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Gonzales J, Gulbransen BD. The Physiology of Enteric Glia. Annu Rev Physiol 2025; 87:353-380. [PMID: 39546562 DOI: 10.1146/annurev-physiol-022724-105016] [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] [Indexed: 11/17/2024]
Abstract
Enteric glia are the partners of neurons in the enteric nervous system throughout the gastrointestinal tract. Roles fulfilled by enteric glia are diverse and contribute to maintaining intestinal homeostasis through interactions with neurons, immune cells, and the intestinal epithelium. Glial influences optimize physiological gut processes such as intestinal motility and epithelial barrier integrity through actions that regulate the microenvironment of the enteric nervous system, the activity of enteric neurons, intestinal epithelial functions, and immune response. Changes to glial phenotype in disease switch glial functions and contribute to intestinal inflammation, dysmotility, pain, neuroplasticity, and tumorigenesis. This review summarizes current concepts regarding the physiological roles of enteric glial cells and their potential contributions to gut disease. The discussion is focused on recent evidence that suggests important glial contributions to gastrointestinal health and pathophysiology.
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Affiliation(s)
- Jacques Gonzales
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
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Sun Q, Li BR, Li DH, Wang XY, Wang QY, Jiang ZM, Ning SB, Sun T. WKB ameliorates DSS-induced colitis through inhibiting enteric glial cells activation and altering the intestinal microbiota. J Transl Med 2025; 23:93. [PMID: 39838431 PMCID: PMC11748877 DOI: 10.1186/s12967-025-06085-2] [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: 09/15/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic condition influenced by diet, which affects gut microbiota and immune functions. The rising prevalence of IBD, linked to Western diets in developing countries, highlights the need for dietary interventions. This study aimed to assess the impact of white kidney beans (WKB) on gut inflammation and microbiota changes, focusing on their effects on enteric glial cells (EGCs) and immune activity in colitis. METHODS Male C57BL/6 mice were divided into four groups: normal diet (ND), ND with 2.5% dextran sulfate sodium (DSS) for colitis induction, ND with 20% WKB, and WKB with 2.5% DSS. The dietary intervention lasted 17 weeks, with DSS given in the final week. Colonic inflammation was assessed by body weight, disease activity index, and histopathology. Epithelial barrier integrity was evaluated using immunofluorescence, transmission electron microscopy, and permeability assays. EGCs activity was analyzed via immunofluorescence and quantitative real-time PCR. Immune responses were measured using flow cytometry and cytokine profiling, while gut microbiota changes were examined through metagenomic sequencing. RESULTS WKB supplementation significantly alleviated DSS-induced colitis in mice, evidenced by reduced weight loss, disease activity, and improved colonic histology. This effect was linked to enhanced mucosal barrier integrity, seen through increased tight junction protein and Muc2 expression, accompanied by favorable ultrastructural changes. WKB modulated EGCs activity via TNF-like cytokine 1 A inhibition, resulting in reduced glial fibrillary acidic protein expression. Immunologically, it downregulated Th1 and Th17 pro-inflammatory cells, increased Treg cells, and altered cytokine profiles (reduced TNF-α, IFN-γ, IL-17; increased IL-10). Metagenomic analysis showed that WKB restored gut microbiota balance, particularly enhancing beneficial bacteria like Akkermansia. KEGG pathway analysis further indicated that WKB supplementation improved key metabolic pathways, notably those related to phenylalanine, tyrosine, and tryptophan biosynthesis, thereby countering DSS-induced metabolic disruptions. CONCLUSIONS WKB shows promise for treating IBD by enhancing mucosal barriers, inhibiting EGCs activity, balancing Th1/Th17/Treg cells, and restoring gut microbiota and metabolic homeostasis, thereby alleviating colitis symptoms.
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Affiliation(s)
- Qi Sun
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Bai-Rong Li
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Dong-Hao Li
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xiao-Ying Wang
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Qian-Yi Wang
- School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China
| | - Zhi-Meng Jiang
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Shou-Bin Ning
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Tao Sun
- Department of Gastroenterology, Air Force Medical Center, No. 30 Fucheng Road, Haidian District, Beijing, 100142, China.
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Prochera A, Muppirala AN, Kuziel GA, Soualhi S, Shepherd A, Sun L, Issac B, Rosenberg HJ, Karim F, Perez K, Smith KH, Archibald TH, Rakoff-Nahoum S, Hagen SJ, Rao M. Enteric glia regulate Paneth cell secretion and intestinal microbial ecology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.15.589545. [PMID: 38659931 PMCID: PMC11042301 DOI: 10.1101/2024.04.15.589545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
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Affiliation(s)
- Aleksandra Prochera
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Anoohya N Muppirala
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Gavin A Kuziel
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Salima Soualhi
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Amy Shepherd
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Liang Sun
- Research Computing, Department of Information Technology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Biju Issac
- Research Computing, Department of Information Technology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Harry J Rosenberg
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Farah Karim
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA
| | - Kristina Perez
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Kyle H Smith
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Tonora H Archibald
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Seth Rakoff-Nahoum
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Susan J Hagen
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Meenakshi Rao
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
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Karjalainen J, Hain S, Progatzky F. Glial-immune interactions in barrier organs. Mucosal Immunol 2024:S1933-0219(24)00135-1. [PMID: 39716688 DOI: 10.1016/j.mucimm.2024.12.012] [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: 10/20/2024] [Revised: 12/10/2024] [Accepted: 12/16/2024] [Indexed: 12/25/2024]
Abstract
Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.
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Affiliation(s)
| | - Sofia Hain
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Fränze Progatzky
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
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Zhang X, Qi F, Yang J, Xu C. Distribution and ultrastructural characteristics of enteric glial cell in the chicken cecum. Poult Sci 2024; 103:104070. [PMID: 39094494 PMCID: PMC11345566 DOI: 10.1016/j.psj.2024.104070] [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: 04/10/2024] [Revised: 06/29/2024] [Accepted: 07/02/2024] [Indexed: 08/04/2024] Open
Abstract
Enteric glial cell (EGC) is involved in neuroimmune regulation within the enteric nervous system (ENS); however, limited information exists on the distribution and ultrastructure of EGC in the poultry gut. We aim to investigate the morphological features and distribution of EGC in the chicken cecum. Here, we investigated the distribution and ultrastructural features of chicken cecum EGC using immunohistochemistry (IHC) and transmission electron microscopy (TEM). IHC showed that EGC was widely distributed throughout the chicken cecum. In the mucosal layer, EGC was morphologically irregular, with occasionally interconnecting protrusions that outlined signal-negative neurons. The morphology of EGC in the submucosal layer was also irregular. In the inner circular muscle layer and between the inner circular and outer longitudinal muscle layers, EGC aligned parallel to the circular muscle cells. A small number of EGC with an irregular morphology were found in the outer longitudinal muscle layer. In addition, in the submucosal and myenteric plexus, EGC were aggregated, and the protrusions of the immunoreactive cells interconnected to outline the bodies of nonreactive neurons. TEM-guided ultrastructural characterization confirmed the IHC findings that EGC were morphologically irregular and revealed they developed either a star, bipolar, or fibrous shape. The nucleus was also irregular, with electron-dense heterochromatin distributed in the center of the nucleus or on the nuclear membrane. The cytoplasm contained many glial filaments and vesicle-containing protrusions from neuronal cells; organelles were rare. EGC was in close contact with other cells in their vicinity. These findings suggest that EGC is well-situated to exert influence on intestinal motility and immune functions through mechanical contraction and chemical secretion.
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Affiliation(s)
- Xiaoting Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Fenghua Qi
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Jie Yang
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Chunsheng Xu
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China.
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He K, Wang H, Huo R, Jiang SH, Xue J. Schwann cells and enteric glial cells: Emerging stars in colorectal cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189160. [PMID: 39059672 DOI: 10.1016/j.bbcan.2024.189160] [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: 05/03/2024] [Revised: 07/21/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024]
Abstract
Cancer neuroscience, a promising field dedicated to exploring interactions between cancer and the nervous system, has attracted growing attention. The gastrointestinal tracts exhibit extensive innervation, notably characterized by intrinsic innervation. The gut harbors a substantial population of glial cells, including Schwann cells wrapping axons of neurons in the peripheral nervous system and enteric glial cells intricately associated with intrinsic innervation. Glial cells play a crucial role in maintaining the physiological functions of the intestine, encompassing nutrient absorption, barrier integrity, and immune modulation. Nevertheless, it has only been in recent times that the significance of glial cells within colorectal cancer (CRC) has begun to receive considerable attention. Emerging data suggests that glial cells in the gut contribute to the progression and metastasis of CRC, by interacting with cancer cells, influencing inflammation, and modulating the tumor microenvironment. Here, we summarize the significant roles of glial cells in the development and progression of CRC and discuss the latest technologies that can be integrated into this field for in-depth exploration, as well as potential specific targeted strategies for future exploration to benefit patients.
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Affiliation(s)
- Kexin He
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Hao Wang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Ruixue Huo
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China
| | - Shu-Heng Jiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China.
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, PR China.
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González-Fernández R, Martín-Ramírez R, Maeso MDC, Lázaro A, Ávila J, Martín-Vasallo P, Morales M. Changes in AmotL2 Expression in Cells of the Human Enteral Nervous System in Oxaliplatin-Induced Enteric Neuropathy. Biomedicines 2024; 12:1952. [PMID: 39335466 PMCID: PMC11429461 DOI: 10.3390/biomedicines12091952] [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: 07/29/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
Gastrointestinal (GI) toxicity is a common side effect in patients undergoing oxaliplatin (OxPt)-based chemotherapy for colorectal cancer (CRC). Frequently, this complication persists in the long term and could affect the efficacy of the treatment and the patient's life quality. This long-term GI toxicity is thought to be related to OxPt-induced enteral neuropathy. AmotL2 is a member of the Angiomotin family of proteins, which play a role in cell survival, neurite outgrowth, synaptic maturation, oxidative stress protection, and inflammation. In order to assess the role of AmotL2 in OxPt-induced enteral neuropathy, we studied the expression of AmotL2 in cells of the enteric nervous system (ENS) of untreated and OxPt-treated CRC patients and its relationship with inflammation, using immunofluorescence confocal microscopy. Our results in human samples show that the total number of neurons and glial cells decreased in OxPt-treated patients, and TNF-α and AmotL2 expression was increased and colocalized in both neurons and glia. AmotL2 differential expression between OxPt-treated and untreated CRC patients shows the involvement of this scaffold protein in the inflammatory component and toxicity by OxPt in the ENS.
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Affiliation(s)
- Rebeca González-Fernández
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de La Laguna, Av. Astrofísico Sánchez s/n, 38206 San Cristóbal de La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, C/Sta. María de la Soledad, Sección Medicina, 38071 San Cristóbal de La Laguna, Spain
| | - Rita Martín-Ramírez
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de La Laguna, Av. Astrofísico Sánchez s/n, 38206 San Cristóbal de La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, C/Sta. María de la Soledad, Sección Medicina, 38071 San Cristóbal de La Laguna, Spain
| | - María-Del-Carmen Maeso
- Servicio de Patología, Hospital Universitario Nuestra Señora de la Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Alberto Lázaro
- Laboratorio de Fisiopatología Renal, Departamento de Nefrología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Julio Ávila
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de La Laguna, Av. Astrofísico Sánchez s/n, 38206 San Cristóbal de La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, C/Sta. María de la Soledad, Sección Medicina, 38071 San Cristóbal de La Laguna, Spain
| | - Pablo Martín-Vasallo
- Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de La Laguna, Av. Astrofísico Sánchez s/n, 38206 San Cristóbal de La Laguna, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, C/Sta. María de la Soledad, Sección Medicina, 38071 San Cristóbal de La Laguna, Spain
| | - Manuel Morales
- Servicio de Oncología Médica, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
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Le Thuc O, García-Cáceres C. Obesity-induced inflammation: connecting the periphery to the brain. Nat Metab 2024; 6:1237-1252. [PMID: 38997442 DOI: 10.1038/s42255-024-01079-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 06/11/2024] [Indexed: 07/14/2024]
Abstract
Obesity is often associated with a chronic, low-grade inflammatory state affecting the entire body. This sustained inflammatory state disrupts the coordinated communication between the periphery and the brain, which has a crucial role in maintaining homeostasis through humoural, nutrient-mediated, immune and nervous signalling pathways. The inflammatory changes induced by obesity specifically affect communication interfaces, including the blood-brain barrier, glymphatic system and meninges. Consequently, brain areas near the third ventricle, including the hypothalamus and other cognition-relevant regions, become susceptible to impairments, resulting in energy homeostasis dysregulation and an elevated risk of cognitive impairments such as Alzheimer's disease and dementia. This Review explores the intricate communication between the brain and the periphery, highlighting the effect of obesity-induced inflammation on brain function.
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Affiliation(s)
- Ophélia Le Thuc
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Cristina García-Cáceres
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.
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Mandal A, Moneme C, Tewari BP, Goldstein AM, Sontheimer H, Cheng L, Moore SR, Levin D. A novel method for culturing enteric neurons generates neurospheres containing functional myenteric neuronal subtypes. J Neurosci Methods 2024; 407:110144. [PMID: 38670535 PMCID: PMC11144385 DOI: 10.1016/j.jneumeth.2024.110144] [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: 12/23/2023] [Revised: 03/04/2024] [Accepted: 04/20/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND The enteric nervous system (ENS) is comprised of neurons, glia, and neural progenitor cells that regulate essential gastrointestinal functions. Advances in high-efficiency enteric neuron culture would facilitate discoveries surrounding ENS regulatory processes, pathophysiology, and therapeutics. NEW METHOD Development of a simple, robust, one-step method to culture murine enteric neurospheres in a 3D matrix that supports neural growth and differentiation. RESULTS Myenteric plexus cells isolated from the entire length of adult murine small intestine formed ≥3000 neurospheres within 7 days. Matrigel-embedded neurospheres exhibited abundant neural stem and progenitor cells expressing Sox2, Sox10 and Msi1 by day 4. By day 5, neural progenitor cell marker Nestin appeared in the periphery of neurospheres prior to differentiation. Neurospheres produced extensive neurons and neurites, confirmed by Tubulin beta III, PGP9.5, HuD/C, and NeuN immunofluorescence, including neural subtypes Calretinin, ChAT, and nNOS following 8 days of differentiation. Individual neurons within and external to neurospheres generated depolarization induced action potentials which were inhibited in the presence of sodium channel blocker, Tetrodotoxin. Differentiated neurospheres also contained a limited number of glia and endothelial cells. COMPARISON WITH EXISTING METHODS This novel one-step neurosphere growth and differentiation culture system, in 3D format (in the presence of GDNF, EGF, and FGF2), allows for ∼2-fold increase in neurosphere count in the derivation of enteric neurons with measurable action potentials. CONCLUSION Our method describes a novel, robust 3D culture of electrophysiologically active enteric neurons from adult myenteric neural stem and progenitor cells.
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Affiliation(s)
- Arabinda Mandal
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Chioma Moneme
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Bhanu P Tewari
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Harald Sontheimer
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Lily Cheng
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Sean R Moore
- Department of Pediatrics, Division of Pediatric Gastroenterology Hepatology, and Nutrition, University of Virginia, Charlottesville, VA, USA.
| | - Daniel Levin
- Department of Surgery, University of Virginia, Charlottesville, VA, USA.
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Santhosh S, Zanoletti L, Stamp LA, Hao MM, Matteoli G. From diversity to disease: unravelling the role of enteric glial cells. Front Immunol 2024; 15:1408744. [PMID: 38957473 PMCID: PMC11217337 DOI: 10.3389/fimmu.2024.1408744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 07/04/2024] Open
Abstract
Enteric glial cells (EGCs) are an essential component of the enteric nervous system (ENS) and play key roles in gastrointestinal development, homeostasis, and disease. Derived from neural crest cells, EGCs undergo complex differentiation processes regulated by various signalling pathways. Being among the most dynamic cells of the digestive system, EGCs react to cues in their surrounding microenvironment and communicate with various cell types and systems within the gut. Morphological studies and recent single cell RNA sequencing studies have unveiled heterogeneity among EGC populations with implications for regional functions and roles in diseases. In gastrointestinal disorders, including inflammatory bowel disease (IBD), infections and cancer, EGCs modulate neuroplasticity, immune responses and tumorigenesis. Recent evidence suggests that EGCs respond plastically to the microenvironmental cues, adapting their phenotype and functions in disease states and taking on a crucial role. They exhibit molecular abnormalities and alter communication with other intestinal cell types, underscoring their therapeutic potential as targets. This review delves into the multifaceted roles of EGCs, particularly emphasizing their interactions with various cell types in the gut and their significant contributions to gastrointestinal disorders. Understanding the complex roles of EGCs in gastrointestinal physiology and pathology will be crucial for the development of novel therapeutic strategies for gastrointestinal disorders.
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Affiliation(s)
- Sneha Santhosh
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Lisa Zanoletti
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia, Italy
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Leuven Institute for Single-cell Omics (LISCO), KU Leuven, Leuven, Belgium
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11
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Bali V, Grubišić V. Enteric glia as friends and foes of the intestinal epithelial barrier function. Front Immunol 2024; 15:1394654. [PMID: 38873614 PMCID: PMC11169670 DOI: 10.3389/fimmu.2024.1394654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/07/2024] [Indexed: 06/15/2024] Open
Affiliation(s)
- Vedrana Bali
- Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States
| | - Vladimir Grubišić
- Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States
- Center for Biomedical Innovation, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States
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Li HY, Yan WX, Li J, Ye J, Wu ZG, Hou ZK, Chen B. Global research status and trends of enteric glia: a bibliometric analysis. Front Pharmacol 2024; 15:1403767. [PMID: 38855748 PMCID: PMC11157232 DOI: 10.3389/fphar.2024.1403767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/08/2024] [Indexed: 06/11/2024] Open
Abstract
Background Enteric glia are essential components of the enteric nervous system. Previously believed to have a passive structural function, mounting evidence now suggests that these cells are indispensable for maintaining gastrointestinal homeostasis and exert pivotal influences on both wellbeing and pathological conditions. This study aimed to investigate the global status, research hotspots, and future directions of enteric glia. Methods The literature on enteric glia research was acquired from the Web of Science Core Collection. VOSviewer software (v1.6.19) was employed to visually represent co-operation networks among countries, institutions, and authors. The co-occurrence analysis of keywords and co-citation analysis of references were conducted using CiteSpace (v6.1.R6). Simultaneously, cluster analysis and burst detection of keywords and references were performed. Results A total of 514 publications from 36 countries were reviewed. The United States was identified as the most influential country. The top-ranked institutions were University of Nantes and Michigan State University. Michel Neunlist was the most cited author. "Purinergic signaling" was the largest co-cited reference cluster, while "enteric glial cells (EGCs)" was the cluster with the highest number of co-occurring keywords. As the keyword with the highest burst strength, Crohns disease was a hot topic in the early research on enteric glia. The burst detection of keywords revealed that inflammation, intestinal motility, and gut microbiota may be the research frontiers. Conclusion This study provides a comprehensive bibliometric analysis of enteric glia research. EGCs have emerged as a crucial link between neurons and immune cells, attracting significant research attention in neurogastroenterology. Their fundamental and translational studies on inflammation, intestinal motility, and gut microbiota may promote the treatment of some gastrointestinal and parenteral disorders.
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Affiliation(s)
- Huai-Yu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Wei-Xin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Jia Li
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Ye
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Zhi-Guo Wu
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng-Kun Hou
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Bin Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
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13
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Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci 2024; 344:122547. [PMID: 38460810 DOI: 10.1016/j.lfs.2024.122547] [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: 12/25/2023] [Revised: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.
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Affiliation(s)
- Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yu Ji Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical School, Jeonbuk National University, Research Institute of Clinical Medicine of Jeonbuk National University - Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea.
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14
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Sawant N, Watanabe A, Ueda H, Okano H, Morita M. Incomplete accumulation of perilesional reactive astrocytes exacerbates wound healing after closed-head injury by increasing inflammation and BBB disruption. Exp Neurol 2024; 374:114700. [PMID: 38272160 DOI: 10.1016/j.expneurol.2024.114700] [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: 10/15/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Wound healing after closed-head injury is a significant medical issue. However, conventional models of focal traumatic brain injury, such as fluid percussion injury and controlled cortical impact, employ mechanical impacts on the exposed cerebral cortex after craniotomy. These animal models are inappropriate for studying gliosis, as craniotomy itself induces gliosis. To address this, we developed a closed-head injury model and named "photo injury", which employs intense light illumination through a thinned-skull cranial window. Our prior work demonstrated that the gliosis of focal cerebral lesion after the photo injury does not encompass artificial gliosis and comprises two distinct reactive astrocyte subpopulations. The reactive astrocytes accumulated in the perilesional recovery area actively proliferate and express Nestin, a neural stem cell marker, while those in distal regions do not exhibit these traits. The present study investigated the role of perilesional reactive astrocytes (PRAs) in wound healing using the ablation of reactive astrocytes by the conditional knockout of Stat3. The extensive and non-selective ablation of reactive astrocytes in Nestin-Cre:Stat3f/f mice resulted in an exacerbation of injury, marked by increased inflammation and BBB disruption. On the other hand, GFAP-CreERT2:Stat3f/f mice exhibited the partial and selective ablation of the PRAs, while their exacerbation of injury was at the same extent as in Nestin-Cre:Stat3f/f mice. The comparison of these two mouse strains indicates that the PRAs are an essential astrocyte component for wound healing after closed-head injury, and their anti-inflammatory and regenerative functions are significantly affected even by incomplete accumulation. In addition, the reporter gene expression in the PRAs by GFAP-CreERT2 indicated a substantial elimination of these cells and an absence of differentiation into other cell types, despite Nestin expression, after wound healing. Thus, the accumulation and subsequent elimination of PRA are proposed as promising diagnostic and therapeutic avenues to bolster wound healing after closed-head injury.
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Affiliation(s)
- Nitin Sawant
- Biomolecular Organization, Department of Biology, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Airi Watanabe
- Biomolecular Organization, Department of Biology, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Haruna Ueda
- Biomolecular Organization, Department of Biology, Kobe University, Kobe, Hyogo 657-8501, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Mitsuhiro Morita
- Biomolecular Organization, Department of Biology, Kobe University, Kobe, Hyogo 657-8501, Japan; Application Division, Center of Optical Scattering Image Science, Kobe University, Kobe, Hyogo 657-8501, Japan.
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15
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Zeng J, Lu QQ, Du XL, Yuan L, Yang XJ. Toll-like receptor 3 signaling drives enteric glial cells against dextran sulfate sodium-induced colitis in mice. J Mol Histol 2024; 55:201-210. [PMID: 38376631 DOI: 10.1007/s10735-024-10184-7] [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: 11/04/2023] [Accepted: 02/11/2024] [Indexed: 02/21/2024]
Abstract
The activation of toll-like receptor 3 (TLR3) has been reported to attenuate astrocytes injury in central nervous system, but its effect on enteric glial cells (EGCs) remains unknown. Here, we confirmed that the residence of EGCs was regulated by TLR3 agonist (polyinosinic-polycytidylic acid, PIC) or TLR3/dsRNA complex inhibitor in dextran sulfate sodium (DSS)-induced mice. In vitro, TLR3 signaling prevented apoptosis in EGCs and drove the secretion of EGCs-derived glial cell line-derived neurotrophic factor, 15-hydroxyeicosatetraenoic acid and S-nitrosoglutathione. PIC preconditioning enhanced the protective effects of EGCs against the dysfunction of intestinal epithelial barrier and the development of colitis in DSS-induced mice. Interestingly, PIC stimulation also promoted the effects of EGCs on converting macrophages to an M2-like phenotype and regulating the levels of inflammatory cytokines, including IL-1β, TNF-α and IL-10, in DSS-induced mice. These findings imply that TLR3 signaling in EGCs may provide a potential target for the prevention and treatment of colitis.
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Affiliation(s)
- Jian Zeng
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.
| | - Qiong-Qiong Lu
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xiao-Long Du
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Ling Yuan
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xiao-Jun Yang
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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16
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Zhang XL, Sun Q, Quan ZS, Wu L, Liu ZM, Xia YQ, Wang QY, Zhang Y, Zhu JX. Dopamine regulates colonic glial cell-derived neurotrophic factor secretion through cholinergic dependent and independent pathways. Br J Pharmacol 2024; 181:413-428. [PMID: 37614042 DOI: 10.1111/bph.16226] [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: 10/10/2022] [Revised: 06/02/2023] [Accepted: 08/03/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion. EXPERIMENTAL APPROACH D1 receptor knockout (D1 R-/- ) mice, adeno-associated viral 9-short hairpin RNA carrying D2 receptor (AAV9-shD2 R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements. KEY RESULTS D2 receptor-immunoreactivity (IR), but not D1 receptor-IR, was observed on EGCs. Both D1 receptor-IR and D2 receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D1 receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D1 R-/- mice. SKF38393-induced colonic ACh release was absent in D1 R-/- mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D2 receptor agonist quinpirole, and absent in AAV-shD2 R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca2+ levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD2 R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon. CONCLUSION AND IMPLICATIONS Low concentrations of dopamine promote colonic GDNF secretion via D1 receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D2 receptors on EGCs and/or cholinergic neurons.
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Affiliation(s)
- Xiao-Li Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qi Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhu-Sheng Quan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Liang Wu
- Endoscopy Center, Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zi-Ming Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yan-Qi Xia
- Grade 2020 Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qian-Yi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yue Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jin-Xia Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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17
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Pai C, Sengupta R, Heuckeroth RO. Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System. Noncoding RNA 2023; 10:1. [PMID: 38250801 PMCID: PMC10801555 DOI: 10.3390/ncrna10010001] [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: 11/09/2023] [Revised: 12/01/2023] [Accepted: 12/16/2023] [Indexed: 01/23/2024] Open
Abstract
The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) from ENS precursor cells of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNAs in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development.
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Affiliation(s)
- Christopher Pai
- The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA;
- Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rajarshi Sengupta
- American Association for Cancer Research, Philadelphia, PA 19106, USA;
| | - Robert O. Heuckeroth
- The Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA;
- Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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18
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Kirshenbaum GS, Chang CY, Bompolaki M, Bradford VR, Bell J, Kosmidis S, Shansky RM, Orlandi J, Savage LM, Harris AZ, David Leonardo E, Dranovsky A. Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging. Mol Psychiatry 2023; 28:5337-5349. [PMID: 37479778 DOI: 10.1038/s41380-023-02167-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 06/21/2023] [Accepted: 06/26/2023] [Indexed: 07/23/2023]
Abstract
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
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Affiliation(s)
- Greer S Kirshenbaum
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Chia-Yuan Chang
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Psychology, National Taiwan University, Taipei, Taiwan
| | - Maria Bompolaki
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Victoria R Bradford
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Joseph Bell
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Stylianos Kosmidis
- Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, 10027, USA
| | - Rebecca M Shansky
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Psychology, Northeastern University, Boston, MA, 02115, USA
| | | | - Lisa M Savage
- Department of Psychology, Binghamton University, Binghamton, NY, 13902, USA
| | - Alexander Z Harris
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA
- New York State Psychiatric Institute, New York, NY, 10032, USA
| | - E David Leonardo
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA.
- New York State Psychiatric Institute, New York, NY, 10032, USA.
| | - Alex Dranovsky
- Department of Psychiatry, Columbia University, New York, NY, 10032, USA.
- New York State Psychiatric Institute, New York, NY, 10032, USA.
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19
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Kipp M. Astrocytes: Lessons Learned from the Cuprizone Model. Int J Mol Sci 2023; 24:16420. [PMID: 38003609 PMCID: PMC10671869 DOI: 10.3390/ijms242216420] [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: 10/12/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at both the molecular and histological levels. These aberrations are closely linked to dysfunction of oligodendrocytes and alterations in myelin structure, which may be pivotal factors contributing to the disconnection of brain regions and the resulting characteristic clinical impairments observed in these conditions. Astrocytes, which significantly outnumber neurons in the central nervous system by a five-to-one ratio, play indispensable roles in the development, maintenance, and overall well-being of neurons and oligodendrocytes. Consequently, they emerge as potential key players in the onset and progression of a myriad of neurological and psychiatric disorders. Furthermore, targeting astrocytes represents a promising avenue for therapeutic intervention in such disorders. To gain deeper insights into the functions of astrocytes in the context of myelin-related disorders, it is imperative to employ appropriate in vivo models that faithfully recapitulate specific aspects of complex human diseases in a reliable and reproducible manner. One such model is the cuprizone model, wherein metabolic dysfunction in oligodendrocytes initiates an early response involving microglia and astrocyte activation, culminating in multifocal demyelination. Remarkably, following the cessation of cuprizone intoxication, a spontaneous process of endogenous remyelination occurs. In this review article, we provide a historical overview of studies investigating the responses and putative functions of astrocytes in the cuprizone model. Following that, we list previously published works that illuminate various aspects of the biology and function of astrocytes in this multiple sclerosis model. Some of the studies are discussed in more detail in the context of astrocyte biology and pathology. Our objective is twofold: to provide an invaluable overview of this burgeoning field, and, more importantly, to inspire fellow researchers to embark on experimental investigations to elucidate the multifaceted functions of this pivotal glial cell subpopulation.
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Affiliation(s)
- Markus Kipp
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
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20
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MANTANI Y, OHNO N, HARUTA T, NAKANISHI S, MORISHITA R, MURASE S, YOKOYAMA T, HOSHI N. Histological study on the reginal difference in the localization of mucosal enteric glial cells and their sheath structure in the rat intestine. J Vet Med Sci 2023; 85:1034-1039. [PMID: 37612064 PMCID: PMC10600526 DOI: 10.1292/jvms.23-0266] [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: 06/20/2023] [Accepted: 08/07/2023] [Indexed: 08/25/2023] Open
Abstract
The present study aimed to histologically clarify the regional specificity of the mucosal enteric glial cells (mEGCs) in the rat intestine with serial block-face scanning electron microscopy (SBF-SEM). SBF-SEM analysis with the ileum, the cecum and the descending colon revealed that mEGC nuclei were more abundant in the data stacks from the apical portion of the villus and the lateral portion of the crypt of the ileum. mEGCs exhibited a high rate of coverage over the nerve bundle around the lateral portion of the ileal crypt, but showed an extremely low level of coverage in the luminal portion of the cecum. These findings evidenced regional differences in the localization of mEGCs and in their sheath structure in the rat intestine.
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Affiliation(s)
- Youhei MANTANI
- Laboratory of Histophysiology, Department of Bioresource
Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Nobuhiko OHNO
- Department of Anatomy, Division of Histology and Cell
Biology, School of Medicine, Jichi Medical University, Tochigi, Japan
- Division of Ultrastructural Research, National Institute for
Physiological Sciences, Aichi, Japan
| | - Tomohiro HARUTA
- Bio 3D Promotion Group, Application Management Department,
JEOL Ltd., Tokyo, Japan
| | - Satoki NAKANISHI
- Laboratory of Histophysiology, Department of Bioresource
Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Rinako MORISHITA
- Laboratory of Histophysiology, Department of Bioresource
Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Shota MURASE
- Laboratory of Histophysiology, Department of Bioresource
Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Toshifumi YOKOYAMA
- Laboratory of Animal Molecular Morphology, Department of
Bioresource Science, Graduate School of Agricultural Science, Kobe University, Hyogo,
Japan
| | - Nobuhiko HOSHI
- Laboratory of Animal Molecular Morphology, Department of
Bioresource Science, Graduate School of Agricultural Science, Kobe University, Hyogo,
Japan
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21
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Xie H, Zeng X, Wang W, Wang W, Han B, Tan Q, Hu Q, Liu X, Chen S, Chen J, Sun L, Chen Y, Xiao W. Enteric glial cells aggravate the intestinal epithelial barrier damage by secreting S100β under high-altitude conditions. MOLECULAR BIOMEDICINE 2023; 4:31. [PMID: 37779161 PMCID: PMC10542628 DOI: 10.1186/s43556-023-00143-1] [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: 05/10/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100β under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100β secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100β resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100β secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.
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Affiliation(s)
- Huichao Xie
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Xiong Zeng
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Wensheng Wang
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Wei Wang
- Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Ben Han
- Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - QianShan Tan
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qiu Hu
- Institute of Medicine and Equipment for High Altitude Region, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xingyu Liu
- Department of Nutrition, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Shuaishuai Chen
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Jun Chen
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Lihua Sun
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - Yihui Chen
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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22
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Mariant CL, Bacola G, Van Landeghem L. Mini-Review: Enteric glia of the tumor microenvironment: An affair of corruption. Neurosci Lett 2023; 814:137416. [PMID: 37572875 PMCID: PMC10967235 DOI: 10.1016/j.neulet.2023.137416] [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: 02/22/2023] [Revised: 07/07/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023]
Abstract
The tumor microenvironment corresponds to a complex mixture of bioactive products released by local and recruited cells whose normal functions have been "corrupted" by cues originating from the tumor, mostly to favor cancer growth, dissemination and resistance to therapies. While the immune and the mesenchymal cellular components of the tumor microenvironment in colon cancer have been under intense scrutiny over the last two decades, the influence of the resident neural cells of the gut on colon carcinogenesis has only very recently begun to draw attention. The vast majority of the resident neural cells of the gastrointestinal tract belong to the enteric nervous system and correspond to enteric neurons and enteric glial cells, both of which have been understudied in the context of colon cancer development and progression. In this review, we especially discuss available evidence on enteric glia impact on colon carcinogenesis. To highlight "corrupted" functioning in enteric glial cells of the tumor microenvironment and its repercussion on tumorigenesis, we first review the main regulatory effects of enteric glial cells on the intestinal epithelium in homeostatic conditions and we next present current knowledge on enteric glia influence on colon tumorigenesis. We particularly examine how enteric glial cell heterogeneity and plasticity require further appreciation to better understand the distinct regulatory interactions enteric glial cell subtypes engage with the various cell types of the tumor, and to identify novel biological targets to block enteric glia pro-carcinogenic signaling.
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Affiliation(s)
- Chloe L Mariant
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
| | - Gregory Bacola
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
| | - Laurianne Van Landeghem
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
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23
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Bubeck M, Becker C, Patankar JV. Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier. Front Med (Lausanne) 2023; 10:1228938. [PMID: 37692784 PMCID: PMC10485265 DOI: 10.3389/fmed.2023.1228938] [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: 05/25/2023] [Accepted: 07/24/2023] [Indexed: 09/12/2023] Open
Abstract
The intestinal mucosal surface forms one of the largest areas of the body, which is in direct contact with the environment. Co-ordinated sensory functions of immune, epithelial, and neuronal cells ensure the timely detection of noxious queues and potential pathogens and elicit proportional responses to mitigate the threats and maintain homeostasis. Such tuning and maintenance of the epithelial barrier is constantly ongoing during homeostasis and its derangement can become a gateway for systemic consequences. Although efforts in understanding the gatekeeping functions of immune cells have led the way, increasing number of studies point to a crucial role of the enteric nervous system in fine-tuning and maintaining this delicate homeostasis. The identification of immune regulatory functions of enteric neuropeptides and glial-derived factors is still in its infancy, but has already yielded several intriguing insights into their important contribution to the tight control of the mucosal barrier. In this review, we will first introduce the reader to the current understanding of the architecture of the enteric nervous system and the epithelial barrier. Next, we discuss the key discoveries and cellular pathways and mediators that have emerged as links between the enteric nervous, immune, and epithelial systems and how their coordinated actions defend against intestinal infectious and inflammatory diseases. Through this review, the readers will gain a sound understanding of the current neuro-immune-epithelial mechanisms ensuring intestinal barrier integrity and maintenance of intestinal homeostasis.
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Affiliation(s)
- Marvin Bubeck
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V. Patankar
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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24
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Sanchini G, Vaes N, Boesmans W. Mini-review: Enteric glial cell heterogeneity: Is it all about the niche? Neurosci Lett 2023; 812:137396. [PMID: 37442521 DOI: 10.1016/j.neulet.2023.137396] [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: 04/01/2023] [Revised: 06/28/2023] [Accepted: 07/10/2023] [Indexed: 07/15/2023]
Abstract
Enteric glial cells represent the enteric population of peripheral glia. According to their 'glial' nature, their principal function is to support enteric neurons in both structural and functional ways. Mounting evidence however demonstrates that enteric glial cells crucially contribute to the majority of enteric nervous system functions, thus acting as pivotal players in the maintenance of gut homeostasis. Various types of enteric glia are present within the gut wall, creating an intricate interaction network with other gastrointestinal cell types. Their distribution throughout the different layers of the gut wall translates in characteristic phenotypes that are tailored to the local tissue requirements of the digestive tract. This heterogeneity is assumed to be mirrored by functional specialization, but the extensive plasticity and versatility of enteric glial cells complicates a one on one phenotype/function definition. Moreover, the relative contribution of niche-specific signals versus lineage determinants for driving enteric glial heterogeneity is still uncertain. In this review we focus on the current understanding of phenotypic and functional enteric glial cell heterogeneity, from a microenvironmental and developmental perspective.
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Affiliation(s)
- Gabriele Sanchini
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Nathalie Vaes
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Werend Boesmans
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium; Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, the Netherlands.
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25
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Macpherson AJ, Pachnis V, Prinz M. Boundaries and integration between microbiota, the nervous system, and immunity. Immunity 2023; 56:1712-1726. [PMID: 37557080 DOI: 10.1016/j.immuni.2023.07.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023]
Abstract
The enteric nervous system is largely autonomous, and the central nervous system is compartmentalized behind the blood-brain barrier. Yet the intestinal microbiota shapes gut function, local and systemic immune responses, and central nervous system functions including cognition and mood. In this review, we address how the gut microbiota can profoundly influence neural and immune networks. Although many of the interactions between these three systems originate in the intestinal mucosa, intestinal function and immunity are modulated by neural pathways that connect the gut and brain. Furthermore, a subset of microbe-derived penetrant molecules enters the brain and regulates central nervous system function. Understanding how these seemingly isolated entities communicate has the potential to open up new avenues for therapies and interventions.
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Affiliation(s)
- Andrew J Macpherson
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| | - Vassilis Pachnis
- Nervous System Development and Homeostasis Laboratory, The Francis Crick Institute, London, UK
| | - Marco Prinz
- Institute of Neuropathology, University of Freiburg, Faculty of Medicine, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
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26
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Zhang LM, Xin Y, Song RX, Zheng WC, Hu JS, Wang JX, Wu ZY, Zhang DX. CORM-3 alleviates the intestinal injury in a rodent model of hemorrhage shock and resuscitation: roles of GFAP-positive glia. J Mol Histol 2023; 54:271-282. [PMID: 37335421 DOI: 10.1007/s10735-023-10133-w] [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] [Accepted: 06/11/2023] [Indexed: 06/21/2023]
Abstract
Hemorrhagic shock and resuscitation (HSR) can induce severe intestinal damages, thereby leading to sepsis and long-term complications including dysbacteriosis and pulmonary injury. The NOD-like receptor protein 3 (NLRP3) inflammasome facilitates inflammation-associated cell recruitment in the gastrointestinal tract, and participates in many inflammatory bowel diseases. Previous studies have shown that exogenous carbon monoxide (CO) exerts neuroprotective effects against pyroptosis after HSR. We aimed to investigate whether carbon monoxide-releasing molecules-3 (CORM-3), an exogenous CO compound, could attenuate HSR-induced intestinal injury and the potential underlying mechanism.Rats were subjected to a HSR model by bleeding and re-infusion. Following resuscitation, 4 mg/kg of CORM-3 was administered intravenously into femoral vein. At 24 h and 7 d after HSR modeling, the pathological changes in intestinal tissues were evaluated by H&E staining. The intestinal pyroptosis, glial fibrillary acidic protein (GFAP)-positive glial pyroptosis, DAO (diamine oxidase) content, intestine tight junction proteins including zonula occludens-1 (ZO-1) and claudin-1 were further detected by immunofluorescence, western blot and chemical assays at 7 d after HSR. CORM-3 administration led to significantly mitigated HSR-induced intestinal injury, aggravation of intestinal pyroptosis indicated by cleaved caspase-1, IL-1β and IL-18, upregulation of GFAP-positive glial pyroptosis, decreased intensity of ZO-1 and claudin-1 in the jejunum, and increased of DAO in the serum. Nigericin, an agonist of NLRP3, significantly reversed the protective effects of CORM-3. CORM-3 alleviates the intestinal barrier dysfunction in a rodent model of HSR, and the potential mechanism may be associated with inhibition of NLRP3-associated pyroptosis. CORM-3 administration could be a promising therapeutic strategy for intestinal injury after hemorrhagic shock.
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Affiliation(s)
- Li-Min Zhang
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China.
| | - Yue Xin
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China
| | - Rong-Xin Song
- Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Shijiazhuang, China
| | - Wei-Chao Zheng
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China
| | - Jin-Shu Hu
- Department of Clinical Laboratory, Cangzhou Central Hospital, Cangzhou, China
| | - Jie-Xia Wang
- Department of Anesthesiology, Cangzhou Central Hospital, Shijiazhuang, China
| | - Zhi-You Wu
- Department of Neurosurgery, Cangzhou Central Hospital, Hebei Medical University, Shijiazhuang, China
| | - Dong-Xue Zhang
- Department of Gerontology, Cangzhou Central Hospital, Cangzhou, China
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27
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Le Berre C, Naveilhan P, Rolli-Derkinderen M. Enteric glia at center stage of inflammatory bowel disease. Neurosci Lett 2023; 809:137315. [PMID: 37257681 DOI: 10.1016/j.neulet.2023.137315] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/02/2023]
Abstract
Although our understanding of the pathophysiology of inflammatory bowel disease (IBD) is increasing, the expanding body of knowledge does not simplify the equation but rather reveals diverse, interconnected, and complex mechanisms in IBD. In addition to immune overactivation, defects in intestinal epithelial barrier (IEB) functioning, dysbiosis, and structural and functional abnormalities of the enteric nervous system are emerging as new elements contributing to the development of IBD. In addition to molecular changes in IBD, enteric glia from patients with Crohn's disease (CD) exhibits the inability to strengthen the IEB; these defects are not observed in patients with ulcerative colitis. In addition, there is a growing body of work describing that enteric glia interacts with not only enterocytes and enteric neurons but also other local cellular neighbours. Thus, because of their functions as connectors and regulators of immune cells, IEB, and microbiota, enteric glia could be the keystone of digestive homeostasis that is lacking in patients with CD.
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Affiliation(s)
- Catherine Le Berre
- Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Inserm CIC 1413, Institut des Maladies de l'Appareil Digestif (IMAD), CHU Nantes, 1 place Alexis Ricordeau, F-44000 Nantes, France; Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France
| | - Philippe Naveilhan
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France
| | - Malvyne Rolli-Derkinderen
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France.
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28
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Rani R, Gandhi CR. Stellate cell in hepatic inflammation and acute injury. J Cell Physiol 2023; 238:1226-1236. [PMID: 37120832 DOI: 10.1002/jcp.31029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/02/2023]
Abstract
The perisinusoidal hepatic stellate cells (HSCs) have been investigated extensively for their role as the major fibrogenic cells during chronic liver injury. HSCs also produce numerous cytokines, chemokines, and growth mediators, and express cell adhesion molecules constitutively and in response to stimulants such as endotoxin (lipopolysaccharide). With this property and by interacting with resident and recruited immune and inflammatory cells, HSCs regulate hepatic immune homeostasis, inflammation, and acute injury. Indeed, experiments with HSC-depleted animal models and cocultures have provided evidence for the prominent role of HSCs in the initiation and progression of inflammation and acute liver damage due to various toxic agents. Thus HSCs and/or mediators derived thereof during acute liver damage may be considered as potential therapeutic targets.
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Affiliation(s)
- Richa Rani
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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29
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Prochera A, Rao M. Mini-Review: Enteric glial regulation of the gastrointestinal epithelium. Neurosci Lett 2023; 805:137215. [PMID: 37001854 PMCID: PMC10125724 DOI: 10.1016/j.neulet.2023.137215] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/11/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Many enteric glia are located along nerve fibers in the gut mucosa where they form close associations with the epithelium lining the gastrointestinal tract. The gut epithelium is essential for absorbing nutrients, regulating fluid flux, forming a physical barrier to prevent the entry of pathogens and toxins into the host, and participating in immune responses. Disruptions to this epithelium are linked to numerous diseases, highlighting its central importance in maintaining health. Accumulating evidence indicates that glia regulate gut epithelial homeostasis. Observations from glial-epithelial co-cultures in vitro and mouse genetic models in vivo suggest that enteric glia influence several important features of the gut epithelium including barrier integrity, ion transport, and capacity for self-renewal. Here we review the evidence for enteric glial regulation of the intestinal epithelium, with a focus on these three features of its biology.
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Affiliation(s)
- Aleksandra Prochera
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA.
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30
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Fabbri R, Spennato D, Conte G, Konstantoulaki A, Lazzarini C, Saracino E, Nicchia GP, Frigeri A, Zamboni R, Spray DC, Benfenati V. The emerging science of Glioception: Contribution of glia in sensing, transduction, circuit integration of interoception. Pharmacol Ther 2023; 245:108403. [PMID: 37024060 DOI: 10.1016/j.pharmthera.2023.108403] [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: 10/13/2022] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023]
Abstract
Interoception is the process by which the nervous system regulates internal functions to achieve homeostasis. The role of neurons in interoception has received considerable recent attention, but glial cells also contribute. Glial cells can sense and transduce signals including osmotic, chemical, and mechanical status of extracellular milieu. Their ability to dynamically communicate "listening" and "talking" to neurons is necessary to monitor and regulate homeostasis and information integration in the nervous system. This review introduces the concept of "Glioception" and focuses on the process by which glial cells sense, interpret and integrate information about the inner state of the organism. Glial cells are ideally positioned to act as sensors and integrators of diverse interoceptive signals and can trigger regulatory responses via modulation of the activity of neuronal networks, both in physiological and pathological conditions. We believe that understanding and manipulating glioceptive processes and underlying molecular mechanisms provide a key path to develop new therapies for the prevention and alleviation of devastating interoceptive dysfunctions, among which pain is emphasized here with more focused details.
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Affiliation(s)
- Roberta Fabbri
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy; Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi", University of Bologna, viale del Risorgimento 2, 40136 Bologna, Italy.
| | - Diletta Spennato
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy; Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy
| | - Giorgia Conte
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy
| | - Aikaterini Konstantoulaki
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy; Department of Chemistry "Giacomo Ciamician", University of Bologna, Via Selmi, 2, 40126 Bologna, BO, Italy
| | - Chiara Lazzarini
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy
| | - Emanuela Saracino
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy
| | - Grazia Paola Nicchia
- School of Medicine, Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, BA, Italy; Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy
| | - Antonio Frigeri
- Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy
| | - Roberto Zamboni
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy
| | - David C Spray
- Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - Valentina Benfenati
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy.
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31
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Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev 2023; 103:1487-1564. [PMID: 36521049 PMCID: PMC9970663 DOI: 10.1152/physrev.00018.2022] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gary M Mawe
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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32
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Britzen-Laurent N, Weidinger C, Stürzl M. Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases. Int J Mol Sci 2023; 24:ijms24065517. [PMID: 36982601 PMCID: PMC10051397 DOI: 10.3390/ijms24065517] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
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Affiliation(s)
- Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence:
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Stürzl
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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33
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Microbiota-dependent presence of murine enteric glial cells requires myeloid differentiation primary response protein 88 signaling. J Biosci 2023. [DOI: 10.1007/s12038-023-00325-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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34
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Liu X, Bae C, Liu B, Zhang YM, Zhou X, Zhang D, Zhou C, DiBua A, Schutz L, Kaczocha M, Puopolo M, Yamaguchi TP, Chung JM, Tang SJ. Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling. Mol Psychiatry 2023; 28:767-779. [PMID: 36203006 PMCID: PMC10388343 DOI: 10.1038/s41380-022-01815-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 09/15/2022] [Accepted: 09/23/2022] [Indexed: 11/09/2022]
Abstract
Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.
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Affiliation(s)
- Xin Liu
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA.,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
| | - Chilman Bae
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA.,School of Electrical, Computer, and Biomedical Engineering, Southern Illinois University, Carbondale, 62901, IL, USA
| | - Bolong Liu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA.,Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 W Tianhe Rd, Guangzhou, 510630, China
| | - Yong-Mei Zhang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA.,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, China
| | - Xiangfu Zhou
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 W Tianhe Rd, Guangzhou, 510630, China
| | - Donghang Zhang
- Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Cheng Zhou
- Laboratory of Anesthesia & Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - Adriana DiBua
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA.,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
| | - Livia Schutz
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA.,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
| | - Martin Kaczocha
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA.,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
| | - Michelino Puopolo
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA.,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA
| | - Terry P Yamaguchi
- Center for Cancer Research, Cancer and Developmental Biology Laboratory, Cell Signaling in Vertebrate Development Section, NCI-Frederick, NIH, Frederick, 21702, MD, USA
| | - Jin Mo Chung
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA
| | - Shao-Jun Tang
- Stony Brook University Pain and Anesthesia Research Center (SPARC), Stony Brook University, Stony Brook, 11794, NY, USA. .,Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, 11794, NY, USA. .,Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA.
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35
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Dranovsky A, Kirshenbaum G, Chang CY, Bompolaki M, Bradford V, Bell J, Kosmidis S, Shansky R, Orlandi J, Savage L, Leonardo E, Harris A. Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging. RESEARCH SQUARE 2023:rs.3.rs-1851645. [PMID: 36778445 PMCID: PMC9915786 DOI: 10.21203/rs.3.rs-1851645/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
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Affiliation(s)
- Alex Dranovsky
- Columbia University, New York State Psychiatric Institute
| | | | | | | | | | - Joseph Bell
- Columbia University, New York State Psychiatric Institute
| | | | | | - Javier Orlandi
- Columbia University, New York State Psychiatric Institute
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36
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Baghdadi MB, Kim TH. The multiple roles of enteric glial cells in intestinal homeostasis and regeneration. Semin Cell Dev Biol 2023:S1084-9521(23)00005-8. [PMID: 36658046 DOI: 10.1016/j.semcdb.2023.01.005] [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: 07/17/2022] [Revised: 12/16/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
The gastrointestinal tract is innervated by the enteric nervous system (ENS), a complex network of neurons and glial cells, also called the "second brain". Enteric glial cells, one of the major cell types in the ENS, are located throughout the entire gut wall. Accumulating evidence has demonstrated their critical requirement for gut physiology. Notably, recent studies have shown that enteric glial cells control new aspects of gut function such as regulation of intestinal stem cell behavior and immunity. In addition, the emergence of single-cell genomics technologies has revealed enteric glial cell heterogeneity and plasticity. In this review, we discuss established and emerging concepts regarding the roles of mammalian enteric glial cells and their heterogeneity in gut development, homeostasis, and regeneration.
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Affiliation(s)
- Meryem B Baghdadi
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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Costa DVS, Shin JH, Goldbeck SM, Bolick DT, Mesquita FS, Loureiro AV, Rodrigues-Jesus MJ, Brito GAC, Warren CA. Adenosine receptors differentially mediate enteric glial cell death induced by Clostridioides difficile Toxins A and B. Front Immunol 2023; 13:956326. [PMID: 36726986 PMCID: PMC9885079 DOI: 10.3389/fimmu.2022.956326] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
Increased risk of intestinal dysfunction has been reported in patients after Clostridioides difficile infection (CDI). Enteric glial cells (EGCs), a component of the enteric nervous system (ENS), contribute to gut homeostasis. Previous studies showed that adenosine receptors, A2A and A2B, modulate inflammation during CDI. However, it is unknown how these receptors can modulate the EGC response to the C. difficile toxins (TcdA and TcdB). We investigated the effects of these toxins on the expression of adenosine receptors in EGCs and the role of these receptors on toxin-induced EGC death. Rat EGCs line were incubated with TcdA or TcdB alone or in combination with adenosine analogues 1h prior to toxins challenge. After incubation, EGCs were collected to evaluate gene expression (adenosine receptors and proinflammatory markers) and cell death. In vivo, WT, A2A, and A2B KO mice were infected with C. difficile, euthanized on day 3 post-infection, and cecum tissue was processed. TcdA and TcdB increased A2A and A3 transcripts, as well as decreased A2B. A2A agonist, but not A2A antagonist, decreased apoptosis induced by TcdA and TcdB in EGCs. A2B blocker, but not A2B agonist, diminished apoptosis in EGCs challenged with both toxins. A3 agonist, but not A3 blocker, reduced apoptosis in EGCs challenged with TcdA and TcdB. Inhibition of protein kinase A (PKA) and CREB, both involved in the main signaling pathway driven by activation of adenosine receptors, decreased EGC apoptosis induced by both toxins. A2A agonist and A2B antagonist decreased S100B upregulation induced by C. difficile toxins in EGCs. In vivo, infected A2B KO mice, but not A2A, exhibited a decrease in cell death, including EGCs and enteric neuron loss, compared to infected WT mice, reduced intestinal damage and decreased IL-6 and S100B levels in cecum. Our findings indicate that upregulation of A2A and A3 and downregulation of A2B in EGCs and downregulation of A2B in intestinal tissues elicit a protective response against C. difficile toxins. Adenosine receptors appear to play a regulatory role in EGCs death and proinflammatory response induced by TcdA and TcdB, and thus may be potential targets of intervention to prevent post-CDI intestinal dysmotility.
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Affiliation(s)
- Deiziane V S Costa
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Jae H Shin
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Sophia M Goldbeck
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - David T Bolick
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Flavio S Mesquita
- Department of Microbiology, University of Sao Paulo, Sao Paulo, Brazil
| | - Andrea V Loureiro
- Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Mônica J Rodrigues-Jesus
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Gerly A C Brito
- Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Cirle A Warren
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
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Zanoletti L, Valdata A, Nehlsen K, Faris P, Casali C, Cacciatore R, Sbarsi I, Carriero F, Arfini D, van Baarle L, De Simone V, Barbieri G, Raimondi E, May T, Moccia F, Bozzola M, Matteoli G, Comincini S, Manai F. Cytological, molecular, cytogenetic, and physiological characterization of a novel immortalized human enteric glial cell line. Front Cell Neurosci 2023; 17:1170309. [PMID: 37153631 PMCID: PMC10158601 DOI: 10.3389/fncel.2023.1170309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/22/2023] [Indexed: 05/10/2023] Open
Abstract
Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100β, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.
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Affiliation(s)
- Lisa Zanoletti
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Aurora Valdata
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Pawan Faris
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Iraq
| | - Claudio Casali
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Rosalia Cacciatore
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Ilaria Sbarsi
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Francesca Carriero
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Davide Arfini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Veronica De Simone
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Giulia Barbieri
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Elena Raimondi
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Francesco Moccia
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Sergio Comincini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Federico Manai
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- *Correspondence: Federico Manai,
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Ji H, Lai D, Tou J. Neuroimmune regulation in Hirschsprung's disease associated enterocolitis. Front Immunol 2023; 14:1127375. [PMID: 37138874 PMCID: PMC10149972 DOI: 10.3389/fimmu.2023.1127375] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/31/2023] [Indexed: 05/05/2023] Open
Abstract
Neuroimmune pathways are important part of the regulation of inflammatory response. Nerve cells regulate the functions of various immune cells through neurotransmitters, and then participate in the inflammatory immune response. Hirschsprung's disease (HD) is a congenital abnormal development of intestinal neurons, and Hirschsprung-associated enterocolitis (HAEC) is a common complication, which seriously affects the quality of life and even endangers the lives of children. Neuroimmune regulation mediates the occurrence and development of enteritis, which is an important mechanism. However, there is a lack of review on the role of Neuroimmune regulation in enterocolitis associated with Hirschsprung's disease. Therefore, this paper summarizes the characteristics of the interaction between intestinal nerve cells and immune cells, reviews the neuroimmune regulation mechanism of Hirschsprung's disease associated enterocolitis (HAEC), and looks forward to the potential clinical application value.
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40
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Schwann cell functions in peripheral nerve development and repair. Neurobiol Dis 2023; 176:105952. [PMID: 36493976 DOI: 10.1016/j.nbd.2022.105952] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.
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41
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Role of Wnt signaling in the maintenance and regeneration of the intestinal epithelium. Curr Top Dev Biol 2023; 153:281-326. [PMID: 36967198 DOI: 10.1016/bs.ctdb.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The intestinal epithelium plays a key role in digestion and protection against external pathogens. This tissue presents a high cellular turnover with the epithelium being completely renewed every 5days, driven by intestinal stem cells (ISCs) residing in the crypt bases. To sustain this dynamic renewal of the intestinal epithelium, the maintenance, proliferation, and differentiation of ISCs must be precisely controlled. One of the central pathways supporting ISC maintenance and dynamics is the Wnt pathway. In this chapter, we examine the role of Wnt signaling in intestinal epithelial homeostasis and tissue regeneration, including mechanisms regulating ISC identity and fine-tuning of Wnt pathway activation. We extensively discuss the contribution of the stem cell niche in maintaining Wnt signaling in the intestinal crypts that support ISC functions. The integration of these findings highlights the complex interplay of multiple niche signals and cellular components sustaining ISC behavior and maintenance, which together supports the immense plasticity of the intestinal epithelium.
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42
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Reed CB, Feltri ML, Wilson ER. Peripheral glia diversity. J Anat 2022; 241:1219-1234. [PMID: 34131911 PMCID: PMC8671569 DOI: 10.1111/joa.13484] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Recent years have seen an evolving appreciation for the role of glial cells in the nervous system. As we move away from the typical neurocentric view of neuroscience, the complexity and variability of central nervous system glia is emerging, far beyond the three main subtypes: astrocytes, oligodendrocytes, and microglia. Yet the diversity of the glia found in the peripheral nervous system remains rarely discussed. In this review, we discuss the developmental origin, morphology, and function of the different populations of glia found in the peripheral nervous system, including: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap-derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body. Further, it highlights a complexity that should be appreciated and considered when it comes to a complete understanding of the peripheral nervous system in health and disease.
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Affiliation(s)
- Chelsey B. Reed
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - M. Laura Feltri
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - Emma R. Wilson
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
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The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196773. [PMID: 36235308 PMCID: PMC9570628 DOI: 10.3390/molecules27196773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
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44
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Bonaz B. Anti-inflammatory effects of vagal nerve stimulation with a special attention to intestinal barrier dysfunction. Neurogastroenterol Motil 2022; 34:e14456. [PMID: 36097404 PMCID: PMC9787579 DOI: 10.1111/nmo.14456] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 12/30/2022]
Abstract
The vagus nerve (VN), the longest nerve of the organism innervating the gastrointestinal tract, is a mixed nerve with anti-inflammatory properties through its afferents, activating the hypothalamic-pituitary adrenal axis, and its efferents through the cholinergic anti-inflammatory pathway inhibiting the release of pro-inflammatory cytokines (e.g., TNFα) by splenic and gut macrophages. In addition, the VN is also able to modulate the permeability of the intestinal barrier although the VN does not innervate directly the intestinal epithelium. Targeting the VN through VN stimulation (VNS) has been developed in experimental model of intestinal inflammation and in inflammatory bowel disease (IBD) and might be of interest to decrease intestinal permeability in gastrointestinal disorders with intestinal barrier defect such as IBD, irritable bowel syndrome (IBS), and celiac disease. In this issue of neurogastroenterology and motility, Mogilevski et al. report that a brief non-invasive transcutaneous auricular VNS in healthy volunteers consistently reduces the permeability of the small intestine induced by intravenous administration of the stress peptide corticotropin releasing hormone, known to increase intestinal permeability and to inhibit the VN. In this review, we outline the mechanistic underpinning the effect of stress, of the VN and VNS on intestinal permeability. In particular, the VN can act on intestinal permeability through enteric nerves, and/or cells such as enteric glial cells. We also review the existing evidence of the effects VNS on intestinal permeability in models such as burn intestinal injury and traumatic brain injury, which pave the way for future clinical trials in IBD, IBS, and celiac disease.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato‐GastroenterologyCentre Hospitalier Universitaire Grenoble AlpesGrenobleFrance,Grenoble Institute of Neurosciences, Inserm U1216University Grenoble AlpesGrenobleFrance
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Wang S, Ding Y, Jiang W. CSE/H2S ameliorates colitis in mice via protection of enteric glial cells and inhibition of the RhoA/ROCK pathway. Front Immunol 2022; 13:966881. [PMID: 36189321 PMCID: PMC9520914 DOI: 10.3389/fimmu.2022.966881] [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: 06/11/2022] [Accepted: 08/26/2022] [Indexed: 11/19/2022] Open
Abstract
The enteric glial cells (EGCs) participate in the homeostasis of the gastrointestinal tract, and RhoA/ROCK signaling pathway plays a vital role in colonic tight junctions. Hydrogen sulfide (H2S) has been reported to alleviate colitis. However, the effect and mechanism of endogenous H2S on colitis remain unclear. This study established a Cystathionine-γ-lyase (CSE) knockout mouse model, a significant source of H2S production in the gut. The role of CSE-produced H2S on EGCs and the RhoA/ROCK signaling pathway was investigated in experimental colitis using CSE knockout (KO) and wild-type (WT) mice. CSE gene knockout animals presented with disease progression, more deteriorated clinical scores, colon shortening, and histological damage. EGCs dysfunction, characterized by decreased expression of the glial fibrillary acidic protein (GFAP), C3, and S100A10, was observed in the colon of WT and KO mice, especially in KO mice. RhoA/ROCK pathway was significantly upregulated in colon of colitis mice, which was more evident in KO mice. Pretreatment with NaHS, an exogenous H2S donor, significantly ameliorated mucosal injury and inhibited the expression of proinflammatory factors. Furthermore, we found that NaHS promoted the transformation of EGCs from “A1” to “A2” type, with decreased expression of C3 and increased expression of S100A10. These findings suggest that CSE/H2S protects mice from colon inflammation, which may be associated with preserving EGCs function by promoting EGCs transformation and inhibiting the RhoA/ROCK pathway.
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Affiliation(s)
- Song Wang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yanyu Ding
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Wenjun Jiang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- *Correspondence: Wenjun Jiang,
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Loureiro AV, Moura-Neto LI, Martins CS, Silva PIM, Lopes MB, Leitão RFC, Coelho-Aguiar JM, Moura-Neto V, Warren CA, Costa DV, Brito GAC. Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia. Front Immunol 2022; 13:956340. [PMID: 36072579 PMCID: PMC9442043 DOI: 10.3389/fimmu.2022.956340] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Clostridioides difficile (C. difficile) produces toxins A (TcdA) and B (TcdB), both associated with intestinal damage and diarrhea. Pannexin-1 (Panx1) channels allows the passage of messenger molecules, such as adenosine triphosphate (ATP), which in turn activate the P2X7 receptors (P2X7R) that regulate inflammation and cell death in inflammatory bowel diseases. The aim of this study was to verify the effect of C. difficile infection (CDI) in the expression of Panx1 and P2X7R in intestinal tissues of mice, as well as their role in cell death and IL-6 expression induced by TcdA and TcdB in enteric glial cells (EGCs). Male C57BL/6 mice (8 weeks of age) were infected with C. difficile VPI10463, and the control group received only vehicle per gavage. After three days post-infection (p.i.), cecum and colon samples were collected to evaluate the expression of Panx1 by immunohistochemistry. In vitro, EGCs (PK060399egfr) were challenged with TcdA or TcdB, in the presence or absence of the Panx1 inhibitor (10Panx trifluoroacetate) or P2X7R antagonist (A438079), and Panx1 and P2X7R expression, caspase-3/7 activity and phosphatidylserine binding to annexin-V, as well as IL-6 expression were assessed. CDI increased the levels of Panx1 in cecum and colon of mice compared to the control group. Panx1 inhibitor decreased caspase-3/7 activity and phosphatidylserine-annexin-V binding, but not IL-6 gene expression in TcdA and TcdB-challenged EGCs. P2X7 receptor antagonist accentually reduced caspase-3/7 activity, phosphatidylserine-annexin-V binding, and IL-6 gene expression in TcdA and TcdB-challenged EGCs. In conclusion, Panx1 is increased during CDI and plays an important role in the effects of C. difficile toxins in EGCs, participating in cell death induced by both toxins by promoting caspase-3/7 activation via P2X7R, which is also involved in IL-6 expression induced by both toxins.
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Affiliation(s)
- Andrea V. Loureiro
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Lauro I. Moura-Neto
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Conceição S. Martins
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Pedro I. M. Silva
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Matheus B.S. Lopes
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Renata F. C. Leitão
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Juliana M. Coelho-Aguiar
- Paulo Niemeyer Brain Institute, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivaldo Moura-Neto
- Paulo Niemeyer Brain Institute, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cirle A. Warren
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Deiziane V.S. Costa
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
- *Correspondence: Gerly A. C. Brito, ; Deiziane V.S. Costa,
| | - Gerly A. C. Brito
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brazil
- *Correspondence: Gerly A. C. Brito, ; Deiziane V.S. Costa,
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47
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Schneider R, Leven P, Mallesh S, Breßer M, Schneider L, Mazzotta E, Fadda P, Glowka T, Vilz TO, Lingohr P, Kalff JC, Christofi FL, Wehner S. IL-1-dependent enteric gliosis guides intestinal inflammation and dysmotility and modulates macrophage function. Commun Biol 2022; 5:811. [PMID: 35962064 PMCID: PMC9374731 DOI: 10.1038/s42003-022-03772-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 07/26/2022] [Indexed: 11/08/2022] Open
Abstract
Muscularis Externa Macrophages (ME-Macs) and enteric glial cells (EGCs) are closely associated cell types in the bowel wall, and important interactions are thought to occur between them during intestinal inflammation. They are involved in developing postoperative ileus (POI), an acute, surgery-induced inflammatory disorder triggered by IL-1 receptor type I (IL1R1)-signaling. In this study, we demonstrate that IL1R1-signaling in murine and human EGCs induces a reactive state, named enteric gliosis, characterized by a strong induction of distinct chemokines, cytokines, and the colony-stimulating factors 1 and 3. Ribosomal tagging revealed enteric gliosis as an early part of POI pathogenesis, and mice with an EGC-restricted IL1R1-deficiency failed to develop postoperative enteric gliosis, showed diminished immune cell infiltration, and were protected from POI. Furthermore, the IL1R1-deficiency in EGCs altered the surgery-induced glial activation state and reduced phagocytosis in macrophages, as well as their migration and accumulation around enteric ganglia. In patients, bowel surgery also induced IL-1-signaling, key molecules of enteric gliosis, and macrophage activation. Together, our data show that IL1R1-signaling triggers enteric gliosis, which results in ME-Mac activation and the development of POI. Intervention in this pathway might be a useful prophylactic strategy in preventing such motility disorders and gut inflammation.
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Affiliation(s)
| | - Patrick Leven
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | | | - Mona Breßer
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Linda Schneider
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Elvio Mazzotta
- Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Paola Fadda
- Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Tim Glowka
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Tim O Vilz
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Philipp Lingohr
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Jörg C Kalff
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Fievos L Christofi
- Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Sven Wehner
- Department of Surgery, University Hospital Bonn, Bonn, Germany.
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48
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Progatzky F, Pachnis V. The role of enteric glia in intestinal immunity. Curr Opin Immunol 2022; 77:102183. [DOI: 10.1016/j.coi.2022.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 11/17/2022]
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49
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Yang YH, Qian W, Hou XH, Dai CB. Bifidobacterium bifidum and Bacteroides fragilis Induced Differential Immune Regulation of Enteric Glial Cells Subjected to Exogenous Inflammatory Stimulation. Inflammation 2022; 45:2388-2405. [PMID: 35776290 DOI: 10.1007/s10753-022-01700-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022]
Abstract
Enteric glial cells (EGCs) are involved in intestinal inflammation. In this study, we will investigate how Bifidobacterium bifidum (B.b.) and Bacteroides fragilis (B.f.) influence EGC regulation. After pretreatment with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), the expressions of major histocompatibility complex class II (MHC-II), CD80, CD86, glial cell line-derived neurotrophic factor (GDNF), toll-like receptor 2 (TLR-2), and tumor necrosis factor-α (TNF-α) in EGCs were detected using polymerase chain reaction and western blot after co-culture with the supernatants of B.b. or B.f. (multiplicity of infection, 40:1 or 80:1). Finally, EGCs were co-cultured with naive CD4+ T cells, and the expressions of interleukin (IL)-2, IL-4, IL-10, and IL-17 in supernatant were measured using enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of MHC-II and CD86 in EGCs were increased after combined stimulation with LPS and IFN-γ. The expressions of MHC-II, GDNF, TLR-2, and TNF-α were all significantly upregulated in stimulated EGCs. The B.b. supernatant downregulated the expressions of MHC-II, GDNF, TLR-2, and TNF-α in stimulated EGCs, whereas the B.f. supernatant upregulated TLR-2 expression and downregulated MHC-II expression. The expressions of IL-4, IL-2, and IL-17 after co-culture of naive CD4+ T cells and stimulated EGCs were significantly increased. The supernatant of B.b. or B.f. downregulated the expressions of these cytokines. The low-concentration B.b. supernatant upregulated IL-10 expression. Conclusions B.b. and B.f. may influence intestinal inflammation by regulating MHC-II, GDNF, TLR-2, and TNF-α expression in EGCs and IL-4, IL-2, IL-17, and IL-10 secretion.
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Affiliation(s)
- Yan-Hua Yang
- Division of Gastroenterology, Affiliated RenHe Hospital of Three Gorges University, Yichang, 443001, China
- Division of Gastroenterology, Central Hospital of Enshi Autonomous Prefecture, Hubei Province, Enshi, 445000, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Hua Hou
- Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chi-Bing Dai
- Division of Gastroenterology, Affiliated RenHe Hospital of Three Gorges University, Yichang, 443001, China.
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50
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Hacene S, Le Friec A, Desmoulin F, Robert L, Colitti N, Fitremann J, Loubinoux I, Cirillo C. Present and future avenues of cell-based therapy for brain injury: The enteric nervous system as a potential cell source. Brain Pathol 2022; 32:e13105. [PMID: 35773942 PMCID: PMC9425017 DOI: 10.1111/bpa.13105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/09/2022] [Indexed: 01/01/2023] Open
Abstract
Cell therapy is a promising strategy in the field of regenerative medicine; however, several concerns limit the effective clinical use, namely a valid cell source. The gastrointestinal tract, which contains a highly organized network of nerves called the enteric nervous system (ENS), is a valuable reservoir of nerve cells. Together with neurons and neuronal precursor cells, it contains glial cells with a well described neurotrophic potential and a newly identified neurogenic one. Recently, enteric glia is looked at as a candidate for cell therapy in intestinal neuropathies. Here, we present the therapeutic potential of the ENS as cell source for brain repair, too. The example of stroke is introduced as a brain injury where cell therapy appears promising. This disease is the first cause of handicap in adults. The therapies developed in recent years allow a partial response to the consequences of the disease. The only prospect of recovery in the chronic phase is currently based on rehabilitation. The urgency to offer other treatments is therefore tangible. In the first part of the review, some elements of stroke pathophysiology are presented. An update on the available therapeutic strategies is provided, focusing on cell‐ and biomaterial‐based approaches. Following, the ENS is presented with its anatomical and functional characteristics, focusing on glial cells. The properties of these cells are depicted, with particular attention to their neurotrophic and, recently identified, neurogenic properties. Finally, preliminary data on a possible therapeutic approach combining ENS‐derived cells and a biomaterial are presented.
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Affiliation(s)
- Sirine Hacene
- National Veterinary School of Toulouse, University of Toulouse, Toulouse, France.,Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Alice Le Friec
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France.,Department of Biological and Chemical Engineering-Medical Biotechnology, Aarhus University, Aarhus, Denmark
| | - Franck Desmoulin
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Lorenne Robert
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Nina Colitti
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Juliette Fitremann
- Laboratoire des IMRCP, CNRS UMR 5623, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Isabelle Loubinoux
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Carla Cirillo
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
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