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Wen W, Li H, Lauffer M, Hu D, Zhang Z, Lin H, Wang Y, Leidinger M, Luo J. Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice. Front Pharmacol 2024; 15:1407576. [PMID: 39130640 PMCID: PMC11310019 DOI: 10.3389/fphar.2024.1407576] [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: 03/26/2024] [Accepted: 07/09/2024] [Indexed: 08/13/2024] Open
Abstract
Excessive alcohol exposure can cause neurobehavioral deficits and structural alterations in the brain. Emerging research evidence suggests that endoplasmic reticulum (ER) stress plays an important role in alcohol-induced neurotoxicity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein and is responsible to maintain ER homeostasis. MANF is highly expressed in both the developing and mature brain. We have previously shown that MANF deficiency exacerbated alcohol induced neurodegeneration and ER stress in the developing brain. However, little is known regarding the role of MANF in alcohol induced neuronal damage in the adult brain. In this study, we used a neuron-specific MANF knockout (KO) mouse model to investigate the effect of MANF deficiency on acute binge alcohol exposure-induced neurobehavioral deficits and ER stress. Adult male and female MANF KO mice and littermate controls received daily alcohol gavage (5 g/kg) for 10 days and then subjected to a battery of neurobehavioral tests including rotarods, balance beam, DigiGait, open field, elevated plus maze, Barnes maze, and three-chamber sociability task. Female MANF KO animals were more susceptible to alcohol-induced body weight loss. Alcohol exposure did not affect motor function, however female but not male MANF KO mice exhibited an increased locomotor activity in open field test. Learning and memory was not significantly impaired, but it was altered by MANF deficiency in females while it was affected by alcohol treatment in males. Both alcohol-exposed male and female MANF KO mice displayed increased sociability. Alcohol induced the expression of ER chaperones GRP78 and GRP94 and altered the levels of several unfolded protein response (UPR) and neuroinflammation markers in MANF KO mice in a sex-specific manner. The expression of MANF interacting proteins neuroplastin, PDIA1, and PDIA6 was increased in MANF KO mice, and was further induced by alcohol. In conclusion, alcohol exposure and neuronal MANF deficiency interacted to alter neurobehavioral outcomes, ER homeostasis and neuroinflammation in a sex-specific manner.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Marisol Lauffer
- Neural Circuits and Behavior Core, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Di Hu
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Zuohui Zhang
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Hong Lin
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Yongchao Wang
- Vanderbilt Memory and Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Mariah Leidinger
- Comparative Pathology Laboratory, University of Iowa Carver College of Medicine, Iowa City, IA, United States
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
- Iowa City VA Health Care System, Iowa City, IA, United States
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2
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Kulesskaya N, Bhattacharjee A, Holmström KM, Vuorio P, Henriques A, Callizot N, Huttunen HJ. HER-096 is a CDNF-derived brain-penetrating peptidomimetic that protects dopaminergic neurons in a mouse synucleinopathy model of Parkinson's disease. Cell Chem Biol 2024; 31:593-606.e9. [PMID: 38039968 DOI: 10.1016/j.chembiol.2023.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 09/28/2023] [Accepted: 11/07/2023] [Indexed: 12/03/2023]
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models. HER-096 is metabolically stable and able to penetrate to cerebrospinal (CSF) and brain interstitial fluids (ISF) after subcutaneous administration, with an extended CSF and brain ISF half-life compared to plasma. Subcutaneously administered HER-096 modulated UPR pathway activity, protected dopamine neurons, and reduced α-synuclein aggregates and neuroinflammation in substantia nigra of aged mice with synucleinopathy. Peptidomimetic HER-096 is a candidate for development of a disease-modifying therapy for Parkinson's disease with a patient-friendly route of administration.
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Gong L, Dong J, Huang K, Pan K, Wang S, Liu H. Effect of mesencephalic astrocyte-derived neurotrophic factor on the inflammatory response in human gingival fibroblasts cells. Eur J Oral Sci 2023; 131:e12945. [PMID: 37461146 DOI: 10.1111/eos.12945] [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: 01/12/2023] [Accepted: 07/06/2023] [Indexed: 11/04/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a unique member of the neurotrophic factor family residing in the endoplasmic reticulum, where it functions as a stress response protein maintaining endoplasmic reticulum homeostasis, in addition to being secreted extracellularly as a neurotrophic factor to bind with receptors to initiate intracellular signal transduction pathways. Interestingly, MANF has shown an important protective role in the inflammatory response of many diseases. In neural stem cells, pancreatic β cells, and retinal cells, MANF can inhibit the inflammatory response, modulate the immune response, and promote tissue repair. However, the role of MANF in the periodontal inflammatory response remains unclear. In the present study, we used lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg) to establish a Pg-LPS-stimulated periodontal inflammatory model in human gingival fibroblasts cells (HGF-1) to investigate the role of MANF in vitro. We found that MANF could inhibit pro-inflammatory cytokine secretion, alleviate the endoplasmic reticulum stress response, promote cell survival, and inhibit cell apoptosis. Therefore, MANF might be a novel promising target for the treatment of periodontitis.
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Affiliation(s)
- Lei Gong
- Department of Laboratory Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Jie Dong
- Department of Laboratory Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Kai Huang
- College of Stomatology, Binzhou Medical University, Yantai, Shandong, China
| | - Keqing Pan
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shengzhi Wang
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Hao Liu
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
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Kim JH, Irfan M, Hossain MA, George A, Chung S. BDNF/TrkB Is a Crucial Regulator in the Inflammation-Mediated Odontoblastic Differentiation of Dental Pulp Stem Cells. Cells 2023; 12:1851. [PMID: 37508514 PMCID: PMC10378460 DOI: 10.3390/cells12141851] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there is a link between inflammation and dental tissue regeneration, identified via enhanced DPSC-mediated dentinogenesis in vitro. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor-related gene family molecule which functions through tropomyosin receptor kinase B (TrkB). While the roles of BDNF in neural tissue repair and other regeneration processes are well identified, its role in dentinogenesis has not been explored. Furthermore, the role of BDNF receptor-TrkB in inflammation-induced dentinogenesis remains unknown. The role of BDNF/TrkB was examined during a 17-day odontogenic differentiation of DPSCs. Human DPSCs were subjected to odontogenic differentiation in dentinogenic media treated with inflammation inducers (LTA or TNFα), BDNF, and a TrkB agonist (LM22A-4) and/or antagonist (CTX-B). Our data show that BDNF and TrkB receptors affect the early and late stages of the odontogenic differentiation of DPSCs. Immunofluorescent data confirmed the expression of BDNF and TrkB in DPSCs. Our ELISA and qPCR data demonstrate that TrkB agonist treatment increased the expression of dentin matrix protein-1 (DMP-1) during early DPSC odontoblastic differentiation. Coherently, the expression levels of runt-related transcription factor 2 (RUNX-2) and osteocalcin (OCN) were increased. TNFα, which is responsible for a diverse range of inflammation signaling, increased the levels of expression of dentin sialophosphoprotein (DSPP) and DMP1. Furthermore, BDNF significantly potentiated its effect. The application of CTX-B reversed this effect, suggesting TrkB`s critical role in TNFα-mediated dentinogenesis. Our studies provide novel findings on the role of BDNF-TrkB in the inflammation-induced odontoblastic differentiation of DPSCs. This finding will address a novel regulatory pathway and a therapeutic approach in dentin tissue engineering using DPSCs.
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Affiliation(s)
| | | | | | | | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA; (J.-H.K.); (M.I.); (M.A.H.); (A.G.)
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Caglayan AB, Beker MC, Sertel Evren E, Caglayan B, Kilic Ü, Ates N, Caglayan A, Dasdelen MF, Doeppner TR, Saarma M, Hermann DM, Kilic E. The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte-Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity. Transl Stroke Res 2023; 14:263-277. [PMID: 35583716 DOI: 10.1007/s12975-022-01035-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 12/22/2022]
Abstract
Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.
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Affiliation(s)
- Ahmet Burak Caglayan
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- International School of Medicine, Department of Physiology, Istanbul Medipol University, Istanbul, Turkey
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
| | - Mustafa Caglar Beker
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Elif Sertel Evren
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Berrak Caglayan
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- International School of Medicine, Dept. of Medical Biology, Istanbul Medipol University, Istanbul, Turkey
| | - Ülkan Kilic
- Hamidiye School of Medicine, Department of Medical Biology, University of Health Sciences Turkey, Istanbul, Turkey
| | - Nilay Ates
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- Faculty of Medicine, Department of Pharmacology, Istanbul Medipol University, Istanbul, Turkey
| | - Aysun Caglayan
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Muhammed Furkan Dasdelen
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Thorsten Roland Doeppner
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- Department of Neurology, University Hospital Giessen, Giessen, Germany
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Dirk Matthias Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ertugrul Kilic
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey.
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey.
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Palasz E, Wilkaniec A, Stanaszek L, Andrzejewska A, Adamczyk A. Glia-Neurotrophic Factor Relationships: Possible Role in Pathobiology of Neuroinflammation-Related Brain Disorders. Int J Mol Sci 2023; 24:ijms24076321. [PMID: 37047292 PMCID: PMC10094105 DOI: 10.3390/ijms24076321] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 03/30/2023] Open
Abstract
Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs can lead to many diseases of the nervous system, including degenerative diseases, mental diseases, and neurodevelopmental disorders. Each CNS disease is characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation, dysregulation of NTFs levels, or mitochondrial dysfunction. It has been shown that NTFs can control the activation of glial cells by directing them toward a neuroprotective and anti-inflammatory phenotype and activating signaling pathways responsible for neuronal survival. In this review, our goal is to outline the current state of knowledge about the processes affected by NTFs, the crosstalk between NTFs, mitochondria, and the nervous and immune systems, leading to the inhibition of neuroinflammation and oxidative stress, and thus the inhibition of the development and progression of CNS disorders.
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Affiliation(s)
- Ewelina Palasz
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Correspondence: (E.P.); (A.A.)
| | - Anna Wilkaniec
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Luiza Stanaszek
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Anna Andrzejewska
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Agata Adamczyk
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Correspondence: (E.P.); (A.A.)
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Sousa NS, Brás MF, Antunes IB, Lindholm P, Neves J, Sousa-Victor P. Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration. NATURE AGING 2023; 3:585-599. [PMID: 37118549 DOI: 10.1038/s43587-023-00382-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 02/16/2023] [Indexed: 04/30/2023]
Abstract
Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet the contribution of immune dysfunction to regenerative failure is unknown. Macrophages are essential for effective debris clearance and muscle stem cell activity during muscle regeneration, but the regulatory mechanisms governing macrophage function during muscle repair are largely unexplored. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator mesencephalic astrocyte-derived neurotrophic factor (MANF) is induced following muscle injury in young mice but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring MANF levels is a viable strategy to improve myeloid response and regenerative capacity in aged muscle.
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Affiliation(s)
- Neuza S Sousa
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Margarida F Brás
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Inês B Antunes
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Joana Neves
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
| | - Pedro Sousa-Victor
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
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Huang X, Guo M, Zhang Y, Xie J, Huang R, Zuo Z, Saw PE, Cao M. Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion. Glia 2023; 71:1607-1625. [PMID: 36929654 DOI: 10.1002/glia.24359] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/07/2023] [Accepted: 03/03/2023] [Indexed: 03/18/2023]
Abstract
Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.
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Affiliation(s)
- Xiaoyan Huang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Mingyan Guo
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yangfan Zhang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiatian Xie
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Rong Huang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA
| | - Phei Er Saw
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Minghui Cao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.,Department of Anesthesiology, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Shanwei, China
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9
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Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage. Cell Death Dis 2023; 14:128. [PMID: 36792604 PMCID: PMC9932138 DOI: 10.1038/s41419-022-05520-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 02/17/2023]
Abstract
During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH.
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Cheng L, Liang Z, You X, Jia C, Liu Z, Sun F. The Role of the Mesencephalic Astrocyte-Derived Neurotrophic Factor in Patients in Intensive Care Units Receiving Voriconazole Therapy. J Clin Pharmacol 2023; 63:604-612. [PMID: 36609957 DOI: 10.1002/jcph.2201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023]
Abstract
Recent publications regarding the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in various metabolic and degenerative disorders suggest that MANF is both a marker of disease and a possible therapeutic agent. We investigate the role of plasma MANF levels in patients in intensive care units (ICUs) receiving voriconazole (VCZ) therapy while also comparing MANF levels in healthy individuals. A single-center prospective study was conducted. The plasma MANF level in patients in ICU was found to have high interindividual variability and was significantly higher than that in healthy controls (P < .01). Compared with patients using VCZ only, patients using both VCZ and amikacin had 3-fold lower MANF concentrations (P < .05). The MANF concentrations also decreased when alkaline phosphatase (ALP) and serum creatinine levels were above the upper limits of the normal range (P < .05) and the estimated glomerular filtration rate (eGFR) was below the lower limit of the normal range (P < .01). Receiver operating characteristic curve analysis indicated that low MANF levels were associated with high ALP levels, high creatinine levels, and low eGFR. The cut-off value of MANF for ALP levels higher than 126 U/L was 0.35 ng/mL (area under curve, AUC = 0.62, 95%CI = 0.50-0.74, P = .044); for serum creatinine levels higher than 104 μmol/L, the cut-off value was 0.41 ng/mL (AUC = 0.74, 95%CI = 0.62-0.87, P = .001); and for eGFR below 80 mL/min, the cut-off value was 0.75 ng/mL (AUC = 0.70, 95%CI = 0.59-0.81, P = .002). Monitoring plasma MANF levels may be of value for clinical decision-making regarding the choice of antibiotics and the prediction of impaired liver function and renal function in patients admitted to an ICU.
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Affiliation(s)
- Lin Cheng
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
| | - Zaiming Liang
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
| | - Xi You
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
| | - Changsheng Jia
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhirui Liu
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
| | - Fengjun Sun
- Department of Pharmacy, The First Affiliated Hospital of the Army Medical University (Third Military Medical University), Chongqing, China
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11
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Xu HY, Jiao YH, Li SY, Zhu X, Wang S, Zhang YY, Wei YJ, Shen YJ, Wang W, Shen YX, Shao JT. Hepatocyte-derived MANF mitigates ethanol-induced liver steatosis in mice via enhancing ASS1 activity and activating AMPK pathway. Acta Pharmacol Sin 2023; 44:157-168. [PMID: 35655095 DOI: 10.1038/s41401-022-00920-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/05/2022] [Indexed: 02/06/2023]
Abstract
Hepatic steatosis plays a detrimental role in the onset and progression of alcohol-associated liver disease (ALD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved protein related to the unfolded protein response. Recent studies have demonstrated that MANF plays an important role in liver diseases. In this study, we investigated the role of MANF in ethanol-induced steatosis and the underlying mechanisms. We showed that the hepatic MANF expression was markedly upregulated in mouse model of ALD by chronic-plus-single-binge ethanol feeding. Moreover, after chronic-plus-binge ethanol feeding, hepatocyte-specific MANF knockout (HKO) mice displayed more severe hepatic steatosis and liver injury than wild-type (WT) control mice. Immunoprecipitation-coupled MS proteomic analysis revealed that arginosuccinate synthase 1 (ASS1), a rate-limiting enzyme in the urea cycle, resided in the same immunoprecipitated complex with MANF. Hepatocyte-specific MANF knockout led to decreased ASS1 activity, whereas overexpression of MANF contributed to enhanced ASS1 activity in vitro. In addition, HKO mice displayed unique urea cycle metabolite patterns in the liver with elevated ammonia accumulation after ethanol feeding. ASS1 is known to activate AMPK by generating an intracellular pool of AMP from the urea cycle. We also found that MANF supplementation significantly ameliorated ethanol-induced steatosis in vivo and in vitro by activating the AMPK signaling pathway, which was partly ASS1 dependent. This study demonstrates a new mechanism in which MANF acts as a key molecule in maintaining hepatic lipid homeostasis by enhancing ASS1 activity and uncovers an interesting link between lipid metabolism and the hepatic urea cycle under excessive alcohol exposure.
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Affiliation(s)
- Han-Yang Xu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yan-Hong Jiao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Shi-Yu Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Xu Zhu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Sheng Wang
- Center for Scientific Research of Anhui Medical University, Hefei, 230032, China
| | - Yu-Yang Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yi-Jun Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yu-Jun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Yu-Xian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
| | - Jun-Tang Shao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
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12
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Rauchman SH, Zubair A, Jacob B, Rauchman D, Pinkhasov A, Placantonakis DG, Reiss AB. Traumatic brain injury: Mechanisms, manifestations, and visual sequelae. Front Neurosci 2023; 17:1090672. [PMID: 36908792 PMCID: PMC9995859 DOI: 10.3389/fnins.2023.1090672] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Traumatic brain injury (TBI) results when external physical forces impact the head with sufficient intensity to cause damage to the brain. TBI can be mild, moderate, or severe and may have long-term consequences including visual difficulties, cognitive deficits, headache, pain, sleep disturbances, and post-traumatic epilepsy. Disruption of the normal functioning of the brain leads to a cascade of effects with molecular and anatomical changes, persistent neuronal hyperexcitation, neuroinflammation, and neuronal loss. Destructive processes that occur at the cellular and molecular level lead to inflammation, oxidative stress, calcium dysregulation, and apoptosis. Vascular damage, ischemia and loss of blood brain barrier integrity contribute to destruction of brain tissue. This review focuses on the cellular damage incited during TBI and the frequently life-altering lasting effects of this destruction on vision, cognition, balance, and sleep. The wide range of visual complaints associated with TBI are addressed and repair processes where there is potential for intervention and neuronal preservation are highlighted.
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Affiliation(s)
| | - Aarij Zubair
- NYU Long Island School of Medicine, Mineola, NY, United States
| | - Benna Jacob
- NYU Long Island School of Medicine, Mineola, NY, United States
| | - Danielle Rauchman
- Department of Neuroscience, University of California, Santa Barbara, Santa Barbara, CA, United States
| | - Aaron Pinkhasov
- NYU Long Island School of Medicine, Mineola, NY, United States
| | | | - Allison B Reiss
- NYU Long Island School of Medicine, Mineola, NY, United States
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13
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Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model. Biomedicines 2022; 10:biomedicines10061446. [PMID: 35740467 PMCID: PMC9221078 DOI: 10.3390/biomedicines10061446] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/08/2022] [Accepted: 06/11/2022] [Indexed: 11/30/2022] Open
Abstract
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.
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14
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Wen W, Li H, Luo J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 2022; 59:2992-3015. [PMID: 35254650 PMCID: PMC10928853 DOI: 10.1007/s12035-022-02786-7] [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: 11/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
- Iowa City VA Health Care System, Iowa City, IA, 52246, USA.
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15
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Lindholm P, Saarma M. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry 2022; 27:1310-1321. [PMID: 34907395 PMCID: PMC9095478 DOI: 10.1038/s41380-021-01394-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022]
Abstract
Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf-/- mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.
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Affiliation(s)
- Päivi Lindholm
- grid.7737.40000 0004 0410 2071Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014 Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014, Helsinki, Finland.
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16
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de Seny D, Baiwir D, Bianchi E, Cobraiville G, Deroyer C, Poulet C, Malaise O, Paulissen G, Kaiser MJ, Hauzeur JP, Mazzucchelli G, Delvenne P, Malaise M. New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases. Int J Mol Sci 2021; 23:ijms23010434. [PMID: 35008858 PMCID: PMC8745719 DOI: 10.3390/ijms23010434] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 01/15/2023] Open
Abstract
An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.
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Affiliation(s)
- Dominique de Seny
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
- Correspondence: ; Tel.: +32-366-24-74
| | - Dominique Baiwir
- GIGA Proteomics Facility, University of Liège, 4000 Liège, Belgium; (D.B.); (P.D.)
| | - Elettra Bianchi
- Department of Pathology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium;
| | - Gaël Cobraiville
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Céline Deroyer
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Christophe Poulet
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Olivier Malaise
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Geneviève Paulissen
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Marie-Joëlle Kaiser
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Jean-Philippe Hauzeur
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
| | - Gabriel Mazzucchelli
- Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, 4000 Liège, Belgium;
| | - Philippe Delvenne
- GIGA Proteomics Facility, University of Liège, 4000 Liège, Belgium; (D.B.); (P.D.)
| | - Michel Malaise
- Laboratory and Service of Rheumatology, GIGA Research, Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; (G.C.); (C.D.); (C.P.); (O.M.); (G.P.); (M.-J.K.); (J.-P.H.); (M.M.)
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17
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Welleford AS, Quintero JE, Seblani NE, Blalock E, Gunewardena S, Shapiro SM, Riordan SM, Huettl P, Guduru Z, Stanford JA, van Horne CG, Gerhardt GA. RNA Sequencing of Human Peripheral Nerve in Response to Injury: Distinctive Analysis of the Nerve Repair Pathways. Cell Transplant 2021; 29:963689720926157. [PMID: 32425114 PMCID: PMC7563818 DOI: 10.1177/0963689720926157] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson’s disease, ranging in age between 53 and 70 yr. Two weeks after the initial injury, another section of the nerve fascicles of the distal and pre-degenerated stump of the nerve was dissected and processed for RNA-seq studies. An initial analysis between the pre-lesion status and the postinjury gene expression revealed 3,641 genes that were significantly differentially expressed. In addition, the results support a clear transdifferentiation process that occurred by the end of the 2-wk postinjury. Gene ontology (GO) and hierarchical clustering were used to identify the major signaling pathways affected by the injury. In contrast to previous nonclinical studies, important changes were observed in molecular pathways related to antiapoptotic signaling, neurotrophic factor processes, cell motility, and immune cell chemotactic signaling. The results of our current study provide new insights regarding the essential interactions of different molecular pathways that drive neuronal repair and axonal regeneration in humans.
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Affiliation(s)
- Andrew S Welleford
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA.,* These are co-first authors and have contributed equally to this article
| | - Jorge E Quintero
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA.,Department of Neurosurgery, University of Kentucky Medical Center, Lexington, KY, USA.,* These are co-first authors and have contributed equally to this article
| | - Nader El Seblani
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA.,Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.,* These are co-first authors and have contributed equally to this article
| | - Eric Blalock
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA
| | - Sumedha Gunewardena
- Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, KS, USA
| | - Steven M Shapiro
- Division of Neurology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.,Department of Molecular and Integrative Physiology, University of Kansas Medical Center, KS, USA
| | - Sean M Riordan
- Division of Neurology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA
| | - Peter Huettl
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA
| | - Zain Guduru
- Department of Neurology, University of Kentucky Medical Center, Lexington, KY, USA
| | - John A Stanford
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, KS, USA
| | - Craig G van Horne
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA.,Department of Neurosurgery, University of Kentucky Medical Center, Lexington, KY, USA
| | - Greg A Gerhardt
- Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA.,Brain Restoration Center, University of Kentucky, Lexington, KY, USA.,Department of Neurosurgery, University of Kentucky Medical Center, Lexington, KY, USA.,Department of Neurology, University of Kentucky Medical Center, Lexington, KY, USA
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18
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Tejedor G, Luz-Crawford P, Barthelaix A, Toupet K, Roudières S, Autelitano F, Jorgensen C, Djouad F. MANF Produced by MRL Mouse-Derived Mesenchymal Stem Cells Is Pro-regenerative and Protects From Osteoarthritis. Front Cell Dev Biol 2021; 9:579951. [PMID: 33738280 PMCID: PMC7960785 DOI: 10.3389/fcell.2021.579951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 02/02/2021] [Indexed: 12/16/2022] Open
Abstract
The super healer Murphy Roths Large (MRL) mouse represents the “holy grail” of mammalian regenerative model to decipher the key mechanisms that underlies regeneration in mammals. At a time when mesenchymal stem cell (MSC)-based therapy represents the most promising approach to treat degenerative diseases such as osteoarthritis (OA), identification of key factors responsible for the regenerative potential of MSC derived from MRL mouse would be a major step forward for regenerative medicine. In the present study, we assessed and compared MSC derived from MRL (MRL MSC) and C57BL/6 (BL6 MSC) mice. First, we compare the phenotype and the differentiation potential of MRL and BL6 MSC and did not observe any difference. Then, we evaluated the proliferation and migration potential of the cells and found that while MRL MSC proliferate at a slower rate than BL6 MSC, they migrate at a significantly higher rate. This higher migration potential is mediated, in part, by MRL MSC-secreted products since MRL MSC conditioned medium that contains a complex of released factors significantly increased the migration potential of BL6 MSC. A comparative analysis of the secretome by quantitative shotgun proteomics and Western blotting revealed that MRL MSC produce and release higher levels of mesencephalic astrocyte-derived neurotrophic factor (MANF) as compared to MSC derived from BL6, BALB/c, and DBA1 mice. MANF knockdown in MRL MSC using a specific small interfering RNA (siRNA) reduced both MRL MSC migration potential in scratch wound assay and their regenerative potential in the ear punch model in BL6 mice. Finally, injection of MRL MSC silenced for MANF did not protect mice from OA development. In conclusion, our results evidence that the enhanced regenerative potential and protection from OA of MRL mice might be, in part, attributed to their MSC, an effective reservoir of MANF.
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Affiliation(s)
- Gautier Tejedor
- IRMB, INSERM, University of Montpellier, Montpellier, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | | | - Karine Toupet
- IRMB, INSERM, University of Montpellier, Montpellier, France
| | | | | | - Christian Jorgensen
- IRMB, INSERM, University of Montpellier, Montpellier, France.,Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Farida Djouad
- IRMB, INSERM, University of Montpellier, Montpellier, France
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19
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Schmidt E, Raposo P, Vavrek R, Fouad K. Inducing inflammation following subacute spinal cord injury in female rats: A double-edged sword to promote motor recovery. Brain Behav Immun 2021; 93:55-65. [PMID: 33358981 DOI: 10.1016/j.bbi.2020.12.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 11/20/2020] [Accepted: 12/16/2020] [Indexed: 12/20/2022] Open
Abstract
The inflammatory response following spinal cord injury is associated with increased tissue damage and impaired functional recovery. However, inflammation can also promote plasticity and the secretion of growth-promoting substances. Previously we have shown that inducing inflammation with a systemic injection of lipopolysaccharide in the chronic (8 weeks) stage of spinal cord injury enhances neuronal sprouting and the efficacy of rehabilitative training in rats. Here, we tested whether administration of lipopolysaccharide in female rats in the subacute (10 days) stage of spinal cord injury would have a similar effect. Since the lesioned environment is already in a pro-inflammatory state at this earlier time after injury, we hypothesized that triggering a second immune response may not be beneficial for recovery. Contrary to our hypothesis, we found that eliciting an inflammatory response 10 days after spinal cord injury enhanced the recovery of the ipsilesional forelimb in rehabilitative training. Compared to rats that received rehabilitative training without treatment, rats that received systemic lipopolysaccharide showed restored motor function without the use of compensatory strategies that translated beyond the trained task. Furthermore, lipopolysaccharide treatment paradoxically promoted the resolution of chronic neuroinflammation around the lesion site. Unfortunately, re-triggering a systemic immune response after spinal cord injury also resulted in a long-term increase in anxiety-like behaviour.
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Affiliation(s)
- Emma Schmidt
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Pamela Raposo
- Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
| | - Romana Vavrek
- Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
| | - Karim Fouad
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada; Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada.
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20
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Wu H, Li H, Wen W, Wang Y, Xu H, Xu M, Frank JA, Wei W, Luo J. MANF protects pancreatic acinar cells against alcohol-induced endoplasmic reticulum stress and cellular injury. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:883-892. [PMID: 33644980 DOI: 10.1002/jhbp.928] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/31/2021] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND/PURPOSE Heavy alcohol drinking is associated with pancreatitis. Pancreatitis is initiated by the damage to the pancreatic acinar cells. The endoplasmic reticulum (ER) stress has been shown to play an important role in alcohol-induced pancreatic damage. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible protein. The aim of the study was to determine whether MANF can ameliorate alcohol-induced ER stress and cellular damages to pancreatic acinar cells. METHODS Alcohol-induced damage to mouse pancreatic 266-6 acinar cells was determined by MTT and flow cytometry. MANF expression was downregulated by MANF siRNA using the Neon Transfection System. The overexpression of MANF was performed by the infection with the adenoviral vector carrying mouse MANF gene. The expression of ER stress markers was determined by immunoblotting and immunofluorescence. RESULTS Alcohol caused ER stress, oxidative stress and induced apoptosis of 266-6 acinar cells. Recombinant human MANF alleviated alcohol-induced ER stress and cell death by inhibiting IRE1-caspase 12-caspase 3 apoptotic pathway. Overexpression of mouse MANF also protected cells against alcohol-induced apoptosis. In contrast, inhibiting MANF by siRNA exacerbated alcohol-induced cellular damage. CONCLUSIONS MANF was protective against alcohol-induced ER stress and cellular injury in pancreatic acinar cells. The findings suggest a potential therapeutic value of MANF for alcoholic pancreatitis.
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Affiliation(s)
- Huaxun Wu
- Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Yongchao Wang
- Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Jacqueline A Frank
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Wei Wei
- Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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21
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Yang F, Li WB, Qu YW, Gao JX, Tang YS, Wang DJ, Pan YJ. Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling. World J Stem Cells 2020; 12:633-658. [PMID: 32843919 PMCID: PMC7415242 DOI: 10.4252/wjsc.v12.i7.633] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/04/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced brain repair. However, the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear. Recent evidence suggests that mesencephalic astrocyte–derived neurotrophic factor (MANF) and platelet-derived growth factor-AA (PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization.
AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization.
METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression. Using a rat middle cerebral artery occlusion (MCAO) model transplanted by BMSCs and BMSCs–microglia Transwell coculture system, the effect of BMSCs-induced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence. Additionally, microglia were transfected with mimics of miR-30a*, which influenced expression of X-box binding protein (XBP) 1, a key transcription factor that synergized with activating transcription factor 6 (ATF6) to govern MANF expression. We examined the levels of miR-30a*, ATF6, XBP1, and MANF after PDGF-AA treatment in the activated microglia.
RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production, but increased M1 marker expression in vivo or in vitro. Furthermore, PDGF-AA treatment decreased miR-30a* expression, had no influence on the levels of ATF6, but enhanced expression of both XBP1 and MANF.
CONCLUSION BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.
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Affiliation(s)
- Fan Yang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wen-Bin Li
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ye-Wei Qu
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jin-Xing Gao
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Shi Tang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Dong-Jie Wang
- Department of Respiratory Medicine, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Jun Pan
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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22
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Cerebral Dopamine Neurotrophic Factor Regulates Multiple Neuronal Subtypes and Behavior. J Neurosci 2020; 40:6146-6164. [PMID: 32631936 DOI: 10.1523/jneurosci.2636-19.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 12/23/2022] Open
Abstract
Cerebral dopamine neurotrophic factor (CDNF) protects dopaminergic neurons against toxic damage in the rodent brain and is in clinical trials to treat Parkinson's disease patients. Yet the underlying mechanism is poorly understood. To examine its significance for neural circuits and behavior, we examined the development of neurotransmitter systems from larval to male adult mutant zebrafish lacking cdnf Although a lack of cdnf did not affect overall brain dopamine levels, dopaminergic neuronal clusters showed significant abnormalities. The number of histamine neurons that surround the dopaminergic neurons was significantly reduced. Expression of tyrosine hydroxylase 2 in the brain was elevated in cdnf mutants throughout their lifespan. There were abnormally few GABA neurons in the hypothalamus in the mutant larvae, and expression of glutamate decarboxylase was reduced throughout the brain. cdnf mutant adults showed a range of behavioral phenotypes, including increased sensitivity to pentylenetetrazole-induced seizures. Shoaling behavior of mutant adults was abnormal, and they did not display social attraction to conspecifics. CDNF plays a profound role in shaping the neurotransmitter circuit structure, seizure susceptibility, and complex behaviors in zebrafish. These findings are informative for dissecting the diverse functions of this poorly understood factor in human conditions related to Parkinson's disease and complex behaviors.SIGNIFICANCE STATEMENT A zebrafish lacking cdnf grows normally and shows no overt morphologic phenotype throughout the life span. Remarkably, impaired social cohesion and increased seizure susceptibility were found in adult cdnf KO fish conceivably associated with significant changes of dopaminergic, GABAergic, and histaminergic systems in selective brain areas. These findings suggest that cdnf has broad effects on regulating neurogenesis and maturation of transmitter-specific neuronal types during development and throughout adulthood, rather than ones restricted to the dopaminergic systems.
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23
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Marchetti B, Tirolo C, L'Episcopo F, Caniglia S, Testa N, Smith JA, Pluchino S, Serapide MF. Parkinson's disease, aging and adult neurogenesis: Wnt/β-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell 2020; 19:e13101. [PMID: 32050297 PMCID: PMC7059166 DOI: 10.1111/acel.13101] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/27/2019] [Accepted: 12/25/2019] [Indexed: 12/14/2022] Open
Abstract
A common hallmark of age-dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC-signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct-periventricular region (Aq-PVR) Wnt-sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β-catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial-derived factors regulating WβC-dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in "turning off" the WβC neurogenic switch via down-regulation of the nuclear factor erythroid-2-related factor 2/Wnt-regulated signalosome, a key player in the maintenance of antioxidant self-defense mechanisms and NSC homeostasis. Harnessing WβC-signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.
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Affiliation(s)
- Bianca Marchetti
- Department of Biomedical and Biotechnological Sciences (BIOMETEC)Pharmacology and Physiology SectionsMedical SchoolUniversity of CataniaCataniaItaly
- Neuropharmacology SectionOASI Research Institute‐IRCCSTroinaItaly
| | - Cataldo Tirolo
- Neuropharmacology SectionOASI Research Institute‐IRCCSTroinaItaly
| | | | | | - Nunzio Testa
- Neuropharmacology SectionOASI Research Institute‐IRCCSTroinaItaly
| | - Jayden A. Smith
- Department of Clinical Neurosciences and NIHR Biomedical Research CentreUniversity of CambridgeCambridgeUK
| | - Stefano Pluchino
- Department of Clinical Neurosciences and NIHR Biomedical Research CentreUniversity of CambridgeCambridgeUK
| | - Maria F. Serapide
- Department of Biomedical and Biotechnological Sciences (BIOMETEC)Pharmacology and Physiology SectionsMedical SchoolUniversity of CataniaCataniaItaly
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24
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Neves J, Chirco KR, Cedron-Craft W, Chew S, Zhu J, Jasper H, Lamba DA. MANF delivery improves retinal homeostasis and cell replacement therapies in ageing mice. Exp Gerontol 2020; 134:110893. [PMID: 32119994 PMCID: PMC7483617 DOI: 10.1016/j.exger.2020.110893] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/24/2020] [Accepted: 02/27/2020] [Indexed: 01/24/2023]
Abstract
Ageing is a major risk factor for vision loss, and inflammation is an important contributor to retinal disease in the elderly. Regenerative medicine based on cell replacement strategies has emerged in recent years as a promising approach to restore vision. However, how the ageing process affects retinal homeostasis and inflammation in the retina and how this may impose a limitation to the success of such interventions remains unknown. Here we report that, in mice and humans, retinal ageing is associated with a reduction in MANF protein levels, specifically in the choroid, where increased densities of activated macrophages can be detected. We further show that the retina of old wild type mice, in the absence of any other genetic alteration, has limited homeostatic capacity after damage imposed by light exposure and reduced engraftment efficiency of exogenously supplied photoreceptors. Finally, we show that supplementation of MANF recombinant protein can improve retinal homeostasis and repair capacity in both settings, correlating with reduced numbers of activated macrophages in the old retina. Our work identifies age-related alterations in retinal homeostasis, independent of genetic alterations, leading to age-related retinal inflammation and damage susceptibility. We suggest that MANF therapy is a potential intervention to maintain retinal homeostasis in the elderly and improve the success of retinal regenerative therapies applied to aged individuals.
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Affiliation(s)
- Joana Neves
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Instituto de Medicina Molecular (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisbon 1649-028, Portugal.
| | - Kathleen R Chirco
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Ophthalmology, University of California, San Francisco, SF, USA
| | - Wendy Cedron-Craft
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA
| | - Shereen Chew
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Ophthalmology, University of California, San Francisco, SF, USA
| | - Jie Zhu
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA
| | - Heinrich Jasper
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Deepak A Lamba
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Ophthalmology, University of California, San Francisco, SF, USA.
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25
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Smith DR, Dumont CM, Park J, Ciciriello AJ, Guo A, Tatineni R, Cummings BJ, Anderson AJ, Shea LD. Polycistronic Delivery of IL-10 and NT-3 Promotes Oligodendrocyte Myelination and Functional Recovery in a Mouse Spinal Cord Injury Model. Tissue Eng Part A 2020; 26:672-682. [PMID: 32000627 DOI: 10.1089/ten.tea.2019.0321] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
One million estimated cases of spinal cord injury (SCI) have been reported in the United States and repairing an injury has constituted a difficult clinical challenge. The complex, dynamic, inhibitory microenvironment postinjury, which is characterized by proinflammatory signaling from invading leukocytes and lack of sufficient factors that promote axonal survival and elongation, limits regeneration. Herein, we investigated the delivery of polycistronic vectors, which have the potential to coexpress factors that target distinct barriers to regeneration, from a multiple channel poly(lactide-co-glycolide) (PLG) bridge to enhance spinal cord regeneration. In this study, we investigated polycistronic delivery of IL-10 that targets proinflammatory signaling, and NT-3 that targets axonal survival and elongation. A significant increase was observed in the density of regenerative macrophages for IL-10+NT-3 condition relative to conditions without IL-10. Furthermore, combined delivery of IL-10+NT-3 produced a significant increase of axonal density and notably myelinated axons compared with all other conditions. A significant increase in functional recovery was observed for IL-10+NT-3 delivery at 12 weeks postinjury that was positively correlated to oligodendrocyte myelinated axon density, suggesting oligodendrocyte-mediated myelination as an important target to improve functional recovery. These results further support the use of multiple channel PLG bridges as a growth supportive substrate and platform to deliver bioactive agents to modulate the SCI microenvironment and promote regeneration and functional recovery. Impact statement Spinal cord injury (SCI) results in a complex microenvironment that contains multiple barriers to regeneration and functional recovery. Multiple factors are necessary to address these barriers to regeneration, and polycistronic lentiviral gene therapy represents a strategy to locally express multiple factors simultaneously. A bicistronic vector encoding IL-10 and NT-3 was delivered from a poly(lactide-co-glycolide) bridge, which provides structural support that guides regeneration, resulting in increased axonal growth, myelination, and subsequent functional recovery. These results demonstrate the opportunity of targeting multiple barriers to SCI regeneration for additive effects.
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Affiliation(s)
- Dominique R Smith
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Courtney M Dumont
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Biomedical Engineering, University of Miami, Coral Gables, Florida.,Biomedical Nanotechnology Institute at University of Miami (BioNIUM), University of Miami, Miami, Florida
| | - Jonghyuck Park
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky.,Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
| | - Andrew J Ciciriello
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Biomedical Engineering, University of Miami, Coral Gables, Florida
| | - Amina Guo
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Ravindra Tatineni
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Brian J Cummings
- Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, California.,Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.,Department of Anatomy and Neurobiology, University of California, Irvine, California.,Department of Physical Medicine and Rehabilitation, University of California, Irvine, California
| | - Aileen J Anderson
- Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, California.,Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.,Department of Anatomy and Neurobiology, University of California, Irvine, California.,Department of Physical Medicine and Rehabilitation, University of California, Irvine, California
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan
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26
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Neves J, Sousa-Victor P. Regulation of inflammation as an anti-aging intervention. FEBS J 2019; 287:43-52. [PMID: 31529582 DOI: 10.1111/febs.15061] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/08/2019] [Accepted: 09/12/2019] [Indexed: 12/11/2022]
Abstract
Aging is accompanied by a decline in physiological integrity and a loss of regenerative capacity in many tissues. The development of interventions that prevent or reverse age-related disease requires a better understanding of the interplay of cell intrinsic, inter-cellular communication and systemic deregulations that underlie the aging process. Immune dysfunction and changes in inflammatory pathways are transversal contributors to the aging process and are essential propagators of tissue deterioration. Here, we propose and discuss the rejuvenation potential of interventions that target chronic inflammation and how modulation of tissue repair capacity could be an important mediator of such anti-aging strategies. We highlight how current knowledge on the systemic nature of inflammatory dysregulation in old organisms, together with the development of new animal models that allow for the isolation of the inflammatory component of aging, could provide new targets for interventions in aging based on the modulation of inflammatory pathways.
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Affiliation(s)
- Joana Neves
- Faculdade de Medicina, Instituto de Medicina Molecular (iMM), Universidade de Lisboa, Portugal
| | - Pedro Sousa-Victor
- Faculdade de Medicina, Instituto de Medicina Molecular (iMM), Universidade de Lisboa, Portugal
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27
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Yong HYF, Rawji KS, Ghorbani S, Xue M, Yong VW. The benefits of neuroinflammation for the repair of the injured central nervous system. Cell Mol Immunol 2019; 16:540-546. [PMID: 30874626 DOI: 10.1038/s41423-019-0223-3] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer's disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.
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Affiliation(s)
| | | | | | - Mengzhou Xue
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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