly in the experimental groups (p < 0.05). The results of this study contribute to existing knowledge of regeneration mechanisms in crustaceans.
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Affiliation(s)
- Chaofan Xing
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Mintao Wang
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Zhenxiang Chen
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yong Li
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Xinlei Zhou
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Lei Wang
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Yao Zhong
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Wenjia Li
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
| | - Xin Shen
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang 222005, China
- Jiangsu Institute of Marine Resources Development, Jiangsu Ocean University, Lianyungang 222005, China
| | - Huan Gao
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang 222005, China
- Jiangsu Institute of Marine Resources Development, Jiangsu Ocean University, Lianyungang 222005, China
- The Jiangsu Provincial Infrastructure for Conservation and Utilization of Agricultural Germplasm, Nanjing 210014, China
| | - Panpan Wang
- Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222005, China
- Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, Jiangsu Ocean University, Lianyungang 222005, China
- Jiangsu Institute of Marine Resources Development, Jiangsu Ocean University, Lianyungang 222005, China
- The Jiangsu Provincial Infrastructure for Conservation and Utilization of Agricultural Germplasm, Nanjing 210014, China
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14
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Sittipo P, Anggradita LD, Kim H, Lee C, Hwang NS, Lee YK, Hwang Y. Cell Surface Modification-Mediated Primary Intestinal Epithelial Cell Culture Platforms for Assessing Host-Microbiota Interactions. Biomater Res 2024; 28:0004. [PMID: 38327615 PMCID: PMC10845607 DOI: 10.34133/bmr.0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 12/29/2023] [Indexed: 02/09/2024] Open
Abstract
Background: Intestinal epithelial cells (IECs) play a crucial role in regulating the symbiotic relationship between the host and the gut microbiota, thereby allowing them to modulate barrier function, mucus production, and aberrant inflammation. Despite their importance, establishing an effective ex vivo culture method for supporting the prolonged survival and function of primary IECs remains challenging. Here, we aim to develop a novel strategy to support the long-term survival and function of primary IECs in response to gut microbiota by employing mild reduction of disulfides on the IEC surface proteins with tris(2-carboxyethyl)phosphine. Methods: Recognizing the crucial role of fibroblast-IEC crosstalk, we employed a cell surface modification strategy, establishing layer-to-layer contacts between fibroblasts and IECs. This involved combining negatively charged chondroitin sulfate on cell surfaces with a positively charged chitosan thin film between cells, enabling direct intercellular transfer. Validation included assessments of cell viability, efficiency of dye transfer, and IEC function upon lipopolysaccharide (LPS) treatment. Results: Our findings revealed that the layer-by-layer co-culture platform effectively facilitates the transfer of small molecules through gap junctions, providing vital support for the viability and function of primary IECs from both the small intestine and colon for up to 5 days, as evident by the expression of E-cadherin and Villin. Upon LPS treatment, these IECs exhibited a down-regulation of Villin and tight junction genes, such as E-cadherin and Zonula Occludens-1, when compared to their nontreated counterparts. Furthermore, the transcription level of Lysozyme exhibited an increase, while Mucin 2 showed a decrease in response to LPS, indicating responsiveness to bacterial molecules. Conclusions: Our study provides a layer-by-layer-based co-culture platform to support the prolonged survival of primary IECs and their features, which is important for understanding IEC function in response to the gut microbiota.
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Affiliation(s)
- Panida Sittipo
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
| | - Laurensia Danis Anggradita
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
- Department of Integrated Biomedical Science,
Soonchunhyang University, Asan-si, Chungnam-do 31538, Republic of Korea
| | - Hyunbum Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
- School of Chemical and Biological Engineering, Institute of Chemical Processes,
Seoul National University, Seoul 08826, Republic of Korea
| | - Chanyoung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
- Department of Integrated Biomedical Science,
Soonchunhyang University, Asan-si, Chungnam-do 31538, Republic of Korea
| | - Nathaniel S. Hwang
- School of Chemical and Biological Engineering, Institute of Chemical Processes,
Seoul National University, Seoul 08826, Republic of Korea
- Bio-MAX/N-Bio Institute, Institute of Bio-Engineering,
Seoul National University, Seoul 08826, Republic of Korea
- Institute of Engineering Research,
Seoul National University, Seoul 08826, Republic of Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
- Department of Integrated Biomedical Science,
Soonchunhyang University, Asan-si, Chungnam-do 31538, Republic of Korea
| | - Yongsung Hwang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, Chungnam-do 31151, Republic of Korea
- Department of Integrated Biomedical Science,
Soonchunhyang University, Asan-si, Chungnam-do 31538, Republic of Korea
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15
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Ho KYL, An K, Carr RL, Dvoskin AD, Ou AYJ, Vogl W, Tanentzapf G. Maintenance of hematopoietic stem cell niche homeostasis requires gap junction-mediated calcium signaling. Proc Natl Acad Sci U S A 2023; 120:e2303018120. [PMID: 37903259 PMCID: PMC10636368 DOI: 10.1073/pnas.2303018120] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 09/11/2023] [Indexed: 11/01/2023] Open
Abstract
Regulation of stem cells requires coordination of the cells that make up the stem cell niche. Here, we describe a mechanism that allows communication between niche cells to coordinate their activity and shape the signaling environment surrounding resident stem cells. Using the Drosophila hematopoietic organ, the lymph gland, we show that cells of the hematopoietic niche, the posterior signaling center (PSC), communicate using gap junctions (GJs) and form a signaling network. This network allows PSC cells to exchange Ca2+ signals repetitively which regulate the hematopoietic niche. Disruption of Ca2+ signaling in the PSC or the GJ-mediated network connecting niche cells causes dysregulation of the PSC and blood progenitor differentiation. Analysis of PSC-derived cell signaling shows that the Hedgehog pathway acts downstream of GJ-mediated Ca2+ signaling to modulate the niche microenvironment. These data show that GJ-mediated communication between hematopoietic niche cells maintains their homeostasis and consequently controls blood progenitor behavior.
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Affiliation(s)
- Kevin Y. L. Ho
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
| | - Kevin An
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
| | - Rosalyn L. Carr
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
- British Columbia Children’s Hospital Research Institute, British Columbia Children’s Hospital, Vancouver, BCV5Z 4H4, Canada
| | - Alexandra D. Dvoskin
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
| | - Annie Y. J. Ou
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
- School of Kinesiology, University of British Columbia, Vancouver, BCV6T 1Z1, Canada
| | - Wayne Vogl
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
| | - Guy Tanentzapf
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BCV6T 1Z3, Canada
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16
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Son YJ, Keum C, Kim M, Jeong G, Jin S, Hwang HW, Kim H, Lee K, Jeon H, Kim H, Pahk KJ, Jang HW, Sun JY, Han HS, Lee KH, Ok MR, Kim YC, Jeong Y. Selective Cell-Cell Adhesion Regulation via Cyclic Mechanical Deformation Induced by Ultrafast Nanovibrations. ACS APPLIED MATERIALS & INTERFACES 2023. [PMID: 37751467 DOI: 10.1021/acsami.3c08941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
The adoption of dynamic mechanomodulation to regulate cellular behavior is an alternative to the use of chemical drugs, allowing spatiotemporal control. However, cell-selective targeting of mechanical stimuli is challenging due to the lack of strategies with which to convert macroscopic mechanical movements to different cellular responses. Here, we designed a nanoscale vibrating surface that controls cell behavior via selective repetitive cell deformation based on a poroelastic cell model. The vibrating indentations induce repetitive water redistribution in the cells with water redistribution rates faster than the vibrating rate; however, in the opposite case, cells perceive the vibrations as a one-time stimulus. The selective regulation of cell-cell adhesion through adjusting the frequency of nanovibration was demonstrated by suppression of cadherin expression in smooth muscle cells (fast water redistribution rate) with no change in vascular endothelial cells (slow water redistribution rate). This technique may provide a new strategy for cell-type-specific mechanical stimulation.
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Affiliation(s)
- Young Ju Son
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Changjoon Keum
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Minsoo Kim
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Chemistry, Hanyang University, Seoul 04763, Republic of Korea
| | - Goeen Jeong
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Materials Science and Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Soyeong Jin
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Chemistry, Hanyang University, Seoul 04763, Republic of Korea
| | - Hae Won Hwang
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Materials Science and Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyewon Kim
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Kyungwoo Lee
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hojeong Jeon
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Hojun Kim
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Ki Joo Pahk
- Department of Biomedical Engineering, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Ho Won Jang
- Department of Materials Science and Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeong-Yun Sun
- Department of Materials Science and Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyung-Seop Han
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Kwan Hyi Lee
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Myoung-Ryul Ok
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Yu-Chan Kim
- Center for Biomaterials, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Youngdo Jeong
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
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17
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Gao JW, Sun JW, Tong XR, Wang H, Hu QM, Cao YR, Zhou ZH, Liu ZC. Chromosome-level Dinobdella ferox genome provided a molecular model for its specific parasitism. Parasit Vectors 2023; 16:322. [PMID: 37697397 PMCID: PMC10494388 DOI: 10.1186/s13071-023-05837-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/15/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Dinobdella ferox is the most frequently reported leech species parasitizing the mammalian nasal cavity. However, the molecular mechanism of this special parasitic behavior has remained largely unknown. METHODS PacBio long-read sequencing, next-generation sequencing (NGS), and Hi-C sequencing were employed in this study to generate a novel genome of D. ferox, which was annotated with strong certainty using bioinformatics methods. The phylogenetic and genomic alterations of D. ferox were then studied extensively alongside the genomes of other closely related species. The obligatory parasitism mechanism of D. ferox was investigated using RNA-seq and proteomics data. RESULTS PacBio long-read sequencing and NGS yielded an assembly of 228 Mb and contig N50 of 2.16 Mb. Along Hi-C sequencing, 96% of the sequences were anchored to nine linkage groups and a high-quality chromosome-level genome was generated. The completed genome included 19,242 protein-coding genes. For elucidating the molecular mechanism of nasal parasitism, transcriptome data were acquired from the digestive tract and front/rear ends of D. ferox. Examining secretory proteins in D. ferox saliva helped to identify intimate connections between these proteins and membrane proteins in nasal epithelial cells. These interacting proteins played important roles in extracellular matrix (ECM)-receptor interaction, tight junction, focal adhesion, and adherens junction. The interaction between D. ferox and mammalian nasal epithelial cells included three major steps of pattern recognition, mucin connection and breakdown, and repair of ECM. The remodeling of ECM between epithelial cells of the nasal mucosa and epithelial cells of D. ferox may produce a stable adhesion environment for parasitism. CONCLUSIONS Our study represents the first-ever attempt to propose a molecular model for specific parasitism. This molecular model may serve as a practical reference for parasitism models of other species and a theoretical foundation for a molecular process of parasitism.
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Affiliation(s)
- Jiang-Wei Gao
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
| | - Jian-Wei Sun
- Department of Medical Ultrasonography, Fifth Affiliated Hospital, Kunming Medical University, Gejiu, China
| | - Xiang-Rong Tong
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
| | - Hao Wang
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
| | - Qing-Mei Hu
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
| | - Yan-Ru Cao
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
| | - Zhan-Han Zhou
- School of XJTLU Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Zi-Chao Liu
- Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture & Life Sciences, Kunming University, Kunming, China
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18
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Fisher CG, Falk MM. Endocytosis and Endocytic Motifs across the Connexin Gene Family. Int J Mol Sci 2023; 24:12851. [PMID: 37629031 PMCID: PMC10454166 DOI: 10.3390/ijms241612851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/11/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
Proteins fated to be internalized by clathrin-mediated endocytosis require an endocytic motif, where AP-2 or another adaptor protein can bind and recruit clathrin. Tyrosine and di-leucine-based sorting signals are such canonical motifs. Connexin 43 (Cx43) has three canonical tyrosine-based endocytic motifs, two of which have been previously shown to recruit clathrin and mediate its endocytosis. In addition, di-leucine-based motifs have been characterized in the Cx32 C-terminal domain and shown to mediate its endocytosis. Here, we examined the amino acid sequences of all 21 human connexins to identify endocytic motifs across the connexin gene family. We find that although there is limited conservation of endocytic motifs between connexins, 14 of the 21 human connexins contain one or more canonical tyrosine or di-leucine-based endocytic motif in their C-terminal or intracellular loop domain. Three connexins contain non-canonical (modified) di-leucine motifs. However, four connexins (Cx25, Cx26, Cx31, and Cx40.1) do not harbor any recognizable endocytic motif. Interestingly, live cell time-lapse imaging of different GFP-tagged connexins that either contain or do not contain recognizable endocytic motifs readily undergo endocytosis, forming clearly identifiable annular gap junctions when expressed in HeLa cells. How connexins without defined endocytic motifs are endocytosed is currently not known. Our results demonstrate that an array of endocytic motifs exists in the connexin gene family. Further analysis will establish whether the sites we identified in this in silico analysis are legitimate endocytic motifs.
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Affiliation(s)
| | - Matthias M. Falk
- Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA
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19
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Zhang XE, Liu C, Dai J, Yuan Y, Gao C, Feng Y, Wu B, Wei P, You C, Wang X, Si T. Enabling technology and core theory of synthetic biology. SCIENCE CHINA. LIFE SCIENCES 2023; 66:1742-1785. [PMID: 36753021 PMCID: PMC9907219 DOI: 10.1007/s11427-022-2214-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/04/2022] [Indexed: 02/09/2023]
Abstract
Synthetic biology provides a new paradigm for life science research ("build to learn") and opens the future journey of biotechnology ("build to use"). Here, we discuss advances of various principles and technologies in the mainstream of the enabling technology of synthetic biology, including synthesis and assembly of a genome, DNA storage, gene editing, molecular evolution and de novo design of function proteins, cell and gene circuit engineering, cell-free synthetic biology, artificial intelligence (AI)-aided synthetic biology, as well as biofoundries. We also introduce the concept of quantitative synthetic biology, which is guiding synthetic biology towards increased accuracy and predictability or the real rational design. We conclude that synthetic biology will establish its disciplinary system with the iterative development of enabling technologies and the maturity of the core theory.
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Affiliation(s)
- Xian-En Zhang
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, China.
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Chenli Liu
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, China.
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Junbiao Dai
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, China.
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Yingjin Yuan
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
| | - Caixia Gao
- State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yan Feng
- State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Bian Wu
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Ping Wei
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, China.
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
| | - Chun You
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
| | - Xiaowo Wang
- Ministry of Education Key Laboratory of Bioinformatics; Center for Synthetic and Systems Biology; Bioinformatics Division, Beijing National Research Center for Information Science and Technology; Department of Automation, Tsinghua University, Beijing, 100084, China.
| | - Tong Si
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, China.
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
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20
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Xie W, Patel DJ. Structure-based mechanisms of 2'3'-cGAMP intercellular transport in the cGAS-STING immune pathway. Trends Immunol 2023; 44:450-467. [PMID: 37147228 PMCID: PMC11824902 DOI: 10.1016/j.it.2023.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 05/07/2023]
Abstract
Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2'3'-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2'3'-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2'3'-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2'3'-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation.
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Affiliation(s)
- Wei Xie
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 311027, China; Department of Infectious Diseases, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
| | - Dinshaw J Patel
- Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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21
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Mahadik P, Patwardhan S. ECM stiffness-regulated exosomal thrombospondin-1 promotes tunneling nanotubes-based cellular networking in breast cancer cells. Arch Biochem Biophys 2023; 742:109624. [PMID: 37146866 DOI: 10.1016/j.abb.2023.109624] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 04/22/2023] [Accepted: 05/03/2023] [Indexed: 05/07/2023]
Abstract
Intercellular communication is pivotal in various stages of cancer progression. For smart and effective communication, cancer cells employ diverse modes of messaging that may be further fine-tuned by the microenvironmental changes. Extracellular matrix (ECM) stiffening due to excess deposition and crosslinking of collagen is one of the crucial tumor-microenvironmental changes that influence a plethora of cellular processes, including cell-cell communication. We herein studied the crosstalk between exosomes and tunneling nanotubes (TNT), the two distinct means of cell-cell communication under varying ECM-stiffness conditions. We show that exosomes promote the formation of tunneling nanotubes in breast cancer cells, which results in cellular internet. Interestingly, exosomes drastically increased the fraction of cells connected by TNT; however, they elicited no effect on the number of TNTs per pair of connected cells or the length of TNT. The observed pro-TNT effects of exosomes were found to be ECM-stiffness dependent. ECM-stiffness tuned exosomes were found to promote TNT formation predominantly via the 'cell dislodgment model'. At the molecular level, exosomal thrombospondin-1 was identified as a critical pro-TNT factor. These findings underline the influence of ECM stiffening on two diverse modes of cell communication and their interdependence, which may have significant implications in cancer biomedical research.
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Affiliation(s)
- Pratiksha Mahadik
- Patwardhan Lab, Advanced Centre for Treatment, Research and Education in Cancer, (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India
| | - Sejal Patwardhan
- Patwardhan Lab, Advanced Centre for Treatment, Research and Education in Cancer, (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, India.
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22
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Mamun MAA, Cao W, Nakamura S, Maruyama JI. Large-scale identification of genes involved in septal pore plugging in multicellular fungi. Nat Commun 2023; 14:1418. [PMID: 36932089 PMCID: PMC10023807 DOI: 10.1038/s41467-023-36925-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/23/2023] [Indexed: 03/19/2023] Open
Abstract
Multicellular filamentous fungi have septal pores that allow cytoplasmic exchange, and thus connectivity, between neighboring cells in the filament. Hyphal wounding and other stress conditions induce septal pore closure to minimize cytoplasmic loss. However, the composition of the septal pore and the mechanisms underlying its function are not well understood. Here, we set out to identify new septal components by determining the subcellular localization of 776 uncharacterized proteins in a multicellular ascomycete, Aspergillus oryzae. The set of 776 uncharacterized proteins was selected on the basis that their genes were present in the genomes of multicellular, septal pore-bearing ascomycetes (three Aspergillus species, in subdivision Pezizomycotina) and absent/divergent in the genomes of septal pore-lacking ascomycetes (yeasts). Upon determining their subcellular localization, 62 proteins were found to localize to the septum or septal pore. Deletion of the encoding genes revealed that 23 proteins are involved in regulating septal pore plugging upon hyphal wounding. Thus, this study determines the subcellular localization of many uncharacterized proteins in A. oryzae and, in particular, identifies a set of proteins involved in septal pore function.
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Affiliation(s)
| | - Wei Cao
- Research Center for Agricultural Information Technology, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan
| | - Shugo Nakamura
- Department of Information Networking for Innovation and Design, Faculty of Information Networking for Innovation and Design, Toyo University, Tokyo, Japan
| | - Jun-Ichi Maruyama
- Department of Biotechnology, The University of Tokyo, Tokyo, Japan.
- Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo, Japan.
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23
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Espina JA, Cordeiro MH, Barriga EH. Tissue interplay during morphogenesis. Semin Cell Dev Biol 2023; 147:12-23. [PMID: 37002130 DOI: 10.1016/j.semcdb.2023.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/25/2023] [Accepted: 03/25/2023] [Indexed: 03/31/2023]
Abstract
The process by which biological systems such as cells, tissues and organisms acquire shape has been named as morphogenesis and it is central to a plethora of biological contexts including embryo development, wound healing, or even cancer. Morphogenesis relies in both self-organising properties of the system and in environmental inputs (biochemical and biophysical). The classical view of morphogenesis is based on the study of external biochemical molecules, such as morphogens. However, recent studies are establishing that the mechanical environment is also used by cells to communicate within tissues, suggesting that this mechanical crosstalk is essential to synchronise morphogenetic transitions and self-organisation. In this article we discuss how tissue interaction drive robust morphogenesis, starting from a classical biochemical view, to finalise with more recent advances on how the biophysical properties of a tissue feedback with their surroundings to allow form acquisition. We also comment on how in silico models aid to integrate and predict changes in cell and tissue behaviour. Finally, considering recent advances from the developmental biomechanics field showing that mechanical inputs work as cues that promote morphogenesis, we invite to revisit the concept of morphogen.
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Affiliation(s)
- Jaime A Espina
- Mechanisms of Morphogenesis Lab, Gulbenkian Institute of Science (IGC), Oeiras, Portugal
| | - Marilia H Cordeiro
- Mechanisms of Morphogenesis Lab, Gulbenkian Institute of Science (IGC), Oeiras, Portugal
| | - Elias H Barriga
- Mechanisms of Morphogenesis Lab, Gulbenkian Institute of Science (IGC), Oeiras, Portugal.
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24
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Rojas V, Larrondo LF. Coupling Cell Communication and Optogenetics: Implementation of a Light-Inducible Intercellular System in Yeast. ACS Synth Biol 2023; 12:71-82. [PMID: 36534043 PMCID: PMC9872819 DOI: 10.1021/acssynbio.2c00338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Indexed: 12/23/2022]
Abstract
Cell communication is a widespread mechanism in biology, allowing the transmission of information about environmental conditions. In order to understand how cell communication modulates relevant biological processes such as survival, division, differentiation, and apoptosis, different synthetic systems based on chemical induction have been successfully developed. In this work, we coupled cell communication and optogenetics in the budding yeast Saccharomyces cerevisiae. Our approach is based on two strains connected by the light-dependent production of α-factor pheromone in one cell type, which induces gene expression in the other type. After the individual characterization of the different variants of both strains, the optogenetic intercellular system was evaluated by combining the cells under contrasting illumination conditions. Using luciferase as a reporter gene, specific co-cultures at a 1:1 ratio displayed activation of the response upon constant blue light, which was not observed for the same cell mixtures grown in darkness. Then, the system was assessed at several dark/blue-light transitions, where the response level varies depending on the moment in which illumination was delivered. Furthermore, we observed that the amplitude of response can be tuned by modifying the initial ratio between both strains. Finally, the two-population system showed higher fold inductions in comparison with autonomous strains. Altogether, these results demonstrated that external light information is propagated through a diffusible signaling molecule to modulate gene expression in a synthetic system involving microbial cells, which will pave the road for studies allowing optogenetic control of population-level dynamics.
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Affiliation(s)
- Vicente Rojas
- Departamento
de Genética Molecular y Microbiología, Facultad de Ciencias
Biológicas, Pontificia Universidad
Católica de Chile, Santiago 8331150, Chile
- Millennium
Institute for Integrative Biology (iBio), Santiago 8331150, Chile
| | - Luis F. Larrondo
- Departamento
de Genética Molecular y Microbiología, Facultad de Ciencias
Biológicas, Pontificia Universidad
Católica de Chile, Santiago 8331150, Chile
- Millennium
Institute for Integrative Biology (iBio), Santiago 8331150, Chile
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25
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Rusiecka OM, Tournier M, Molica F, Kwak BR. Pannexin1 channels-a potential therapeutic target in inflammation. Front Cell Dev Biol 2022; 10:1020826. [PMID: 36438559 PMCID: PMC9682086 DOI: 10.3389/fcell.2022.1020826] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/20/2022] [Indexed: 08/11/2023] Open
Abstract
An exaggerated inflammatory response is the hallmark of a plethora of disorders. ATP is a central signaling molecule that orchestrates the initiation and resolution of the inflammatory response by enhancing activation of the inflammasome, leukocyte recruitment and activation of T cells. ATP can be released from cells through pannexin (Panx) channels, a family of glycoproteins consisting of three members, Panx1, Panx2, and Panx3. Panx1 is ubiquitously expressed and forms heptameric channels in the plasma membrane mediating paracrine and autocrine signaling. Besides their involvement in the inflammatory response, Panx1 channels have been shown to contribute to different modes of cell death (i.e., pyroptosis, necrosis and apoptosis). Both genetic ablation and pharmacological inhibition of Panx1 channels decrease inflammation in vivo and contribute to a better outcome in several animal models of inflammatory disease involving various organs, including the brain, lung, kidney and heart. Up to date, several molecules have been identified to inhibit Panx1 channels, for instance probenecid (Pbn), mefloquine (Mfq), flufenamic acid (FFA), carbenoxolone (Cbx) or mimetic peptides like 10Panx1. Unfortunately, the vast majority of these compounds lack specificity and/or serum stability, which limits their application. The recent availability of detailed structural information on the Panx1 channel from cryo-electron microscopy studies may open up innovative approaches to acquire new classes of synthetic Panx1 channel blockers with high target specificity. Selective inhibition of Panx1 channels may not only limit acute inflammatory responses but may also prove useful in chronic inflammatory diseases, thereby improving human health. Here, we reviewed the current knowledge on the role of Panx1 in the initiation and resolution of the inflammatory response, we summarized the effects of Panx1 inhibition in inflammatory pathologies and recapitulate current Panx1 channel pharmacology with an outlook towards future approaches.
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Affiliation(s)
- Olga M. Rusiecka
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Malaury Tournier
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Filippo Molica
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Brenda R. Kwak
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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26
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Ko E, Aydin O, Li Z, Gapinske L, Huang KY, Saif T, Bashir R, Kong H. Empowering engineered muscle in biohybrid pump by extending connexin 43 duration with reduced graphene oxides. Biomaterials 2022; 287:121643. [PMID: 35772349 DOI: 10.1016/j.biomaterials.2022.121643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/08/2022] [Accepted: 06/17/2022] [Indexed: 11/20/2022]
Abstract
Engineered skeletal muscle act as therapeutics invaluable to treat injured or diseased muscle and a "living" material essential to assemble biological machinery. For normal development, skeletal myoblasts should express connexin 43, one of the gap junction proteins that promote myoblast fusion and myogenesis, during the early differentiation stage. However, myoblasts cultured in vitro often down-regulate connexin 43 before differentiation, limiting myogenesis and muscle contraction. This study demonstrates that tethering myoblasts with reduced graphene oxide (rGO) slows connexin 43 regression during early differentiation and increases myogenic mRNA synthesis. The whole RNA sequencing also confirms that the rGO on cells increases regulator genes for myogenesis, including troponin, while decreasing negative regulator genes. The resulting myotubes generated a three-fold larger contraction force than the rGO-free myotubes. Accordingly, a valveless biohybrid pump assembled with the rGO-tethered muscle increased the fluid velocity and flow rate considerably. The results of this study would provide an important foundation for developing physiologically relevant muscle and powering up biomachines that will be used for various bioscience studies and unexplored applications.
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Affiliation(s)
- Eunkyung Ko
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Onur Aydin
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Zhengwei Li
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Lauren Gapinske
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Kai-Yu Huang
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Taher Saif
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Rashid Bashir
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| | - Hyunjoon Kong
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seongbuk-gu, Seoul 02841, South Korea.
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27
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Casanellas I, Lagunas A, Vida Y, Pérez-Inestrosa E, Rodríguez-Pereira C, Magalhaes J, Andrades JA, Becerra J, Samitier J. Nanoscale ligand density modulates gap junction intercellular communication of cell condensates during chondrogenesis. Nanomedicine (Lond) 2022; 17:775-791. [PMID: 35642556 DOI: 10.2217/nnm-2021-0399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To unveil the influence of cell-matrix adhesions in the establishment of gap junction intercellular communication (GJIC) during cell condensation in chondrogenesis. Materials & methods: Previously developed nanopatterns of the cell adhesive ligand arginine-glycine-aspartic acid were used as cell culture substrates to control cell adhesion at the nanoscale. In vitro chondrogenesis of mesenchymal stem cells was conducted on the nanopatterns. Cohesion and GJIC were evaluated in cell condensates. Results: Mechanical stability and GJIC are enhanced by a nanopattern configuration in which 90% of the surface area presents adhesion sites separated less than 70 nm, thus providing an onset for cell signaling. Conclusion: Cell-matrix adhesions regulate GJIC of mesenchymal cell condensates during in vitro chondrogenesis from a threshold configuration at the nanoscale.
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Affiliation(s)
- Ignasi Casanellas
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science &Technology (BIST). c/Baldiri Reixac, 10-12, Barcelona, 08028, Spain.,Department of Electronics & Biomedical Engineering, University of Barcelona (UB). c/Martí i Franquès, 1, 08028, Barcelona, Spain.,Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain
| | - Anna Lagunas
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science &Technology (BIST). c/Baldiri Reixac, 10-12, Barcelona, 08028, Spain.,Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain
| | - Yolanda Vida
- Universidad de Málaga-IBIMA, Dpto. Química Orgánica. Campus de Teatinos s/n, Málaga, 29071, Spain.,Centro Andaluz de Nanomedicina y Biotecnología-BIONAND. Parque Tecnológico de Andalucía, c/Severo Ochoa 35, C,ampanillas, Málaga, 29590, Spain
| | - Ezequiel Pérez-Inestrosa
- Universidad de Málaga-IBIMA, Dpto. Química Orgánica. Campus de Teatinos s/n, Málaga, 29071, Spain.,Centro Andaluz de Nanomedicina y Biotecnología-BIONAND. Parque Tecnológico de Andalucía, c/Severo Ochoa 35, C,ampanillas, Málaga, 29590, Spain
| | - Cristina Rodríguez-Pereira
- Unidad de Medicina Regenerativa, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC). c/Xubias de Arriba, 84, A Coruña, 15006, Spain
| | - Joana Magalhaes
- Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain.,Unidad de Medicina Regenerativa, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC). c/Xubias de Arriba, 84, A Coruña, 15006, Spain
| | - José A Andrades
- Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain.,Centro Andaluz de Nanomedicina y Biotecnología-BIONAND. Parque Tecnológico de Andalucía, c/Severo Ochoa 35, C,ampanillas, Málaga, 29590, Spain.,Department of Cell Biology, Genetics & Physiology, Universidad de Málaga (UMA), Instituto de Investigación Biomédica de Málaga (IBIMA). Av. Cervantes, 2, Málaga, 29071, Spain
| | - José Becerra
- Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain.,Centro Andaluz de Nanomedicina y Biotecnología-BIONAND. Parque Tecnológico de Andalucía, c/Severo Ochoa 35, C,ampanillas, Málaga, 29590, Spain.,Department of Cell Biology, Genetics & Physiology, Universidad de Málaga (UMA), Instituto de Investigación Biomédica de Málaga (IBIMA). Av. Cervantes, 2, Málaga, 29071, Spain
| | - Josep Samitier
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science &Technology (BIST). c/Baldiri Reixac, 10-12, Barcelona, 08028, Spain.,Department of Electronics & Biomedical Engineering, University of Barcelona (UB). c/Martí i Franquès, 1, 08028, Barcelona, Spain.,Biomedical Research Networking Center in Bioengineering,Biomaterials & Nanomedicine (CIBER-BBN). Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid, 28029, Spain
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The best of both worlds: Dual systems of reasoning in animals and AI. Cognition 2022; 225:105118. [PMID: 35453083 DOI: 10.1016/j.cognition.2022.105118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 11/20/2022]
Abstract
Much of human cognition involves two different types of reasoning that operate together. Type 1 reasoning systems are intuitive and fast, whereas Type 2 reasoning systems are reflective and slow. Why has our cognition evolved with these features? Both systems are coherent and in most ecological circumstances either alone is capable of coming up with the right answer most of the time. Neural tissue is costly, and thus far evolutionary models have struggled to identify a benefit of operating two systems of reasoning. To explore this issue we take a broad comparative perspective. We discuss how dual processes of cognition have enabled the emergence of selective attention in insects, transforming the learning capacities of these animals. Modern AIs using dual systems of learning are able to learn how their vast world works and how best to interact with it, allowing them to exceed human levels of performance in strategy games. We propose that the core benefits of dual processes of reasoning are to narrow down a problem space in order to focus cognitive resources most effectively.
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Nunes B, Pópulo H, Lopes JM, Reis M, Nascimento G, Nascimento AG, Fernandes J, Faria M, de Carvalho DP, Soares P, Miranda-Alves L. Connexin Expression in Pituitary Adenomas and the Effects of Overexpression of Connexin 43 in Pituitary Tumor Cell Lines. Genes (Basel) 2022; 13:genes13040674. [PMID: 35456480 PMCID: PMC9032236 DOI: 10.3390/genes13040674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/22/2022] [Accepted: 04/06/2022] [Indexed: 01/27/2023] Open
Abstract
Gap junction intercellular communication (GJIC) is considered a key mechanism in the regulation of tissue homeostasis. GJIC structures are organized in two transmembrane channels, with each channel formed by connexins (Cxs). GJIC and Cxs expression alterations are related to the process of tumorigenesis in different cell types. Pituitary neuroendocrine tumors (PitNETs) represent 15–20% of intracranial neoplasms, and usually display benign behavior. Nevertheless, some may have aggressive behavior, invading adjacent tissues, and featuring a high proliferation rate. We aimed to assess the expression and relevance of GJIC and Cxs proteins in PitNETs. We evaluated the mRNA expression levels of Cx26, 32, and 43, and the protein expression of Cx43 in a series of PitNETs. In addition, we overexpressed Cx43 in pituitary tumor cell lines. At the mRNA level, we observed variable expression of all the connexins in the tumor samples. Cx43 protein expression was absent in most of the pituitary tumor samples that were studied. Moreover, in vitro studies revealed that the overexpression of Cx43 decreases cell growth and induces apoptosis in pituitary tumor cell lines. Our results indicate that the downregulation of Cx43 protein might be involved in the tumorigenesis of most pituitary adenomas and have a potential therapeutic value for pituitary tumor therapy.
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Affiliation(s)
- Bruno Nunes
- Laboratory of Experimental Endocrinology—LEEx, Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (B.N.); (D.P.d.C.); (L.M.-A.)
- Postgraduate Program in Endocrinology, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Laboratory of Endocrine Physiology, Doris Rosenthal, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Helena Pópulo
- Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (H.P.); (J.M.L.); (M.R.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)—Cancer Signalling & Metabolism, 4200-135 Porto, Portugal
- Department of Pathology, Medical Faculty of the University of Porto, 4200-319 Porto, Portugal
| | - José Manuel Lopes
- Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (H.P.); (J.M.L.); (M.R.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)—Cancer Signalling & Metabolism, 4200-135 Porto, Portugal
- Department of Pathology, Medical Faculty of the University of Porto, 4200-319 Porto, Portugal
| | - Marta Reis
- Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (H.P.); (J.M.L.); (M.R.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)—Cancer Signalling & Metabolism, 4200-135 Porto, Portugal
| | - Gilvan Nascimento
- Centre of Clinical Research (CEPEC), President Dutra Hospital of Federal University of Maranhão (UFMA), São Luís 65020-600, Brazil; (G.N.); (M.F.)
- Endocrinology Service, President Dutra Hospital of Federal University of Maranhão (UFMA), São Luís 65060-600, Brazil
| | - Ana Giselia Nascimento
- Pathology Service, President Dutra Hospital of Federal University of Maranhão (UFMA), São Luís 65020-070, Brazil;
| | - Janaína Fernandes
- NUPEX, Polo Duque de Caxias, Universidade Federal do Rio de Janeiro, Rio de Janeiro 25240-005, Brazil;
| | - Manuel Faria
- Centre of Clinical Research (CEPEC), President Dutra Hospital of Federal University of Maranhão (UFMA), São Luís 65020-600, Brazil; (G.N.); (M.F.)
- Endocrinology Service, President Dutra Hospital of Federal University of Maranhão (UFMA), São Luís 65060-600, Brazil
| | - Denise Pires de Carvalho
- Laboratory of Experimental Endocrinology—LEEx, Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (B.N.); (D.P.d.C.); (L.M.-A.)
- Postgraduate Program in Endocrinology, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Laboratory of Endocrine Physiology, Doris Rosenthal, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Paula Soares
- Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (H.P.); (J.M.L.); (M.R.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)—Cancer Signalling & Metabolism, 4200-135 Porto, Portugal
- Department of Pathology, Medical Faculty of the University of Porto, 4200-319 Porto, Portugal
- Correspondence:
| | - Leandro Miranda-Alves
- Laboratory of Experimental Endocrinology—LEEx, Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (B.N.); (D.P.d.C.); (L.M.-A.)
- Postgraduate Program in Endocrinology, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Laboratory of Endocrine Physiology, Doris Rosenthal, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Postgraduate Program in Pharmacology and Medicinal Chemistry, Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
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Karadayi R, Mazzocco J, Leclere L, Buteau B, Gregoire S, Belloir C, Koudsi M, Bessard P, Bizeau JB, Dubus E, Fenech C, Briand L, Bretillon L, Bron AM, Fioramonti X, Acar N. Plasmalogens Regulate Retinal Connexin 43 Expression and Müller Glial Cells Gap Junction Intercellular Communication and Migration. Front Cell Dev Biol 2022; 10:864599. [PMID: 35433704 PMCID: PMC9009447 DOI: 10.3389/fcell.2022.864599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/16/2022] [Indexed: 11/13/2022] Open
Abstract
Plasmalogens are a specific glycerophospholipid subtype characterized by a vinyl-ether bound at their sn-1 moiety. Their biosynthesis is initiated in the peroxisome by dihydroxyacetone phosphate-acyltransferase (DHAPAT), which is encoded by the DAPAT gene. Previous studies have shown that plasmalogen-deficient mice exhibit major physiological dysfunctions including several eye defects, among which abnormal vascular development of the retina and a reactive activation of macroglial Müller cells. Interestingly, plasmalogen deficiency in mice is also associated with a reduced expression of brain connexin 43 (Cx43). Cx43 is the main connexin subtype of retinal glial cells and is involved in several cellular mechanisms such as calcium-based gap junction intercellular communication (GJIC) or cell migration. Thus, the aim of our work was 1) to confirm the alteration of Cx43 expression in the retina of plasmalogen-deficient DAPAT−/- mice and 2) to investigate whether plasmalogens are involved in crucial functions of Müller cells such as GJIC and cell migration. First, we found that plasmalogen deficiency was associated with a significant reduction of Cx43 expression in the retina of DAPAT−/- mice in vivo. Secondly, using a siRNA targeting DHAPAT in vitro, we found that a 50%-reduction of Müller cells content in plasmalogens was sufficient to significantly downregulate Cx43 expression, while increasing its phosphorylation. Furthermore, plasmalogen-depleted Müller cells exhibited several alterations in ATP-induced GJIC, such as calcium waves of higher amplitude that propagated slower to neighboring cells, including astrocytes. Finally, in vitro plasmalogen depletion was also associated with a significant downregulation of Müller cells migration. Taken together, these data confirm that plasmalogens are critical for the regulation of Cx43 expression and for characteristics of retinal Müller glial cells such as GJIC and cell migration.
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Affiliation(s)
- Rémi Karadayi
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Julie Mazzocco
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Laurent Leclere
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Bénédicte Buteau
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Stéphane Gregoire
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Christine Belloir
- Taste and Olfaction Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Mounzer Koudsi
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Pauline Bessard
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Jean-Baptiste Bizeau
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Elisabeth Dubus
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Claire Fenech
- Brain Nutrient Sensing and Energy Homeostasis, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Loïc Briand
- Taste and Olfaction Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Lionel Bretillon
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Alain M. Bron
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
- Department of Ophthalmology, University Hospital, Dijon, France
| | | | - Niyazi Acar
- Eye and Nutrition Research Group, CSGA, Université de Bourgogne Franche-Comté, Dijon, France
- *Correspondence: Niyazi Acar,
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Cai X, Gao C, Cao M, Su B, Liu X, Wang B, Li C. Genome-wide characterization of gap junction (connexins and pannexins) genes in turbot (Scophthalmus maximus L.): evolution and immune response following Vibrio anguillarum infection. Gene 2022; 809:146032. [PMID: 34673208 DOI: 10.1016/j.gene.2021.146032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/10/2021] [Accepted: 10/14/2021] [Indexed: 01/26/2023]
Abstract
Gap junction (GJ), a special intercellular junction between different cell types, directly connects the cytoplasm of adjacent cells, allows various molecules, ions and electrical impulses to pass through the intercellular regulatory gate, and plays vital roles in response to bacterial infection. Up to date, the information about the GJ in turbot (Scophthalmus maximus L.) is still limited. In current study, 43 gap junction genes were identified in turbot, phylogeny analysis suggested that gap junctions from turbot and other species were clustered into six groups, GJA, GJB, GJC, GJD, GJE and PANX, and turbot GJs together with respective GJs from Japanese flounder, half-smooth tongue sole and large yellow croaker, sharing same ancestors. In addition, these 43 GJ genes distributed in different chromosomes unevenly. According to gene structure and domain analysis, these genes (in GJA-GJE group) were highly conserved in that most of them contain the transmembrane area, connexin domain (CNX) and cysteine-rich domain (connexin CCC), while PANXs contain Pfam Innexin. Although only one tandem duplication was identified in turbot gap junction gene, 235 pairs of segmental duplications were identified in the turbot genome. To further investigate their evolutionary relationships, Ka/Ks was calculated, and results showed that most ratios were lower than 1, indicating they had undergone negative selection. Finally, expression analysis showed that gap junction genes were widely distributed in turbot tissues and significantly regulated after Vibrio anguillarum infection. Taken together, our research could provide valuable information for further exploration of the function of gap junction genes in teleost.
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Affiliation(s)
- Xin Cai
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Chengbin Gao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Min Cao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Baofeng Su
- School of Fisheries, Aquaculture and Aquatic Sciences, Auburn University, Auburn, AL 36849, United States
| | - Xiaoli Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Beibei Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.
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32
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Second Messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP):Synthesis, transmission, and degradation. Biochem Pharmacol 2022; 198:114934. [PMID: 35104477 DOI: 10.1016/j.bcp.2022.114934] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 01/07/2023]
Abstract
Cyclic GMP-AMP synthase (cGAS) senses foreign DNA to produce 2'3'-cyclic GMP-AMP (2'3'-cGAMP). 2'3'-cGAMP is a second messenger that binds and activates the adaptor protein STING, which triggers the innate immune response. As a STING agonist, the small molecule 2'3'-cGAMP plays pivotal roles in antiviral defense and has adjuvant applications, and anti-tumor effects. 2'3'-cGAMP and its analogs are thus putative targets for immunotherapy and are currently being testedin clinical trials to treat solid tumors. However, several barriers to further development have emerged from these studies, such as evidence of immune and inflammatory side-effects, poor pharmacokinetics, and undesirable biodistribution. Here, we review the status of 2'3'-cGAMP research and outline the role of 2'3'-cGAMP in immune signaling, adjuvant applications, and cancer immunotherapy, as well as various 2'3'-cGAMP detection methods.
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33
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How Far Are We from the Completion of the Human Protein Interactome Reconstruction? Biomolecules 2022; 12:biom12010140. [PMID: 35053288 PMCID: PMC8774112 DOI: 10.3390/biom12010140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
After more than fifteen years from the first high-throughput experiments for human protein–protein interaction (PPI) detection, we are still wondering how close the completion of the genome-scale human PPI network reconstruction is, what needs to be further explored and whether the biological insights gained from the holistic investigation of the current network are valid and useful. The unique structure of PICKLE, a meta-database of the human experimentally determined direct PPI network developed by our group, presently covering ~80% of the UniProtKB/Swiss-Prot reviewed human complete proteome, enables the evaluation of the interactome expansion by comparing the successive PICKLE releases since 2013. We observe a gradual overall increase of 39%, 182%, and 67% in protein nodes, PPIs, and supporting references, respectively. Our results indicate that, in recent years, (a) the PPI addition rate has decreased, (b) the new PPIs are largely determined by high-throughput experiments and mainly concern existing protein nodes and (c), as we had predicted earlier, most of the newly added protein nodes have a low degree. These observations, combined with a largely overlapping k-core between PICKLE releases and a network density increase, imply that an almost complete picture of a structurally defined network has been reached. The comparative unsupervised application of two clustering algorithms indicated that exploring the full interactome topology can reveal the protein neighborhoods involved in closely related biological processes as transcriptional regulation, cell signaling and multiprotein complexes such as the connexon complex associated with cancers. A well-reconstructed human protein interactome is a powerful tool in network biology and medicine research forming the basis for multi-omic and dynamic analyses.
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Guan L, Yang Y, Liang JJ, Miao Y, Shang AY, Wang B, Wang YC, Ding M. ERGIC2 and ERGIC3 regulate the ER-to-Golgi transport of gap junction proteins in metazoans. Traffic 2022; 23:140-157. [PMID: 34994051 DOI: 10.1111/tra.12830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/16/2021] [Accepted: 01/04/2022] [Indexed: 11/26/2022]
Abstract
The extremely dynamic life cycle of gap junction connections requires highly efficient intracellular trafficking system especially designed for gap junction proteins, but the underlying mechanisms are largely unknown. Here, we identified that the COPII-associated proteins ERGIC2 (ER-Golgi intermediate compartment) and ERGIC3 are specifically required for the efficient intracellular transport of gap junction proteins in both C. elegans and mice. In the absence of Ergic2 or Ergic3, gap junction proteins accumulate in the ER and Golgi apparatus and the size of endogenous gap junction plaques is reduced. Knocking out the Ergic2 or Ergic3 in mice results in heart enlargement and cardiac malfunction accompanied by reduced number and size of connexin 43 (Cx43) gap junctions. Invertebrates' gap junction protein innexins share no sequence similarity with vertebrates' connexins. However, ERGIC2 and ERGIC3 could bind to gap junction proteins in both worms and mice. Characterization of the highly specialized roles of ERGIC2 and ERGIC3 in metazoans reveals how the early secretory pathway could be adapted to facilitate the efficient transport for gap junction proteins in vivo. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Liying Guan
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yongzhi Yang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jing Jing Liang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yue Miao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ang Yang Shang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Baolei Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ying Chun Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Mei Ding
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
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35
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Zhao JJ, Wang ZH, Zhang YJ, Wang WJ, Cheng AF, Rong PJ, Shan CL. The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury. Neural Regen Res 2022; 17:594-600. [PMID: 34380899 PMCID: PMC8504367 DOI: 10.4103/1673-5374.320992] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function. The stimulation of the auricular vagus nerve, which is the only superficial branch of the vagus nerve, may have similar effects to vagus nerve stimulation. However, the precise mechanisms remain poorly understood. In this study, rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation. Twenty-four hours later, 7-day auricular vagus nerve stimulation was performed. The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine, inhibited the secretion of interleukin-1β, interleukin-6, and tumor necrosis factor-α, and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex, promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury. These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43. This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8, 2019 (approval No. PZSHUTCM191108014).
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Affiliation(s)
- Jing-Jun Zhao
- Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine; School of Rehabilitation Science; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China
| | - Zheng-Hui Wang
- Center of Rehabilitation Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Ying-Jie Zhang
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
| | - Wen-Jing Wang
- Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ai-Fang Cheng
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China
| | - Pei-Jing Rong
- Institute of Acupuncture and Moxibustion, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Chun-Lei Shan
- Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine; School of Rehabilitation Science; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China
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Hirashima S, Ohta K, Togo A, Nakamura KI. 3D Mesoscopic Architecture of a Heterogeneous Cellular Network in the Cementum-Periodontal Ligament-Alveolar Bone Complex. Microscopy (Oxf) 2021; 71:22-33. [PMID: 34850074 DOI: 10.1093/jmicro/dfab051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/24/2021] [Accepted: 11/26/2021] [Indexed: 11/14/2022] Open
Abstract
Cell-to-cell communication orchestrates various cell and tissue functions. This communication enables cells to form cellular networks with each other through direct contact via intercellular junctions. Because these cellular networks are closely related to tissue and organ functions, elucidating the morphological characteristics of cellular networks could lead to the development of novel therapeutic approaches. The tooth, periodontal ligament (PDL), and alveolar bone form a complex via collagen fibres. Teeth depend on the co-ordinated activity of this complex to maintain their function, with cellular networks in each of its three components. Imaging methods for three-dimensional (3D) mesoscopic architectural analysis include focused ion beam/scanning electron microscopy (FIB/SEM), which is characterised by its ability to select observation points and acquire data from complex tissue after extensive block-face imaging, without the need to prepare numerous ultrathin sections. Previously, we employed FIB/SEM to analyse the 3D mesoscopic architecture of hard tissue including the PDL, which exists between the bone and tooth root. The imaging results showed that the cementum, PDL, and alveolar bone networks are in contact and form a heterogeneous cellular network. This cellular network may orchestrate mechanical loading-induced remodelling of the cementum-PDL-alveolar bone complex as the remodelling of each complex component is coordinated, as exemplified by tooth movement due to orthodontic treatment and tooth dislocation due to occlusal loss. In this review, we summarise and discuss the 3D mesoscopic architecture of cellular networks in the cementum, PDL, and alveolar bone as observed in our recent mesoscopic and morphological studies.
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Affiliation(s)
- Shingo Hirashima
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Dental and Oral Medical Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Keisuke Ohta
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Advanced Imaging Research Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Akinobu Togo
- Advanced Imaging Research Center, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Kei-Ichiro Nakamura
- Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, 830-0011, Japan.,Cognitive and Molecular Research Institute of Brain Diseases, Kurume University School of Medicine, Kurume, 830-0011, Japan
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Tonti OR, Larson H, Lipp SN, Luetkemeyer CM, Makam M, Vargas D, Wilcox SM, Calve S. Tissue-specific parameters for the design of ECM-mimetic biomaterials. Acta Biomater 2021; 132:83-102. [PMID: 33878474 PMCID: PMC8434955 DOI: 10.1016/j.actbio.2021.04.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/18/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023]
Abstract
The extracellular matrix (ECM) is a complex network of biomolecules that mechanically and biochemically directs cell behavior and is crucial for maintaining tissue function and health. The heterogeneous organization and composition of the ECM varies within and between tissue types, directing mechanics, aiding in cell-cell communication, and facilitating tissue assembly and reassembly during development, injury and disease. As technologies like 3D printing rapidly advance, researchers are better able to recapitulate in vivo tissue properties in vitro; however, tissue-specific variations in ECM composition and organization are not given enough consideration. This is in part due to a lack of information regarding how the ECM of many tissues varies in both homeostatic and diseased states. To address this gap, we describe the components and organization of the ECM, and provide examples for different tissues at various states of disease. While many aspects of ECM biology remain unknown, our goal is to highlight the complexity of various tissues and inspire engineers to incorporate unique components of the native ECM into in vitro platform design and fabrication. Ultimately, we anticipate that the use of biomaterials that incorporate key tissue-specific ECM will lead to in vitro models that better emulate human pathologies. STATEMENT OF SIGNIFICANCE: Biomaterial development primarily emphasizes the engineering of new materials and therapies at the expense of identifying key parameters of the tissue that is being emulated. This can be partially attributed to the difficulty in defining the 3D composition, organization, and mechanics of the ECM within different tissues and how these material properties vary as a function of homeostasis and disease. In this review, we highlight a range of tissues throughout the body and describe how ECM content, cell diversity, and mechanical properties change in diseased tissues and influence cellular behavior. Accurately mimicking the tissue of interest in vitro by using ECM specific to the appropriate state of homeostasis or pathology in vivo will yield results more translatable to humans.
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Affiliation(s)
- Olivia R Tonti
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Hannah Larson
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sarah N Lipp
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Callan M Luetkemeyer
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Megan Makam
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Diego Vargas
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sean M Wilcox
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sarah Calve
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States.
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Chen QH, Wu BK, Pan D, Sang LX, Chang B. Beta-carotene and its protective effect on gastric cancer. World J Clin Cases 2021; 9:6591-6607. [PMID: 34447808 PMCID: PMC8362528 DOI: 10.12998/wjcc.v9.i23.6591] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/16/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Beta-carotene is an important natural pigment that is very beneficial to human health. It is widely found in vegetables and fruits. The three main functions are antioxidant effects, cell gap junction-related functions and immune-related functions. Because of its diverse functions, beta-carotene is believed to prevent and treat many chronic diseases. Gastric cancer is one of the most important diseases it can treat. Gastric cancer is a type of cancer with a high incidence. Its etiology varies, and the pathogenesis is complex. Gastric cancer seriously affects human health. The role of beta-carotene, a natural nutrient, in gastric cancer has been explored by many researchers, including molecular mechanisms and epidemiological studies. Molecular studies have mainly focused on oxidative stress, cell cycle, signal transduction pathways and immune-related mechanisms of beta-carotene in gastric cancer. Many epidemiological surveys and cohort studies of patients with gastric cancer have been conducted, and the results of these epidemiological studies vary due to the use of different research methods and analysis of different regions. This paper will summarize the results of these studies, mainly in terms of molecular mechanisms and epidemiological research results, which will provide a systematic basis for future studies of the treatment and prognosis of gastric cancer. This paper will help researchers identify new research directions.
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Affiliation(s)
- Qian-Hui Chen
- Department of Intensive Care Unit, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bao-Kang Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Robinson DG, Draguhn A. Plants have neither synapses nor a nervous system. JOURNAL OF PLANT PHYSIOLOGY 2021; 263:153467. [PMID: 34247030 DOI: 10.1016/j.jplph.2021.153467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 06/13/2023]
Abstract
The alleged existence of so-called synapses or equivalent structures in plants provided the basis for the concept of Plant Neurobiology (Baluska et al., 2005; Brenner et al., 2006). More recently, supporters of this controversial theory have even speculated that the phloem acts as a kind of nerve system serving long distance electrical signaling (Mediano et al., 2021; Baluska and Mancuso, 2021). In this review we have critically examined the literature cited by these authors and arrive at a completely different conclusion. Plants do not have any structures resembling animal synapses (neither chemical nor electrical). While they certainly do have complex cell contacts and signaling mechanisms, none of these structures provides a basis for neuronal-like synaptic transmission. Likewise, the phloem is undoubtedly a conduit for the propagation of electrical signaling, but the characteristics of this process are in no way comparable to the events underlying information processing in neuronal networks. This has obvious implications in regard to far-going speculations into the realms of cognition, sentience and consciousness.
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Affiliation(s)
- David G Robinson
- Centre for Organismal Studies, University of Heidelberg, 69120, Heidelberg, Germany.
| | - Andreas Draguhn
- Institute for Physiology and Pathophysiology, Medical Faculty, University of Heidelberg, 69120, Heidelberg, Germany
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Hou J, Zhu S, Zhao Z, Shen J, Chao J, Shi J, Li J, Wang L, Ge Z, Li Q. Programming cell communications with pH-responsive DNA nanodevices. Chem Commun (Camb) 2021; 57:4536-4539. [PMID: 33956003 DOI: 10.1039/d1cc00875g] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
DNA nanoswitches on cell surfaces could respond to changes of pH under physiological conditions by switching from a three-chain structure to a double-chain structure, thus connecting another set of cells modified with complementary single-stranded DNA. This pH-triggered cell communication offers a promising approach for cell-based therapy under a tumor microenvironment.
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Affiliation(s)
- Junjun Hou
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China and University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shitai Zhu
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China and University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ziwei Zhao
- Key Laboratory for Organic Electronics & Information Displays (KLOEID), Institute of Advanced Materials (IAM) and School of Materials Science and Engineering, Nanjing University of Posts & Telecommunications, Nanjing, China
| | - Jianlei Shen
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China. ,
| | - Jie Chao
- Key Laboratory for Organic Electronics & Information Displays (KLOEID), Institute of Advanced Materials (IAM) and School of Materials Science and Engineering, Nanjing University of Posts & Telecommunications, Nanjing, China
| | - Jiye Shi
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China
| | - Jiang Li
- The Interdisciplinary Research Center, Shanghai Synchrotron Radiation Facility, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Lihua Wang
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China and The Interdisciplinary Research Center, Shanghai Synchrotron Radiation Facility, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Zhilei Ge
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China. ,
| | - Qian Li
- School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China. ,
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Sandora N, Putra MA, Busro PW, Ardiansyah, Muttaqin C, Makdinata W, Fitria NA, Kusuma TR. Preparation of Cell-Seeded Heart Patch In Vitro; Co-Culture of Adipose-Derived Mesenchymal Stem Cell and Cardiomyocytes in Amnion Bilayer Patch. Cardiovasc Eng Technol 2021; 13:193-206. [PMID: 34322787 DOI: 10.1007/s13239-021-00565-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 07/12/2021] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Cardiovascular disease is the second killer across the globe, while coronary disease is the major cause. Cell therapy is one alternative to regenerate the infarcted heart wall. MATERIALS AND METHODS In this study, the cardiomyogenesis capacity of human adipose stem cells (hAdSC) and human cardiomyocytes (hCardio) cultured in a 3-D biological scaffold (decellularised amnion bilayer) for nine days in a static condition was investigated. The cardiomyogenesis capacity of hAdSC were identified using immunohistochemistry and RT-PCR. The population of the cells isolated from the heart tissue expressed cTnT-1 (13.38 ± 11.38%), cKit (7.85 ± 4.2%), ICAM (85.53 ± 8.69%), PECAM (61.63 ± 7.18%) and VCAM (35.9 ± 9.11%), while from the fat tissue expressed the mesenchymal phenotypes (CD73, CD90, CD105, but not CD45, CD34, CD11b, CD19 and HLA-DR). Two age groups of hAdSC donors were compared, the youngsters (30-40yo) and the elderly (60-70 yo). RESULTS The co-culture showed that after 5-day incubation, the seeded graft in the hAdSC-30 group had a tube-like appearance while the hAdSC-60 group demonstrated a disorganised pattern, despite of the MSC expressions of the hAdSC-60 were significantly higher. Initial co-culture showed no difference of ATP counts among all groups, however the hAdSC-30 group had the highest ATP count after 9 days culture (p = 0.004). After normalising to the normal myocardium, only the hAdSC-60 group expressed cTnT and MHC, very low, seen during the initial cultivation, but then disappeared. Meanwhile, the hAdSC-30 group expressed α-actinin, MHC and cTnT in the Day-5. The PPAR also was higher in the Day-5 compared to the Day-9 (p < 0.005). CONCLUSION Cardiomyogenesis capacity of hAdSC co-cultured with hCardio in a 3-D scaffold taken from the 30-40yo donor showed better morphology and viability than the 60-70yo group, but maintained less than 5 days in this system.
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Affiliation(s)
- Normalina Sandora
- Institute of Medical Education and Research Indonesia, Jakarta, 10430, Indonesia.
| | - Muhammad Arza Putra
- Department of Thoracic Surgery, RSCM, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Pribadi Wiranda Busro
- Department of Thoracic Surgery, RSCM, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ardiansyah
- Department of Thoracic Surgery, RSCM, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Chaidar Muttaqin
- Department of Thoracic Surgery, RSCM, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - William Makdinata
- Department of Thoracic Surgery, RSCM, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Nur Amalina Fitria
- Institute of Medical Education and Research Indonesia, Jakarta, 10430, Indonesia
| | - Tyas Rahmah Kusuma
- Institute of Medical Education and Research Indonesia, Jakarta, 10430, Indonesia
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Wu DP, Zhou Y, Hou LX, Zhu XX, Yi W, Yang SM, Lin TY, Huang JL, Zhang B, Yin XX. Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway. Int J Biol Sci 2021; 17:2380-2398. [PMID: 34326682 PMCID: PMC8315014 DOI: 10.7150/ijbs.55453] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 03/30/2021] [Indexed: 12/25/2022] Open
Abstract
Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.
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Affiliation(s)
- Deng-Pan Wu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
- Department of Pharmacology, Pharmacy School of Xuzhou Medical University, 221004, Xuzhou City, Jiangsu Province, P.R. China
| | - Yan Zhou
- Clinical Pharmacy, Jingjiang People's Hospital, 214500, Jingjiang City, Jiangsu Province, P.R. China
| | - Li-Xiang Hou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
| | - Xiao-Xiao Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
| | - Wen Yi
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
| | - Si-Man Yang
- Scientific research center of traditional Chinese medicine, Guangxi University of Chinese Medicine, Nanning City, Guangxi Zhuang Autonomous Region, P.R. China
| | - Tian-Yu Lin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
| | - Jin-Lan Huang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
- Department of Pharmacology, Pharmacy School of Xuzhou Medical University, 221004, Xuzhou City, Jiangsu Province, P.R. China
| | - Bei Zhang
- Department of gynaecology and obstetrics, Xuzhou Central Hospital, 221009, Xuzhou City, Jiangsu Province, P.R. China
| | - Xiao-Xing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Pharmacy School of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, P.R. China
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Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2. Int J Mol Sci 2021; 22:ijms22126244. [PMID: 34200582 PMCID: PMC8230150 DOI: 10.3390/ijms22126244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 12/27/2022] Open
Abstract
Ouabain is a cardiac glycoside that has been described as a hormone, with interesting effects on epithelial physiology. We have shown previously that ouabain induces gap junctional intercellular communication (GJIC) in wild, sensitive cells (MDCK-S), but not in cells that have become insensitive (MDCK-I) by modifying their Na+-K+-ATPase. We have also demonstrated that prostaglandin E2 (PGE2) is able to induce increased GJIC by a mechanism other than ouabain, that does not depend on Na+-K+-ATPase. In this work we show, by dye transfer assays, that when MDCK-S and MDCK-I are randomly mixed, to form monolayers, the latter stablish GJIC, because of stimulation by a compound released to the extracellular media, by MDCK-S cells, after treatment with ouabain, as evidenced by the fact that monolayers of only MDCK-I cells, treated with a conditioned medium (CM) that is obtained after incubation of MDCK-S monolayers with ouabain, significantly increase their GJIC. The further finding that either (1) pre-treatment with COX-2 inhibitors or (2) addition to CM of antagonists of EP2 receptor abolish CM's ability to induce GJIC in MDCK-I monolayers indicate that PGE2 is the GJIC-inducing compound. Therefore, these results indicate that, in addition to direct stimulation, mediated by Na+-K+-ATPase, ouabain enhances GJIC indirectly through the paracrine production of PGE2.
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Ogazon del Toro A, Jimenez L, Serrano Rubi M, Castillo A, Hinojosa L, Martinez Rendon J, Cereijido M, Ponce A. Prostaglandin E2 Enhances Gap Junctional Intercellular Communication in Clonal Epithelial Cells. Int J Mol Sci 2021; 22:5813. [PMID: 34071686 PMCID: PMC8198183 DOI: 10.3390/ijms22115813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Prostaglandins are a group of lipids that produce diverse physiological and pathological effects. Among them, prostaglandin E2 (PGE2) stands out for the wide variety of functions in which it participates. To date, there is little information about the influence of PGE2 on gap junctional intercellular communication (GJIC) in any type of tissue, including epithelia. In this work, we set out to determine whether PGE2 influences GJIC in epithelial cells (MDCK cells). To this end, we performed dye (Lucifer yellow) transfer assays to compare GJIC of MDCK cells treated with PGE2 and untreated cells. Our results indicated that (1) PGE2 induces a statistically significant increase in GJIC from 100 nM and from 15 min after its addition to the medium, (2) such effect does not require the synthesis of new mRNA or proteins subunits but rather trafficking of subunits already synthesized, and (3) such effect is mediated by the E2 receptor, which, in turn, triggers a signaling pathway that includes activation of adenylyl cyclase and protein kinase A (PKA). These results widen the knowledge regarding modulation of gap junctional intercellular communication by prostaglandins.
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Affiliation(s)
| | | | | | | | | | | | | | - Arturo Ponce
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, CDMX, México C.P. 07360, Mexico; (A.O.d.T.); (L.J.); (M.S.R.); (A.C.); (L.H.); (J.M.R.); (M.C.)
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Frings VG, Goebeler M, Schilling B, Kneitz H. Aberrant cytoplasmic connexin43 expression as a helpful marker in vascular neoplasms. J Cutan Pathol 2021; 48:1335-1341. [PMID: 34021619 DOI: 10.1111/cup.14066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/12/2021] [Accepted: 05/05/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Gap junctions consisting of connexins (Cx) are fundamental in controlling cell proliferation, differentiation, and cell death. Cx43 is the most broadly expressed Cx in humans and is attributed an important role in skin tumor development. Its role in cutaneous vascular neoplasms is yet unknown. METHODS Fifteen cases each of cutaneous angiosarcoma (cAS), Kaposi sarcoma (KS), and cherry hemangioma (CH) were assessed by immunohistochemistry for expression of Cx43. Expression pattern, intensity, and percentage of positively stained cells were analyzed. Solid basal cell carcinomas served as positive and healthy skin as negative controls. RESULTS Most cases of cAS presented with a strong Cx43 staining of almost all tumor cells, whereas endothelia of KS showed medium expression and CH showed mostly weak expression. In comparison with KS or cAS, the staining intensity of CH was significantly lower (P ≤ 0.001). All tissue sections of both cAS and KS were characterized by a mostly diffuse, cytoplasmic staining pattern of the vascular endothelia. None of those showed nuclear staining. CONCLUSION The high-to-intermediate expression of Cx43 observed in all cases of cAS and KS suggests that this Cx may play a role in the development of malignant vascular neoplasms and serve as a helpful diagnostic marker.
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Affiliation(s)
- Verena Gerlinde Frings
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Matthias Goebeler
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Bastian Schilling
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Hermann Kneitz
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
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Acharya BR. Can mechanical forces attune heterotypic cell-cell communications? J Biomech 2021; 121:110409. [PMID: 33845355 DOI: 10.1016/j.jbiomech.2021.110409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 10/21/2022]
Abstract
Heterotypic cell lineages relentlessly exchange biomechanical signals among themselves in metazoan organs. Hence, cell-cell communications are pivotal for organ physiology and pathogenesis. Every cell lineage of an organ responds differently to a specific signal due to its unique receptibility and signal interpretation capacity. These distinct cellular responses generate a system-scale signaling network that helps in generating a specific organ phenotype. Although the reciprocal biochemical signal exchange between non-identical neighboring cells is known to be an essential factor for organ functioning, if, then how, mechanical cues incite these signals is not yet quite explored. Cells within organ tissues experience multiple mechanical forces, such as stretching, bending, compression, and shear stress. Forms and magnitudes of mechanical forces influence biochemical signaling in a cell-specific manner. Additionally, the biophysical state of acellular extracellular matrix (ECM) can transmit exclusive mechanical cues to specific cells of an organ. As it scaffolds heterotypic cells and tissues in close proximities, therefore, ECM can easily be contemplated as a mechanical conduit for signal exchange among them. However, force-stimulated signal transduction is not always physiological, aberrant force sensing by tissue-resident cells can transduce anomalous signals to each other, and potentially can promote pathological phenotypes. Herein, I attempt to put forward a perspective on how mechanical forces may influence signal transductions among heterotypic cell populations and how they feedback each other to achieve a transient or perpetual alteration in metazoan organs. A mechanistic insight of organ scale mechanotransduction can emanate the possibility of finding potential biomarkers and novel therapeutic strategies to deal with pathogenesis and organ regeneration.
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Affiliation(s)
- Bipul R Acharya
- Department of Cell Biology, School of Medicine, University of Virginia, USA.
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Kieninger AK, Maldener I. Cell-cell communication through septal junctions in filamentous cyanobacteria. Curr Opin Microbiol 2021; 61:35-41. [PMID: 33676334 DOI: 10.1016/j.mib.2021.02.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 10/22/2022]
Abstract
Septal junctions are cell-cell connections that mediate intercellular communication in filamentous cyanobacteria. The septal peptidoglycan is perforated by dozens of 20 nm-wide nanopores, through which these proteinaceous structures traverse, physically connecting adjacent cells. On each cytoplasmic side, every septal junction contains a flexible cap structure that closes the connection in a reversible manner upon stress. This gating mechanism reminds of the gap junctions from metazoans and represents a primordial control system for cell-cell communication. In this review, we summarize the knowledge about formation of the nanopore array as the framework for incorporation of cell-cell connecting septal junctions. Furthermore, the architecture of septal junctions, proteins involved in septal junction constitution and regulation of intercellular communication will be addressed.
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Affiliation(s)
- Ann-Katrin Kieninger
- Institute of Microbiology and Infection Medicine, Organismic Interactions, Eberhard Karls University, Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany
| | - Iris Maldener
- Institute of Microbiology and Infection Medicine, Organismic Interactions, Eberhard Karls University, Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
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Giuliani AL, Sarti AC, Di Virgilio F. Ectonucleotidases in Acute and Chronic Inflammation. Front Pharmacol 2021; 11:619458. [PMID: 33613285 PMCID: PMC7887318 DOI: 10.3389/fphar.2020.619458] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP, AMP and NAD+. Ectonucleotidases, expressed by virtually all cell types, immune cells included, either as plasma membrane-associated or secreted enzymes, are classified into four main families: 1) nucleoside triphosphate diphosphohydrolases (NTPDases), 2) nicotinamide adenine dinucleotide glycohydrolase (NAD glycohydrolase/ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1), 3) ecto-5′-nucleotidase (NT5E), and 4) ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). Concentration of ATP, UTP and NAD+ can be increased in the extracellular space thanks to un-regulated, e.g., cell damage or cell death, or regulated processes. Regulated processes include secretory exocytosis, connexin or pannexin hemichannels, ATP binding cassette (ABC) transporters, calcium homeostasis modulator (CALMH) channels, the ATP-gated P2X7 receptor, maxi-anion channels (MACs) and volume regulated ion channels (VRACs). Hydrolysis of extracellular purine nucleotides generates adenosine, an important immunosuppressant. Extracellular nucleotides and nucleosides initiate or dampen inflammation via P2 and P1 receptors, respectively. All these agents, depending on their level of expression or activation and on the agonist concentration, are potent modulators of inflammation and key promoters of host defences, immune cells activation, pathogen clearance, tissue repair and regeneration. Thus, their knowledge is of great importance for a full understanding of the pathophysiology of acute and chronic inflammatory diseases. A selection of these pathologies will be briefly discussed here.
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Affiliation(s)
- Anna Lisa Giuliani
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Alba Clara Sarti
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesco Di Virgilio
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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Tirosh A, Tuncman G, Calay ES, Rathaus M, Ron I, Tirosh A, Yalcin A, Lee YG, Livne R, Ron S, Minsky N, Arruda AP, Hotamisligil GS. Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism. Cell Metab 2021; 33:319-333.e6. [PMID: 33340456 PMCID: PMC7858244 DOI: 10.1016/j.cmet.2020.11.009] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 07/30/2020] [Accepted: 11/12/2020] [Indexed: 12/22/2022]
Abstract
Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.
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Affiliation(s)
- Amir Tirosh
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Harvard Medical School, Boston, MA 02115, USA.
| | - Gurol Tuncman
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Ediz S Calay
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Moran Rathaus
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Idit Ron
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amit Tirosh
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Abdullah Yalcin
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Adnan Menderes Üniversitesi Medical School, Department of Medical Biology, 09100 Aydin, Turkey
| | - Yankun G Lee
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Rinat Livne
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sophie Ron
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Neri Minsky
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ana Paula Arruda
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Gökhan S Hotamisligil
- Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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50
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Wu Z, Zhou C, Yuan Q, Zhang D, Xie J, Zou S. CTGF facilitates cell-cell communication in chondrocytes via PI3K/Akt signalling pathway. Cell Prolif 2021; 54:e13001. [PMID: 33522639 PMCID: PMC7941231 DOI: 10.1111/cpr.13001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/06/2021] [Accepted: 01/19/2021] [Indexed: 02/05/2023] Open
Abstract
Purposes Gap junction intercellular communication (GJIC) is essential for articular cartilage to respond appropriately to physical or biological stimuli and maintain homeostasis. Connective tissue growth factor (CTGF), identified as an endochondral ossification genetic factor, plays a vital role in cell proliferation, migration and adhesion. However, how CTGF regulates GJIC in chondrocytes is still unknown. This study aims to explore the effects of CTGF on GJIC in chondrocytes and its potential biomechanism. Materials and methods qPCR was performed to determine the expression of gene profile in the CCN family in chondrocytes. After CTGF treatment, CCK‐8 assay and scratch assay were performed to explore cell proliferation and migration. A scrape loading/dye transfer assay was adopted to visualize GJIC in living chondrocytes. Western blot analysis was done to detect the expression of Cx43 and PI3K/Akt signalling. Immunofluorescence staining was used to show protein distribution. siRNA targeting CTGF was used to detect the influence on cell‐cell communication. Results The CTGF (CCN2) was shown to be the highest expressed member of the CCN family in chondrocytes. CTGF facilitated functional gap junction intercellular communication in chondrocytes through up‐regulation of Cx43 expressions. CTGF activated PI3K/Akt signalling to promote Akt phosphorylation and translocation. Suppressing CTGF also reduced the expression of Cx43. The inhibition of PI3K/Akt signalling decreased the expressions of Cx43 and thus impaired gap junction intercellular communication enhanced by CTGF. Conclusions For the first time, we provide evidence to show CTGF facilitates cell communication in chondrocytes via PI3K/Akt signalling pathway.
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Affiliation(s)
- Zuping Wu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Demao Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shujuan Zou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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