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Li W, Zhang J, Gao Y, Kong X, Sun X. Nervous system in hepatocellular carcinoma: Correlation, mechanisms, therapeutic implications, and future perspectives. Biochim Biophys Acta Rev Cancer 2025; 1880:189345. [PMID: 40355012 DOI: 10.1016/j.bbcan.2025.189345] [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: 12/13/2024] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous and complex cancer influenced by both the tumor microenvironment and multi-level regulation of the nervous system. Increasing evidence highlights critical roles of the central nervous system (CNS) and peripheral nervous system (PNS) in modulating HCC progression. Psychological stress and emotional disturbances, representing CNS dysregulation, directly accelerate tumor growth, metastasis, and impair anti-tumor immunity in HCC. PNS involvement, particularly autonomic innervation, extensively reshapes the hepatic tumor microenvironment. Specifically, sympathetic activation promotes immune suppression, tumor cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stemness via β-adrenergic signaling and hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, whereas parasympathetic signals generally exert anti-inflammatory and tumor-suppressive effects mediated by acetylcholine. Neurotransmitters including epinephrine, norepinephrine, dopamine, serotonin, and acetylcholine precisely regulate critical pathways such as AKT/mTOR, ERK, and NF-κB, thereby driving malignant cell behaviors, immune evasion, and chemoresistance. Neuro-targeted pharmacological interventions (e.g., SSRIs, β-blockers, dopamine antagonists) and behavioral therapies have shown efficacy in preclinical studies, underscoring their therapeutic potential. Additionally, neural-associated biomarkers like NEDD9, CNTN1, and nerve growth factor (NGF) exhibit prognostic significance, supporting their future clinical application. By systematically integrating neuroscience with oncology, this review identifies innovative neural-based therapeutic strategies, highlights key mechanistic insights, and outlines promising directions for future research and personalized clinical management of HCC.
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Affiliation(s)
- Wenxuan Li
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Jinghao Zhang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xuehua Sun
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
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Hammond NL, Murtuza Baker S, Georgaka S, Al-Anbaki A, Jokl E, Simpson K, Sanchez-Alvarez R, Athwal VS, Purssell H, Siriwardena AK, Spiers HVM, Dixon MJ, Bere LD, Jones AP, Haley MJ, Couper KN, Bobola N, Sharrocks AD, Hanley NA, Rattray M, Piper Hanley K. Spatial gene regulatory networks driving cell state transitions during human liver disease. EMBO Mol Med 2025:10.1038/s44321-025-00230-6. [PMID: 40281306 DOI: 10.1038/s44321-025-00230-6] [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: 09/26/2024] [Revised: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025] Open
Abstract
Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory between hepatocytes and cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated with liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.
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Affiliation(s)
- Nigel L Hammond
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Syed Murtuza Baker
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Sokratia Georgaka
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Ali Al-Anbaki
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Elliot Jokl
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Kara Simpson
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Rosa Sanchez-Alvarez
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Varinder S Athwal
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
- Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK
| | - Huw Purssell
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
- Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK
| | - Ajith K Siriwardena
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
- Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK
| | | | - Mike J Dixon
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Leoma D Bere
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Adam P Jones
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Michael J Haley
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Kevin N Couper
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Nicoletta Bobola
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Andrew D Sharrocks
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Neil A Hanley
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
- College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2GW, UK
| | - Magnus Rattray
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK
| | - Karen Piper Hanley
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK.
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Mravec B, Szantova M. Liver Neurobiology: Regulation of Liver Functions by the Nervous System. Semin Liver Dis 2025. [PMID: 40239709 DOI: 10.1055/a-2562-2000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
The nervous system plays an important role in the regulation of liver functions during physiological as well as pathological conditions. This regulatory effect is based on the processing of signals transmitted to the brain by sensory nerves innervating the liver tissue and other visceral organs and by humoral pathways transmitting signals from peripheral tissues and organs. Based on these signals, the brain modulates metabolism, detoxification, regeneration, repair, inflammation, and other processes occurring in the liver. The nervous system thus determines the functional and morphological characteristics of the liver. Liver innervation also mediates the influence of psychosocial factors on liver functions. The aim of this review is to describe complexity of bidirectional interactions between the brain and liver and to characterize the mechanisms and pathways through which the nervous system influences liver function during physiological conditions and maintains liver and systemic homeostasis.
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Affiliation(s)
- Boris Mravec
- Department of Physiology Faculty of Medicine, Comenius University, Bratislava, Slovakia
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria Szantova
- 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [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: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Song R, Ma J, Yin S, Wu Z, Liu C, Sun R, Cao G, Lu Y, Liu J, Su L, Wang Y. Receptor activity-modifying protein 1 regulates the differentiation of mouse skin fibroblasts by downregulating α-SMA expression via suppression of high mobility group AT-hook 1 to promote skin wound repair. BURNS & TRAUMA 2025; 13:tkae068. [PMID: 39839760 PMCID: PMC11750253 DOI: 10.1093/burnst/tkae068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 05/21/2024] [Accepted: 10/11/2024] [Indexed: 01/23/2025]
Abstract
Background Skin innervation is very important for normal wound healing, and receptor activity-modifying protein 1 (RAMP1) has been reported to modulate calcitonin gene-related peptide (CGRP) receptor function and thus be a potential treatment target. This study aimed to elucidate the intricate regulatory effect of RAMP1 on skin fibroblast function, thereby addressing the existing knowledge gap in this area. Methods Immunohistochemical staining and immunofluorescence (IF) staining were used to measure the dynamic changes in the expression of RAMP1 and α-smooth muscle actin (α-SMA) in skin wound tissue in mice. Mouse skin fibroblasts (MSFs) stably transfected with Tet-on-Flag-RAMP1 overexpression (OE) and Tet-on-Flag control (Ctrl) lentiviruses were constructed for in vitro experiments. High mobility group AT-hook 1 (HMGA1) plasmids and α-SMA plasmids were used to overexpress HMGA1 and α-SMA, respectively. An α-SMA siRNA was used to silence α-SMA. Quantitative real-time polymerase chain reaction (qPCR), western blot and IF staining analyses were used to determine the mRNA and protein levels in the cells in different groups. A scratch wound healing assay was used to evaluate the cell migration ability of different groups. Cleavage under targets and release using nuclease (CUT & RUN) assays and dual-luciferase reporter assays were used to predict and verify the interaction between HMGA1 and the α-SMA promoter. Results RAMP1 and α-SMA protein expression levels in the dermis changed dynamically and were negatively correlated during dorsal skin wound healing in mice. RAMP1 OE in vitro inhibited the differentiation and promoted the migration of MSFs by decreasing α-SMA expression via the suppression of HMGA1, which was shown for the first time to bind to the α-SMA promoter and increase α-SMA transcription. RAMP1 OE also modulated extracellular matrix (ECM) synthesis and remodeling by promoting collagen III and MMP9 expression and decreasing collagen I, MMP2, and tissue inhibitor of metalloproteinases 1 expression. Conclusions Our findings suggest that RAMP1 OE decreases differentiation and promotes migration in MSFs by downregulating α-SMA expression via the suppression of HMGA1 and modulates ECM synthesis and remodeling, revealing a novel mechanism regulating α-SMA transcription, providing new insights into the RAMP1-mediated regulation of fibroblast function, and identifying effective nerve-related targets for skin wound repair.
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Affiliation(s)
- Ru Song
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Jiaxu Ma
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Siyuan Yin
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Zhenjie Wu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Chunyan Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Rui Sun
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Guoqi Cao
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Yongpan Lu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Jian Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Linqi Su
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
| | - Yibing Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong 250014, P. R. China
- Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 44, Wenhua Xilu, Lixia District, Jinan, Shandong 250012, P. R. China
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Townsend KL. One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes. Diabetes 2024; 73:1967-1975. [PMID: 39401394 DOI: 10.2337/dbi24-0004] [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: 04/19/2024] [Accepted: 09/09/2024] [Indexed: 11/22/2024]
Abstract
There are key differences between the central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS), such as glial cell types, whether there is protection by the blood-brain barrier, modes of synaptic connections, etc. However, there are many more similarities between these two arms of the nervous system, including neuronal structure and function, neuroimmune and neurovascular interactions, and, perhaps most essentially, the balance between neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) and neurodegeneration (neuronal death, peripheral neuropathies like axonopathy and demyelination). This article brings together current research evidence on shared mechanisms of nervous system health and disease between the CNS and PNS, particularly with metabolic diseases like obesity and diabetes. This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms. This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study. There are likely shared and linked mechanisms for how neurons stay healthy versus undergo damage and disease among this one nervous system in the body-providing new opportunities for understanding neurological disease etiology and future development of neuroprotective therapeutics. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Kristy L Townsend
- Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH
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Wang Y, Stoess C, Holzmann G, Mogler C, Stupakov P, Altmayr F, Schulze S, Wang B, Steffani M, Friess H, Hüser N, Holzmann B, Hartmann D, Laschinger M. Signalling of the neuropeptide calcitonin gene-related peptide (CGRP) through RAMP1 promotes liver fibrosis via TGFβ1/Smad2 and YAP pathways. Exp Cell Res 2024; 442:114193. [PMID: 39103072 DOI: 10.1016/j.yexcr.2024.114193] [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: 02/01/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/07/2024]
Abstract
The liver is innervated by primary sensory nerve fibres releasing the neuropeptide calcitonin gene-related peptide (CGRP). Elevated plasma levels of CGRP have been found in patients with liver fibrosis or cirrhosis. We hypothesised that signalling of CGRP and its receptors might regulate liver fibrosis and propose a novel potential target for the treatment. In this study, hepatic expression of CGRP and its receptor component, the receptor activity-modifying protein 1 (RAMP1), was dramatically increased in diseased livers of patients. In a murine liver fibrosis model, deficiency of RAMP1 resulted in attenuated fibrogenesis characterized by less collagen deposition and decreased activity of hepatic stellate cells (HSC). Mechanistically, activity of the TGFβ1 signalling core component Smad2 was severely impaired in the absence of RAMP1, and Yes-associated protein (YAP) activity was found to be diminished in RAMP1-deficient liver parenchyma. In vitro, stimulation of the HSC line LX-2 cells with CGRP induces TGFβ1 production and downstream signalling as well as HSC activation documented by increased α-SMA expression and collagen synthesis. We further demonstrate in LX-2 cells that CGRP promotes YAP activation and its nuclear translocation subsequent to TGFβ1/Smad2 signals. These data support a promotive effect of CGRP signalling in liver fibrosis via stimulation of TGFβ1/Smad2 and YAP activity.
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Affiliation(s)
- Yang Wang
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; Department of Hepato-Pancreato-Biliary Center, Zhongda Hospital, Southeast University School of Medicine, Dingjia Road 87, 210009, Nanjing, China
| | - Christian Stoess
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Gabriela Holzmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Carolin Mogler
- Technical University of Munich, TUM School of Medicine and Health, Institute of Pathology, Trogerstr. 18, 81675, Munich, Germany
| | - Pavel Stupakov
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Felicitas Altmayr
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sarah Schulze
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Baocai Wang
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; University Hospital of Tübingen, Department of General, Visceral and Transplantation Surgery, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; The M3 Research Center, Eberhard Karls University, Otfried-Müller-Str. 37, 72076 Tübingen, Germany
| | - Marcella Steffani
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Helmut Friess
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Norbert Hüser
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Bernhard Holzmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany
| | - Daniel Hartmann
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany; University Hospital of Tübingen, Department of General, Visceral and Transplantation Surgery, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany; The M3 Research Center, Eberhard Karls University, Otfried-Müller-Str. 37, 72076 Tübingen, Germany
| | - Melanie Laschinger
- Technical University of Munich, TUM School of Medicine and Health, Department of Surgery, Klinikum rechts der Isar, Ismaninger Str. 22, 81675, Munich, Germany.
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Jiang L, Zhou Y, Tang S, Yang D, Zhang Y, Zhang J, Yang F, Zhou T, Xia X, Chen Q, Jiang L, Jiang Y, Feng X. Nociceptive adenosine A 2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma. Int J Oral Sci 2024; 16:46. [PMID: 38886342 PMCID: PMC11183250 DOI: 10.1038/s41368-024-00308-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: 12/04/2023] [Revised: 04/16/2024] [Accepted: 04/21/2024] [Indexed: 06/20/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.
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Grants
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- 82170971, 82373187, 82002888 National Natural Science Foundation of China (National Science Foundation of China)
- Fundamental Research Funds for the Central Universities (YJ201987); Sichuan Science and Technology Program (2021ZYD0090 and 2022YFS0207); Scientific Research Foundation, West China Hospital of Stomatology Sichuan University (QDJF2019-3 and RD-03-202110); CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004)
- Fundamental Research Funds for the Central Universities (YJ201987), Sichuan Science and Technology Program (2021ZYD0090 and 2022YFS0207), Scientific Research Foundation, West China Hospital of Stomatology Sichuan University (QDJF2019-3 and RD-03-202110), and CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004)
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Affiliation(s)
- Lanxin Jiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shijie Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dan Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yixin Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiuge Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fan Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Tong Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoqiang Xia
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qianming Chen
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of Stomatology, Hangzhou, China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuchen Jiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Xiaodong Feng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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9
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Tang Y, Yuan Z, Lu X, Song Y, Zhu S, Qiu C, zhang Q, Fu B, Jia C, Li H. RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway. J Clin Transl Hepatol 2024; 12:357-370. [PMID: 38638379 PMCID: PMC11022058 DOI: 10.14218/jcth.2023.00339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 01/03/2024] [Accepted: 02/02/2024] [Indexed: 04/20/2024] Open
Abstract
Background and Aims Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. Methods We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Conclusions Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.
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Affiliation(s)
- Yongsheng Tang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zenan Yuan
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xu Lu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingqiu Song
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuguang Zhu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chunhui Qiu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qi zhang
- Department of Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Binsheng Fu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Changchang Jia
- Department of Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hua Li
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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10
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Noble A, Qubrosi R, Cariba S, Favaro K, Payne SL. Neural dependency in wound healing and regeneration. Dev Dyn 2024; 253:181-203. [PMID: 37638700 DOI: 10.1002/dvdy.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/29/2023] Open
Abstract
In response to injury, humans and many other mammals form a fibrous scar that lacks the structure and function of the original tissue, whereas other vertebrate species can spontaneously regenerate damaged tissues and structures. Peripheral nerves have been identified as essential mediators of wound healing and regeneration in both mammalian and nonmammalian systems, interacting with the milieu of cells and biochemical signals present in the post-injury microenvironment. This review examines the diverse functions of peripheral nerves in tissue repair and regeneration, specifically during the processes of wound healing, blastema formation, and organ repair. We compare available evidence in mammalian and nonmammalian models, identifying critical nerve-mediated mechanisms for regeneration and providing future perspectives toward integrating these mechanisms into a therapeutic framework to promote regeneration.
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Affiliation(s)
- Alexandra Noble
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Rozana Qubrosi
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Solsa Cariba
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Kayla Favaro
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Samantha L Payne
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
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11
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Xue J, Jiang T, Humaerhan J, Wang M, Ning J, Zhao H, Aji T, Shao Y. Impact of Liver Sympathetic Nervous System on Liver Fibrosis and Regeneration After Bile Duct Ligation in Rats. J Mol Neurosci 2024; 74:4. [PMID: 38183518 DOI: 10.1007/s12031-023-02176-1] [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: 08/18/2023] [Accepted: 11/27/2023] [Indexed: 01/08/2024]
Abstract
The sympathetic nervous system (SNS) affects many functions of the body. SNS fibers regulate many aspects of liver function, repair, and regeneration. However, in the model of bile duct ligation (BDL) in rats, the kind of impact caused by the regulation of liver SNS on liver fibrosis and liver regeneration is unclear. The main research objective of this experiment is to examine the effect of SNS on liver fibrosis and liver regeneration. Twenty-four male Sprague-Dawley (SD) rats were assigned randomly to four groups. These groups included the sham surgery group (sham), model group (BDL), 6-hydroxydopamine group (BDL+6-OHDA), and spinal cord injury group (BDL+SCI). In the sham group, only exploratory laparotomy was performed without BDL. In the 6-OHDA group, 6-OHDA was used to remove sympathetic nerves after BDL. In the spinal cord injury group, rats underwent simultaneous BDL and spinal cord injury. After 3 weeks of feeding, four groups of rats were euthanized using high-dose anesthesia without pain. Moreover, liver tissue and blood were taken to detect liver fibrosis and regeneration indicators. After intraperitoneal injection of 6-OHDA into BDL rats, liver fibrosis indicators decreased. The administration of the injection effectively alleviated liver fibrosis and inhibited liver regeneration. However, after SCI surgery in BDL rats, liver fibrosis indicators increased. This resulted in exacerbating liver fibrosis and activating liver regeneration. The SNS plays a role in contributing to the liver injury process in the rat BDL model. Therefore, regulating the SNS may become a novel method for liver injury treatment.
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Affiliation(s)
- Junlong Xue
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Tiemin Jiang
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Clinical Medical College of Xinjiang Medical University, Urumqi, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Jiayidaer Humaerhan
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Maolin Wang
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Jianghong Ning
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Hanyue Zhao
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- The First Clinical Medical, College of Xinjiang Medical University, Urumqi, 830054, China
| | - Tuerganaili Aji
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
- State Key Laboratory of Pathogenesis, Prevention and Management of High Incidence Diseases in Central Asia, The First Clinical Medical College of Xinjiang Medical University, Urumqi, China
| | - Yingmei Shao
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China.
- Xinjiang Clinical Research Center for Echinococcosis and Hepatobiliary Diseases, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
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12
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Sun W, Ye B, Chen S, Zeng L, Lu H, Wan Y, Gao Q, Chen K, Qu Y, Wu B, Lv X, Guo X. Neuro-bone tissue engineering: emerging mechanisms, potential strategies, and current challenges. Bone Res 2023; 11:65. [PMID: 38123549 PMCID: PMC10733346 DOI: 10.1038/s41413-023-00302-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 12/23/2023] Open
Abstract
The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.
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Affiliation(s)
- Wenzhe Sun
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bing Ye
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Siyue Chen
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lian Zeng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hongwei Lu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yizhou Wan
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qing Gao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaifang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yanzhen Qu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bin Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
| | - Xiaodong Guo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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13
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Wei Y, Hui VLZ, Chen Y, Han R, Han X, Guo Y. YAP/TAZ: Molecular pathway and disease therapy. MedComm (Beijing) 2023; 4:e340. [PMID: 37576865 PMCID: PMC10412783 DOI: 10.1002/mco2.340] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/27/2023] [Accepted: 07/04/2023] [Indexed: 08/15/2023] Open
Abstract
The Yes-associated protein and its transcriptional coactivator with PDZ-binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism-related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ-induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.
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Affiliation(s)
- Yuzi Wei
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Victoria Lee Zhi Hui
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Yilin Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Ruiying Han
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Xianglong Han
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Yongwen Guo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
- Department of OrthodonticsLanzhou Stomatological HospitalLanzhouGansuChina
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14
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Sun M, Wan Y, Shi M, Meng ZX, Zeng W. Neural innervation in adipose tissue, gut, pancreas, and liver. LIFE METABOLISM 2023; 2:load022. [PMID: 39872245 PMCID: PMC11749697 DOI: 10.1093/lifemeta/load022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/22/2023] [Accepted: 06/05/2023] [Indexed: 01/30/2025]
Abstract
Efficient communication between the brain and peripheral organs is indispensable for regulating physiological function and maintaining energy homeostasis. The peripheral nervous system (PNS) in vertebrates, consisting of the autonomic and somatic nervous systems, bridges the peripheral organs and the central nervous system (CNS). Metabolic signals are processed by both vagal sensory nerves and somatosensory nerves. The CNS receives sensory inputs via ascending nerves, serves as the coordination and integration center, and subsequently controls internal organs and glands via descending nerves. The autonomic nervous system consists of sympathetic and parasympathetic branches that project peripheral nerves into various anatomical locations to regulate the energy balance. Sympathetic and parasympathetic nerves typically control the reflexive and involuntary functions in organs. In this review article, we outline the innervation of adipose tissue, gut, pancreas, and liver, to illustrate the neurobiological basis of central-peripheral interactions. We emphasize the importance of understanding the functional atlas of neural control of energy metabolism, and more importantly, provide potential avenues for further research in this area.
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Affiliation(s)
- Mengxue Sun
- Institute for Immunology and School of Medicine, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Yongwen Wan
- Institute for Immunology and School of Medicine, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Mengjie Shi
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Zhuo-Xian Meng
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Wenwen Zeng
- Institute for Immunology and School of Medicine, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
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15
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Jiang Y, Zhu Z, Wang B, Yuan Y, Zhang Q, Li Y, Du Y, Gong P. Neuronal TRPV1-CGRP axis regulates bone defect repair through Hippo signaling pathway. Cell Signal 2023:110779. [PMID: 37336315 DOI: 10.1016/j.cellsig.2023.110779] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed on sensory neurons where it serves as a polymodal receptor for detecting physical and chemical stimuli. However, the role of TRPV1 in bone metabolism remains largely unclear. This study aimed to investigate the underlying mechanism of neuronal TRPV1 in regulating bone defect repair. In vivo experiment verified that TRPV1 activation could trigger dorsal root ganglion (DRG) producing the neuropeptide calcitonin gene-related peptide (CGRP) in mice. The accelerated bone healing of femoral defect in this process was observed compared to the control group (p < 0.05). Conversely, Trpv1 knockdown led to the reduced CGRP expression in DRG and nerves innervating femur bone tissue, following impaired bone formation and osteogenic capability in the defect region (p < 0.05), which could be rescued by local CGRP treatment. In vitro, results revealed that TRPV1 function in DRG neurons contributed essentially to the regulation of osteoblast physiology through affecting the production and secretion of CGRP. The capsaicin-activated neuronal TRPV1-CGRP axis could enhance the proliferation, migration and differentiation of osteoblasts (p < 0.05). Furthermore, we found that the promoting role of neuronal TRPV1 in osteogenesis were associated with Hippo signaling pathway, reflected by the phosphorylation protein level of large tumor suppressor 1 (LATS1), MOB kinase activator 1 (MOB1) and Yes-associated protein (YAP), as well as the subcellular location of YAP. Our study clarified the effects and intrinsic mechanisms of neuronal TRPV1 on bone defect repair, which might offer us a therapeutic implication for bone disorders.
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Affiliation(s)
- Yixuan Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhanfeng Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bin Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanxi Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Du
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Mancinelli R, Ceci L, Kennedy L, Francis H, Meadows V, Chen L, Carpino G, Kyritsi K, Wu N, Zhou T, Sato K, Pannarale L, Glaser S, Chakraborty S, Alpini G, Gaudio E, Onori P, Franchitto A. The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling. Cells 2022; 11:1591. [PMID: 35563897 PMCID: PMC9104610 DOI: 10.3390/cells11091591] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/07/2022] [Accepted: 05/04/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND & AIMS Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3',5'-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. METHODS Wild-type and α-CGRP-/- mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. RESULTS TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP-/- mice fed TC coupled with changes in hepatic BA composition. CONCLUSION Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.
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Affiliation(s)
- Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy;
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA; (S.G.); (S.C.)
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University, Bryan, TX 77807, USA; (S.G.); (S.C.)
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (L.C.); (L.K.); (H.F.); (V.M.); (L.C.); (K.K.); (N.W.); (T.Z.); (K.S.); (G.A.)
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (L.P.); (E.G.); (P.O.)
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Yin S, Song R, Ma J, Liu C, Wu Z, Cao G, Liu J, Zhang G, Zhang H, Sun R, Chen A, Wang Y. Receptor activity-modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis. Cell Commun Signal 2022; 20:52. [PMID: 35413847 PMCID: PMC9004193 DOI: 10.1186/s12964-022-00852-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 03/01/2022] [Indexed: 01/13/2023] Open
Abstract
Background Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity‐modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation. Methods In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions. Results RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation. Conclusions Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment.
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