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Zhang YY, Li F, Zeng XK, Zou YH, Zhu BB, Ye JJ, Zhang YX, Jin Q, Nie X. Single cell RNA sequencing reveals mesenchymal heterogeneity and critical functions of Cd271 in tooth development. World J Stem Cells 2023; 15:589-606. [PMID: 37424952 PMCID: PMC10324503 DOI: 10.4252/wjsc.v15.i6.589] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/18/2023] [Accepted: 05/05/2023] [Indexed: 06/20/2023] Open
Abstract
BACKGROUND Accumulating evidence suggests that the maxillary process, to which cranial crest cells migrate, is essential to tooth development. Emerging studies indicate that Cd271 plays an essential role in odontogenesis. However, the underlying mechanisms have yet to be elucidated.
AIM To establish the functionally heterogeneous population in the maxillary process, elucidate the effects of Cd271 deficiency on gene expression differences.
METHODS p75NTR knockout (Cd271-/-) mice (from American Jackson laboratory) were used to collect the maxillofacial process tissue of p75NTR knockout mice, and the wild-type maxillofacial process of the same pregnant mouse wild was used as control. After single cell suspension, the cDNA was prepared by loading the single cell suspension into the 10x Genomics Chromium system to be sequenced by NovaSeq6000 sequencing system. Finally, the sequencing data in Fastq format were obtained. The FastQC software is used to evaluate the quality of data and CellRanger analyzed the data. The gene expression matrix is read by R software, and Seurat is used to control and standardize the data, reduce the dimension and cluster. We search for marker genes for subgroup annotation by consulting literature and database; explore the effect of p75NTR knockout on mesenchymal stem cells (MSCs) gene expression and cell proportion by cell subgrouping, differential gene analysis, enrichment analysis and protein-protein interaction network analysis; understand the interaction between MSCs cells and the differentiation trajectory and gene change characteristics of p75NTR knockout MSCs by cell communication analysis and pseudo-time analysis. Last we verified the findings single cell sequencing in vitro.
RESULTS We identified 21 cell clusters, and we re-clustered these into three subclusters. Importantly, we revealed the cell–cell communication networks between clusters. We clarified that Cd271 was significantly associated with the regulation of mineralization.
CONCLUSION This study provides comprehensive mechanistic insights into the maxillary- process-derived MSCs and demonstrates that Cd271 is significantly associated with the odontogenesis in mesenchymal populations.
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Affiliation(s)
- Yan-Yan Zhang
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Feng Li
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Xiao-Ke Zeng
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Yan-Hui Zou
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Bing-Bing Zhu
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Jia-Jia Ye
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Yun-Xiao Zhang
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Qiu Jin
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Xin Nie
- School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
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Badiola-Mateos M, Osaki T, Kamm RD, Samitier J. In vitro modelling of human proprioceptive sensory neurons in the neuromuscular system. Sci Rep 2022; 12:21318. [PMID: 36494423 PMCID: PMC9734133 DOI: 10.1038/s41598-022-23565-3] [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: 04/21/2022] [Accepted: 11/02/2022] [Indexed: 12/13/2022] Open
Abstract
Proprioceptive sensory neurons (pSN) are an essential and undervalued part of the neuromuscular circuit. A protocol to differentiate healthy and amyotrophic lateral sclerosis (ALS) human neural stem cells (hNSC) into pSN, and their comparison with the motor neuron (MN) differentiation process from the same hNSC sources, facilitated the development of in vitro co-culture platforms. The obtained pSN spheroids cultured interact with human skeletal myocytes showing the formation of annulospiral wrapping-like structures between TrkC + neurons and a multinucleated muscle fibre, presenting synaptic bouton-like structures in the contact point. The comparative analysis of the genetic profile performed in healthy and sporadic ALS hNSC differentiated to pSN suggested that basal levels of ETV1, critical for motor feedback from pSN, were much lower for ALS samples and that the differences between healthy and ALS samples, suggest the involvement of pSN in ALS pathology development and progression.
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Affiliation(s)
- Maider Badiola-Mateos
- grid.424736.00000 0004 0536 2369Institute for Bioengineering of Catalonia (IBEC)—Barcelona Institute of Science and Technology, 08028 Barcelona, Spain ,grid.5841.80000 0004 1937 0247Department of Electronic and Biomedical Engineering, Universitat de Barcelona, 08028 Barcelona, Spain ,grid.116068.80000 0001 2341 2786Department of Biological Engineering, Massachusetts Institute of Technology (MIT), 500 Technology Square, MIT Building, Cambridge, MA 02139 USA ,grid.263145.70000 0004 1762 600XPresent Address: The BioRobotics Institute, Department of Excellence in Robotics and AI, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
| | - Tatsuya Osaki
- grid.116068.80000 0001 2341 2786Department of Biological Engineering, Massachusetts Institute of Technology (MIT), 500 Technology Square, MIT Building, Cambridge, MA 02139 USA ,grid.26999.3d0000 0001 2151 536XPresent Address: Institute of Industrial Science, The University of Tokyo, 4-6-1, Komaba, Meguro-Ku, Tokyo, 153-8505 Japan
| | - Roger Dale Kamm
- grid.116068.80000 0001 2341 2786Department of Biological Engineering, Massachusetts Institute of Technology (MIT), 500 Technology Square, MIT Building, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786Department of Mechanical Engineering, Massachusetts Institute of Technology, 500 Technology Square, MIT Building, Cambridge, MA 02139 USA
| | - Josep Samitier
- grid.424736.00000 0004 0536 2369Institute for Bioengineering of Catalonia (IBEC)—Barcelona Institute of Science and Technology, 08028 Barcelona, Spain ,grid.5841.80000 0004 1937 0247Department of Electronic and Biomedical Engineering, Universitat de Barcelona, 08028 Barcelona, Spain ,grid.512890.7Centro de Investigación Biomédica en Red (CIBER-BBN), 28029 Madrid, Spain
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Amato G, Romano G, Rodolico V, Puleio R, Calò PG, Di Buono G, Cicero L, Romano G, Goetze TO, Agrusa A. Dynamic Responsive Inguinal Scaffold Activates Myogenic Growth Factors Finalizing the Regeneration of the Herniated Groin. J Funct Biomater 2022; 13:jfb13040253. [PMID: 36412894 PMCID: PMC9680268 DOI: 10.3390/jfb13040253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/12/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Postoperative chronic pain caused by fixation and/or fibrotic incorporation of hernia meshes are the main concerns in inguinal herniorrhaphy. As inguinal hernia is a degenerative disease, logically the treatment should aim at stopping degeneration and activating regeneration. Unfortunately, in conventional prosthetic herniorrhaphy no relationship exists between pathogenesis and treatment. To overcome these incongruences, a 3D dynamic responsive multilamellar scaffold has been developed for fixation-free inguinal hernia repair. Made of polypropylene like conventional flat meshes, the dynamic behavior of the scaffold allows for the regeneration of all typical inguinal components: connective tissue, vessels, nerves, and myocytes. This investigation aims to demonstrate that, moving in tune with the groin, the 3D scaffold attracts myogenic growth factors activating the development of mature myocytes and, thus, re-establishing the herniated inguinal barrier. METHODS Biopsy samples excised from the 3D scaffold at different postoperative stages were stained with H&E and Azan-Mallory; immunohistochemistry for NGF and NGFR p75 was performed to verify the degree of involvement of muscular growth factors in the neomyogenesis. RESULTS Histological evidence of progressive muscle development and immunohistochemical proof of NFG and NFGRp75 contribution in neomyogenesis within the 3D scaffold was documented and statistically validated. CONCLUSION The investigation appears to confirm that a 3D polypropylene scaffold designed to confer dynamic responsivity, unlike the fibrotic scar plate of static meshes, attracts myogenic growth factors turning the biological response into tissue regeneration. Newly developed muscles allow the scaffold to restore the integrity of the inguinal barrier.
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Affiliation(s)
- Giuseppe Amato
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
- Correspondence: (G.A.); (L.C.)
| | - Giorgio Romano
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Vito Rodolico
- Department PROMISE, Section Pathological Anatomy, University of Palermo, 90127 Palermo, Italy
| | - Roberto Puleio
- Department of Pathologic Anatomy and Histology, IZSS, 90129 Palermo, Italy
| | - Pietro Giorgio Calò
- Department of Surgical Sciences, University of Cagliari, 09042 Cagliari, Italy
| | - Giuseppe Di Buono
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Luca Cicero
- CEMERIT—IZSS, Via Gino Marinuzzi, 3, 90129 Palermo, Italy
- Correspondence: (G.A.); (L.C.)
| | - Giorgio Romano
- Postgraduate School of General Surgery, University of Palermo, 90127 Palermo, Italy
| | - Thorsten Oliver Goetze
- Institut für Klinisch-Onkologische Forschung Krankenhaus Nordwest, 60488 Frankfurt/Main, Germany
| | - Antonino Agrusa
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
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Morano NC, Smith RS, Danelon V, Schreiner R, Patel U, Herrera NG, Smith C, Olson SM, Laerke MK, Celikgil A, Garforth SJ, Garrett-Thomson SC, Lee FS, Hempstead BL, Almo SC. Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor. J Clin Invest 2022; 132:e157002. [PMID: 36107635 PMCID: PMC9663165 DOI: 10.1172/jci157002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 09/13/2022] [Indexed: 12/30/2023] Open
Abstract
Cell surface receptors, ligands, and adhesion molecules underlie development, circuit formation, and synaptic function of the central nervous system and represent important therapeutic targets for many neuropathologies. The functional contributions of interactions between cell surface proteins of neurons and nonneuronal cells have not been fully addressed. Using an unbiased protein-protein interaction screen, we showed that the human immunomodulatory ligand B7-1 (hB7-1) interacts with the p75 neurotrophin receptor (p75NTR) and that the B7-1:p75NTR interaction is a recent evolutionary adaptation present in humans and other primates, but absent in mice, rats, and other lower mammals. The surface of hB7-1 that engages p75NTR overlaps with the hB7-1 surface involved in CTLA-4/CD28 recognition, and these molecules directly compete for binding to p75NTR. Soluble or membrane-bound hB7-1 altered dendritic morphology of cultured hippocampal neurons, with loss of the postsynaptic protein PSD95 in a p75NTR-dependent manner. Abatacept, an FDA-approved therapeutic (CTLA-4-hFc fusion) inhibited these processes. In vivo injection of hB7-1 into the murine subiculum, a hippocampal region affected in Alzheimer's disease, resulted in p75NTR-dependent pruning of dendritic spines. Here, we report the biochemical interaction between B7-1 and p75NTR, describe biological effects on neuronal morphology, and identify a therapeutic opportunity for treatment of neuroinflammatory diseases.
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Affiliation(s)
- Nicholas C. Morano
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
- Zuckerman Mind Brain Behavior Institute, Columbia University, New York, New York, USA
| | - Roshelle S. Smith
- Department of Medicine, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
| | - Victor Danelon
- Department of Medicine, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
| | - Ryan Schreiner
- Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Uttsav Patel
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
| | - Natalia G. Herrera
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
| | - Carla Smith
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
| | - Steven M. Olson
- Department of Computer Science, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Michelle K. Laerke
- Department of Medicine, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
| | - Alev Celikgil
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
| | - Scott J. Garforth
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
| | | | - Francis S. Lee
- Department of Psychiatry, Weill Cornell Medicine, New York, New York, USA
| | - Barbara L. Hempstead
- Department of Medicine, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
| | - Steven C. Almo
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
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BEX1 and BEX4 Induce GBM Progression through Regulation of Actin Polymerization and Activation of YAP/TAZ Signaling. Int J Mol Sci 2021; 22:ijms22189845. [PMID: 34576008 PMCID: PMC8471324 DOI: 10.3390/ijms22189845] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/02/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022] Open
Abstract
GBM is a high-grade cancer that originates from glial cells and has a poor prognosis. Although a combination of surgery, radiotherapy, and chemotherapy is prescribed to patients, GBM is highly resistant to therapies, and surviving cells show increased aggressiveness. In this study, we investigated the molecular mechanism underlying GBM progression after radiotherapy by establishing a GBM orthotopic xenograft mouse model. Based on transcriptomic analysis, we found that the expression of BEX1 and BEX4 was upregulated in GBM cells surviving radiotherapy. We also found that upregulated expression of BEX1 and BEX4 was involved in the formation of the filamentous cytoskeleton and altered mechanotransduction, which resulted in the activation of the YAP/TAZ signaling pathway. BEX1- and BEX4-mediated YAP/TAZ activation enhanced the tumor formation, growth, and radioresistance of GBM cells. Additionally, latrunculin B inhibited GBM progression after radiotherapy by suppressing actin polymerization in an orthotopic xenograft mouse model. Taken together, we suggest the involvement of cytoskeleton formation in radiation-induced GBM progression and latrunculin B as a GBM radiosensitizer.
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6
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Fédou C, Lescat O, Feuillet G, Buléon M, Neau E, Breuil B, Alvès M, Batut J, Blader P, Decramer S, Saulnier-Blache JS, Klein J, Buffin-Meyer B, Schanstra JP. The low affinity p75 neurotrophin receptor is down-regulated in congenital anomalies of the kidney and the urinary tract: Possible involvement in early nephrogenesis. Biochem Biophys Res Commun 2020; 533:786-791. [PMID: 32988586 DOI: 10.1016/j.bbrc.2020.09.084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 09/20/2020] [Indexed: 12/14/2022]
Abstract
Congenital Anomalies of the Kidney and of the Urinary Tract (CAKUT) cover a broad range of disorders including abnormal kidney development caused by defective nephrogenesis. Here we explored the possible involvement of the low affinity p75 neurotrophin receptor (p75NTR) in CAKUT and nephrogenesis. In mouse, p75NTR was highly expressed in fetal kidney, located within cortical early nephrogenic bodies, and decreased rapidly after birth. In human control fetal kidney, p75NTR was also located within the early nephrogenic bodies as well as in the mature glomeruli, presumably in the mesangium. In CAKUT fetal kidneys, the kidney cortical structure and the localization of p75NTR were often disorganized, and quantification of p75NTR in amniotic fluid revealed a significant reduction in CAKUT compared to control. Finally, invalidation of p75NTR in zebrafish embryo with an antisense morpholino significantly altered pronephros development. Our results indicate that renal p75NTR is altered in CAKUT fetuses, and could participate to early nephrogenesis.
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Affiliation(s)
- Camille Fédou
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Ophélie Lescat
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Guylène Feuillet
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Marie Buléon
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Eric Neau
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Benjamin Breuil
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Mélinda Alvès
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Julie Batut
- Centre de Biologie du Développement (CBD, UMR5547), Centre de Biologie Intégrative (CBI, FR3743), Université de Toulouse, Toulouse, France
| | - Patrick Blader
- Centre de Biologie du Développement (CBD, UMR5547), Centre de Biologie Intégrative (CBI, FR3743), Université de Toulouse, Toulouse, France
| | - Stéphane Decramer
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Service de Néphrologie Pédiatrique, Hôpital des Enfants, CHU Toulouse, Toulouse, France; Centre De Référence des Maladies Rénales Rares du Sud-Ouest (SORARE), Toulouse, France
| | - Jean Sébastien Saulnier-Blache
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
| | - Julie Klein
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Bénédicte Buffin-Meyer
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
| | - Joost P Schanstra
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
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7
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Guilherme JPLF, Semenova EA, Borisov OV, Kostryukova ES, Vepkhvadze TF, Lysenko EA, Andryushchenko ON, Andryushchenko LB, Lednev EM, Larin AK, Bondareva EA, Generozov EV, Ahmetov II. The BDNF-Increasing Allele is Associated With Increased Proportion of Fast-Twitch Muscle Fibers, Handgrip Strength, and Power Athlete Status. J Strength Cond Res 2020; 36:1884-1889. [PMID: 33306590 DOI: 10.1519/jsc.0000000000003756] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Guilherme, JPLF, Semenova, EA, Borisov, OV, Kostryukova, ES, Vepkhvadze, TF, Lysenko, EA, Andryushchenko, ON, Andryushchenko, LB, Lednev, EM, Larin, AK, Bondareva, EA, Generozov, EV, and Ahmetov, II. The BDNF-increasing allele is associated with increased proportion of fast-twitch muscle fibers, handgrip strength, and power athlete status. J Strength Cond Res XX(X): 000-000, 2020-The brain-derived neurotrophic factor (BDNF) is involved in neurogenesis and formation of regenerated myofibers following injury or damage. A recent study suggested that the BDNF overexpression increases the proportion of fast-twitch muscle fibers, while the BDNF deletion promotes a fast-to-slow transition. The purpose of this study was to evaluate the association between the BDNF gene rs10501089 polymorphism (associated with blood BDNF levels), muscle fiber composition, and power athlete status. Muscle fiber composition was determined in 164 physically active individuals (113 men, 51 women). BDNF genotype and allele frequencies were compared between 508 Russian power athletes, 178 endurance athletes, and 190 controls. We found that carriers of the minor A-allele (the BDNF-increasing allele) had significantly higher percentage of fast-twitch muscle fibers than individuals homozygous for the G-allele (males: 64.3 [7.8] vs. 50.3 [15.8]%, p = 0.0015; all subjects: 64.1 ± 7.9 vs. 49.6 ± 14.7%, p = 0.0002). Furthermore, the A-allele was associated (p = 0.036) with greater handgrip strength in a sub-group of physically active subjects (n = 83) and over-represented in power athletes compared with controls (7.7 vs. 2.4%, p = 0.0001). The presence of the A-allele (i.e., AA+AG genotypes) rather than GG genotype increased the odds ratio of being a power athlete compared with controls (odds ratio [OR]: 3.43, p = 0.00071) or endurance athletes (OR: 2.36, p = 0.0081). In conclusion, the rs10501089 A-allele is associated with increased proportion of fast-twitch muscle fibers and greater handgrip strength, and these may explain, in part, the association between the AA/AG genotypes and power athlete status.
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Affiliation(s)
- João Paulo L F Guilherme
- Laboratory of Applied Nutrition and Metabolism, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Ekaterina A Semenova
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Oleg V Borisov
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.,Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
| | - Elena S Kostryukova
- Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Tatiana F Vepkhvadze
- Laboratory of Exercise Physiology, Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia
| | - Evgeny A Lysenko
- Laboratory of Exercise Physiology, Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia
| | - Oleg N Andryushchenko
- Department of Physical Education, Financial University under the Government of the Russian Federation, Moscow, Russia
| | | | - Egor M Lednev
- Laboratory of Exercise Physiology, Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia
| | - Andrey K Larin
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Elvira A Bondareva
- Research Institute and Museum of Anthropology, Lomonosov Moscow State University, Moscow, Russia
| | - Edward V Generozov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
| | - Ildus I Ahmetov
- Department of Physical Education, Plekhanov Russian University of Economics, Moscow, Russia.,Sports Genetics Laboratory, St Petersburg Research Institute of Physical Culture, St. Petersburg, Russia.,Laboratory of Molecular Genetics, Kazan State Medical University, Kazan, Russia.,Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
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8
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ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells. Cells 2020; 9:cells9102232. [PMID: 33023189 PMCID: PMC7599914 DOI: 10.3390/cells9102232] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/16/2022] Open
Abstract
Despite its undisputable role in the homeostatic regulation of the nervous system, the nerve growth factor (NGF) also governs the relevant cellular processes in other tissues and organs. In this study, we aimed at assessing the expression and the putative involvement of NGF signaling in skeletal muscle physiology. To reach this objective, we employed satellite cell-derived myoblasts as an in vitro culture model. In vivo experiments were performed on Tibialis anterior from wild-type mice and an mdx mouse model of Duchenne muscular dystrophy. Targets of interest were mainly assessed by means of morphological, Western blot and qRT-PCR analysis. The results show that proNGF is involved in myogenic differentiation. Importantly, the proNGF/p75NTR pathway orchestrates a slow-to-fast fiber type transition by counteracting the expression of slow myosin heavy chain and that of oxidative markers. Concurrently, proNGF/p75NTR activation facilitates the induction of fast myosin heavy chain and of fast/glycolytic markers. Furthermore, we also provided evidence that the oxidative metabolism is impaired in mdx mice, and that these alterations are paralleled by a prominent buildup of proNGF and p75NTR. These findings underline that the proNGF/p75NTR pathway may play a crucial role in fiber type determination and suggest its prospective modulation as an innovative therapeutic approach to counteract muscle disorders.
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Carrero-Rojas G, Benítez-Temiño B, Pastor AM, Davis López de Carrizosa MA. Muscle Progenitors Derived from Extraocular Muscles Express Higher Levels of Neurotrophins and their Receptors than other Cranial and Limb Muscles. Cells 2020; 9:cells9030747. [PMID: 32197508 PMCID: PMC7140653 DOI: 10.3390/cells9030747] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/02/2020] [Accepted: 03/17/2020] [Indexed: 01/19/2023] Open
Abstract
Extraocular muscles (EOMs) show resistance to muscle dystrophies and sarcopenia. It has been recently demonstrated that they are endowed with different types of myogenic cells, all of which present an outstanding regenerative potential. Neurotrophins are important modulators of myogenic regeneration and act promoting myoblast proliferation, enhancing myogenic fusion rates and protecting myotubes from inflammatory stimuli. Here, we adapted the pre-plate cell isolation technique to obtain myogenic progenitors from the rat EOMs, and quantified their in vitro expression of neurotrophins and their receptors by RT–qPCR and immunohistochemistry, respectively. The results were compared with the expression on progenitors isolated from buccinator, tongue and limb muscles. Our quantitative analysis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) transcripts showed, for the first time, that EOMs-derived cells express more of these factors and that they expressed TrkA, but not TrkB and TrkC receptors. On the contrary, the immunofluorescence analysis demonstrated high expression of p75NTR on all myogenic progenitors, with the EOMs-derived cells showing higher expression. Taken together, these results suggest that the intrinsic trophic differences between EOMs-derived myogenic progenitors and their counterparts from other muscles could explain why those cells show higher proliferative and fusion rates, as well as better regenerative properties.
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McKay BR, Nederveen JP, Fortino SA, Snijders T, Joanisse S, Kumbhare DA, Parise G. Brain-derived neurotrophic factor is associated with human muscle satellite cell differentiation in response to muscle-damaging exercise. Appl Physiol Nutr Metab 2019; 45:581-590. [PMID: 31661631 DOI: 10.1139/apnm-2019-0501] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Muscle satellite cell (SC) regulation is a complex process involving many key signalling molecules. Recently, the neurotrophin brain-derived neurotropic factor (BDNF) has implicated in SC regulation in animals. To date, little is known regarding the role of BDNF in human SC function in vivo. Twenty-nine males (age, 21 ± 0.5 years) participated in the study. Muscle biopsies from the thigh were obtained prior to a bout of 300 maximal eccentric contractions (Pre), and at 6 h, 24 h, 72 h, and 96 h postexercise. BDNF was not detected in any quiescent (Pax7+/MyoD-) SCs across the time-course. BDNF colocalized to 39% ± 5% of proliferating (Pax7+/MyoD+) cells at Pre, which increased to 84% ± 3% by 96 h (P < 0.05). BDNF was only detected in 13% ± 5% of differentiating (Pax7-/MyoD+) cells at Pre, which increased to 67% ± 4% by 96 h (P < 0.05). The number of myogenin+ cells increased 95% from Pre (1.6 ± 0.2 cells/100 myofibres (MF)) at 24 h (3.1 ± 0.3 cells/100 MF) and remained elevated until 96 h (cells/100 MF), P < 0.05. The proportion of BDNF+/myogenin+ cells was 26% ± 0.3% at Pre, peaking at 24 h (49% ± 3%, P < 0.05) and remained elevated at 96 h (P < 0.05). These data are the first to demonstrate an association between SC proliferation and differentiation and BDNF expression in humans in vivo, with BDNF colocalization to SCs increasing during the later stages of proliferation and early differentiation. Novelty BDNF is associated with SC response to muscle injury. BDNF was not detected in nonactivated (quiescent) SCs. BDNF is associated with late proliferation and early differentiation of SCs in vivo in humans.
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Affiliation(s)
- Bryon R McKay
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Joshua P Nederveen
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Stephen A Fortino
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Tim Snijders
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada.,Department of Human Biology, Maastricht University, 6211 LK Maastricht, Netherlands
| | - Sophie Joanisse
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Dinesh A Kumbhare
- Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Gianni Parise
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
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11
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Wen Y, Liu G, Jia L, Ji W, Li H. MicroRNA-141 binds to the nerve growth factor receptor associated protein 1 gene and restores the erectile function of diabetic rats through down-regulating the nerve growth factor/neurotrophin receptor p75 (NGF/p75NTR) signaling. J Cell Biochem 2019; 120:7940-7951. [PMID: 30426562 DOI: 10.1002/jcb.28071] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/22/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND Erectile dysfunction (ED) is one of the major complications in diabetes mellitus (DM). We have previously reported that the nerve growth factor (NGF)/tyrosine kinase receptor (TrkA) signaling is actively involved in DM-induced ED (DMED). Here, we investigate the effect of micro-RNA-141 (miR-141) on the NGF/p75 neurotrophin receptor (p75NTR) signaling and erectile function of diabetic rats. METHODS Sprague-Dawlay (SD) rats were used to establish a DMED model. The dual-luciferase reporter gene assay was first performed to identify the nerve growth factor receptor-associated protein 1 (NGFRAP1) gene as the target gene of miR-141. The regulatory mechanisms underlying miR-141 governing NGFRAP1 in vivo were then validated by modulating the expressions of miR-141 and knocking down NGFRAP1. RESULTS The expressions of miR-141 were decreased while the expressions of NGFRAP1, NGF, and p75NTR were increased in DMED. miR-141 and downregulation of NGFRAP1, respectively, increased the density of corpus cavernosum smooth muscle and the ratio of intracavernosal pressure (ICP)/mean arterial blood pressure (MAP) and promoted the expression of α-actin and desmin as well. miR-141 also upregulated the expressions of NGFRAP1 in DMED, and knockdown of NGFRAP1 inhibited the productions of NGF and p75NTR. Furthermore, miR-141 suppressed the NGF/p75NTR signaling via binding to NGFRAP1. CONCLUSIONS NGF/p75NTR signaling actively participates in the pathogenesis of DMED. miR-141 binds to NGFRAP1 and restores the erectile function of diabetic rats via downregulation of NGF/p75NTR signaling.
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Affiliation(s)
- Yan Wen
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Guohui Liu
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Linpei Jia
- Department of Nephrology, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Wei Ji
- Department of Vascular Surgery, Jilin Provincial People's Hospital, Changchun, China
| | - Hai Li
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, China
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12
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Khamo JS, Krishnamurthy VV, Chen Q, Diao J, Zhang K. Optogenetic Delineation of Receptor Tyrosine Kinase Subcircuits in PC12 Cell Differentiation. Cell Chem Biol 2018; 26:400-410.e3. [PMID: 30595532 DOI: 10.1016/j.chembiol.2018.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 08/13/2018] [Accepted: 11/02/2018] [Indexed: 01/19/2023]
Abstract
Nerve growth factor elicits signaling outcomes by interacting with both its high-affinity receptor, TrkA, and its low-affinity receptor, p75NTR. Although these two receptors can regulate distinct cellular outcomes, they both activate the extracellular-signal-regulated kinase pathway upon nerve growth factor stimulation. To delineate TrkA subcircuits in PC12 cell differentiation, we developed an optogenetic system whereby light was used to specifically activate TrkA signaling in the absence of nerve growth factor. By using tyrosine mutants of the optogenetic TrkA in combination with pathway-specific pharmacological inhibition, we find that Y490 and Y785 each contributes to PC12 cell differentiation through the extracellular-signal-regulated kinase pathway in an additive manner. Optogenetic activation of TrkA eliminates the confounding effect of p75NTR and other potential off-target effects of the ligand. This approach can be generalized for the mechanistic study of other receptor-mediated signaling pathways.
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Affiliation(s)
- John S Khamo
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Vishnu V Krishnamurthy
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Qixin Chen
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jiajie Diao
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
| | - Kai Zhang
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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13
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Sousa-Victor P, Jasper H, Neves J. Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF. Front Physiol 2018; 9:1629. [PMID: 30515104 PMCID: PMC6255971 DOI: 10.3389/fphys.2018.01629] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 10/29/2018] [Indexed: 12/26/2022] Open
Abstract
Regeneration is an important process in multicellular organisms, responsible for homeostatic renewal and repair of different organs after injury. Immune cell activation is observed at early stages of the regenerative response and its regulation is essential for regenerative success. Thus, immune regulators play central roles in optimizing regenerative responses. Neurotrophic factors (NTFs) are secreted molecules, defined by their ability to support neuronal cell types. However, emerging evidence suggests that they can also play important functions in the regulation of immune cell activation and tissue repair. Here we discuss the literature supporting a role of NTFs in the regulation of inflammation and regeneration. We will focus, in particular, in the emerging roles of mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) in the regulation of immune cell function and in the central role that immune modulation plays in their biological activity in vivo. Finally, we will discuss the potential use of these factors to optimize regenerative success in vivo, both within and beyond the nervous system.
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Affiliation(s)
- Pedro Sousa-Victor
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, Novato, CA, United States
| | - Heinrich Jasper
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, Novato, CA, United States.,Immunology Discovery, Genentech, Inc., South San Francisco, CA, United States
| | - Joana Neves
- Paul F. Glenn Center for Biology of Aging Research, Buck Institute for Research on Aging, Novato, CA, United States
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Zhao M, Wen X, Li G, Ju Y, Wang Y, Zhou Z, Song J. The spatiotemporal expression and mineralization regulation of p75 neurotrophin receptor in the early tooth development. Cell Prolif 2018; 52:e12523. [PMID: 30357966 DOI: 10.1111/cpr.12523] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 05/07/2018] [Accepted: 05/29/2018] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate the spatiotemporal expression and potential role of p75NTR in tooth morphogenesis and tissue mineralization. MATERIALS AND METHODS The dynamic morphology of the four stages (from the beginning of E12.5 d, then E13.5 d and E15.5 d, to the end of E18.5 d) was observed, and the expressions of p75NTR and Runx2 were traced. The ectomesenchymal stem cells (EMSCs) were harvested in vitro, and the biological characteristics were observed. Moreover, the mineralization capability of EMSCs was evaluated. The relations between p75NTR and ALP, Col-1 and Runx2 were investigated. RESULTS The morphologic results showed that the dental lamina appeared at E12.5 d, the bud stage at E13.5 d, the cap stage at E15.5 d and the bell stage at E18.5 d. p75NTR and Runx2 showed the similar expression pattern. EMSCs from the four stages showed no significant difference in proliferation. But the positive rate of p75NTR in the E12.5 d cells was significantly lower than that in the other three stages (P < 0.05). Moreover, the higher positive rate of p75NTR the cells were, the stronger mineralization capability they showed. p75NTR was well positively correlated with the mineralization-related markers ALP, Col-1 and Runx2, which increased gradually with the mature of dental germs. CONCLUSION p75NTR might play an important role in the regulation of tooth morphogenesis, especially dental hard tissue formation.
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Affiliation(s)
- Manzhu Zhao
- College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, China
| | - Xiujie Wen
- Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Gang Li
- Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Yingxin Ju
- Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Yingying Wang
- Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing, China
| | - Zhi Zhou
- College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, China
| | - Jinlin Song
- College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, China
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15
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AAV1.NT-3 gene therapy increases muscle fiber diameter through activation of mTOR pathway and metabolic remodeling in a CMT mouse model. Gene Ther 2018. [PMID: 29523879 DOI: 10.1038/s41434-018-0009-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neurotrophin 3 (NT-3) has well-recognized effects on peripheral nerve and Schwann cells, promoting axonal regeneration and associated myelination. In this study, we assessed the effects of AAV.NT-3 gene therapy on the oxidative state of the neurogenic muscle from the TremblerJ (Tr J ) mice at 16 weeks post-gene injection and found that the muscle fiber size increase was associated with a change in the oxidative state of muscle fibers towards normalization of the fiber type ratio seen in the wild type. NT-3-induced fiber size increase was most prominent for the fast twitch glycolytic fiber population. These changes in the Tr J muscle were accompanied by increased phosphorylation levels of 4E-BP1 and S6 proteins as evidence of mTORC1 activation. In parallel, the expression levels of the mitochondrial biogenesis regulator PGC1α, and the markers of glycolysis (HK1 and PK1) increased in the TrJ muscle. In vitro studies showed that recombinant NT-3 can directly induce Akt/mTOR pathway activation in the TrkC expressing myotubes but not in myoblasts. In addition, myogenin expression levels were increased in myotubes while p75 NTR expression was downregulated compared to myoblasts, indicating that NT-3 induced myoblast differentiation is associated with mTORC1 activation. These studies for the first time have shown that NT-3 increases muscle fiber diameter in the neurogenic muscle through direct activation of mTOR pathway and that the fiber size increase is more prominent for fast twitch glycolytic fibers.
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16
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de Perini A, Dimauro I, Duranti G, Fantini C, Mercatelli N, Ceci R, Di Luigi L, Sabatini S, Caporossi D. The p75 NTR-mediated effect of nerve growth factor in L6C5 myogenic cells. BMC Res Notes 2017; 10:686. [PMID: 29202822 PMCID: PMC5716223 DOI: 10.1186/s13104-017-2994-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 11/25/2017] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVE During muscle development or regeneration, myocytes produce nerve growth factor (NGF) as well as its tyrosine-kinase and p75-neurotrophin (p75NTR) receptors. It has been published that the p75NTR receptor could represent a key regulator of NGF-mediated myoprotective effect on satellite cells, but the precise function of NGF/p75 signaling pathway on myogenic cell proliferation, survival and differentiation remains fragmented and controversial. Here, we verified the role of NGF in the growth, survival and differentiation of p75NTR-expressing L6C5 myogenic cells, specifically inquiring for the putative involvement of the nuclear factor κB (NFκB) and the small heat shock proteins (sHSPs) αB-crystallin and Hsp27 in these processes. RESULTS Although NGF was not effective in modulating myogenic cell growth or survival in both standard or stress conditions, we demonstrated for the first time that, under serum deprivation, NGF sustained the activity of some key enzymes involved in energy metabolism. Moreover, we confirmed that NGF promotes myogenic fusion and expression of the structural protein myosin heavy chain while modulating NFκB activation and the content of sHSPs correlated with the differentiation process. We conclude that p75NTR is sufficient to mediate the modulation of L6C5 myogenic differentiation by NGF in term of structural, metabolic and functional changes.
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Affiliation(s)
- Alessandra de Perini
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Ivan Dimauro
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Guglielmo Duranti
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Cristina Fantini
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Neri Mercatelli
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
- Laboratory of Cellular and Molecular Neurobiology, CERC, Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy
| | - Roberta Ceci
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Luigi Di Luigi
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Stefania Sabatini
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
| | - Daniela Caporossi
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis, 15, 00135 Rome, Italy
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Mora M, Angelini C, Bignami F, Bodin AM, Crimi M, Di Donato JH, Felice A, Jaeger C, Karcagi V, LeCam Y, Lynn S, Meznaric M, Moggio M, Monaco L, Politano L, de la Paz MP, Saker S, Schneiderat P, Ensini M, Garavaglia B, Gurwitz D, Johnson D, Muntoni F, Puymirat J, Reza M, Voit T, Baldo C, Bricarelli FD, Goldwurm S, Merla G, Pegoraro E, Renieri A, Zatloukal K, Filocamo M, Lochmüller H. The EuroBioBank Network: 10 years of hands-on experience of collaborative, transnational biobanking for rare diseases. Eur J Hum Genet 2015; 23:1116-23. [PMID: 25537360 PMCID: PMC4538193 DOI: 10.1038/ejhg.2014.272] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/15/2014] [Accepted: 11/10/2014] [Indexed: 11/09/2022] Open
Abstract
The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field.
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Affiliation(s)
- Marina Mora
- Muscle Cell Biology Lab, Neuromuscular Diseases and Neuroimmunolgy Unit, Fondazione Istituto Neurologico C. Besta, Milano, Italy
| | - Corrado Angelini
- IRCCS Fondazione San Camillo Hospital, Lido Venice, Italy
- Department of Neurosciences, NPSRR University of Padova, Padova, Italy
| | | | - Anne-Mary Bodin
- EURORDIS, European Organisation for Rare Diseases, Paris, France
| | | | | | - Alex Felice
- Laboratory of Molecular Genetics and Malta BioBank, University of Malta, and Thalassaemia Clinic, Mater Dei Hospital, Msida, Malta
| | | | - Veronika Karcagi
- Department of Molecular Genetics and Diagnostics, National Institute of Environmental Health, Budapest, Hungary
| | - Yann LeCam
- EURORDIS, European Organisation for Rare Diseases, Paris, France
| | - Stephen Lynn
- MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK
| | - Marija Meznaric
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Maurizio Moggio
- Neuromuscular Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy
| | | | - Luisa Politano
- Division of Cardiomyology and Medical Genetics, Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Manuel Posada de la Paz
- Manuel Posada de la Paz, Institute of Rare Diseases Research, IIER, ISCIII and Spain RDR & CIBERER, Madrid, Spain
| | | | - Peter Schneiderat
- Muscle Tissue Culture Collection, Friedrich-Baur-Institute, Neurological Department, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Monica Ensini
- MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK
| | - Barbara Garavaglia
- Molecular Neurogenetics Unit, Fondazione Istituto Neurologico C. Besta, Milano, Italy
| | - David Gurwitz
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Diana Johnson
- Dubowitz Neuromuscular Centre, MRC Neuromuscular Centre at UCL Institute of Child Health, London, UK
| | - Francesco Muntoni
- Dubowitz Neuromuscular Centre, MRC Neuromuscular Centre at UCL Institute of Child Health, London, UK
| | - Jack Puymirat
- Department of Human Genetics, Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
| | - Mojgan Reza
- MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK
| | - Thomas Voit
- Inserm U974—Institute of Myology, University Pierre and Marie Curie Paris 6, Paris, France
| | - Chiara Baldo
- Laboratorio di Genetica Umana, E.O. Ospedali Galliera, Genova, Italy
| | | | - Stefano Goldwurm
- Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy
| | - Giuseppe Merla
- Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Elena Pegoraro
- Department of Neurosciences, NPSRR University of Padova, Padova, Italy
| | - Alessandra Renieri
- Division of Medical Genetics, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Kurt Zatloukal
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Mirella Filocamo
- Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy
| | - Hanns Lochmüller
- MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK
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Kalinkovich A, Livshits G. Sarcopenia--The search for emerging biomarkers. Ageing Res Rev 2015; 22:58-71. [PMID: 25962896 DOI: 10.1016/j.arr.2015.05.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 05/06/2015] [Accepted: 05/06/2015] [Indexed: 12/12/2022]
Abstract
Sarcopenia, an age-related decline in skeletal muscle mass and function, dramatically affects the life quality of elder people. In view of increasing life expectancy, sarcopenia renders a heavy burden on the health care system. However, although there is a consensus that sarcopenia is a multifactorial syndrome, its etiology, underlying mechanisms, and even definition remain poorly delineated, thus, preventing development of a precise treatment strategy. The main aim of our review is to critically analyze potential sarcopenia biomarkers in light of the molecular mechanisms of their involvement in sarcopenia pathogenesis. Normal muscle mass and function maintenance are proposed to be dependent on the dynamic balance between the positive regulators of muscle growth such as bone morphogenetic proteins (BMPs), brain-derived neurotrophic factor (BDNF), follistatin (FST) and irisin, and negative regulators including TGFβ, myostatin, activins A and B, and growth and differentiation factor-15 (GDF-15). We hypothesize that the shift in this balance to muscle growth inhibitors, along with increased expression of the C- terminal agrin fragment (CAF) associated with age-dependent neuromuscular junction (NMJ) dysfunction, as well as skeletal muscle-specific troponin T (sTnT), a key component of contractile machinery, is a main mechanism underlying sarcopenia pathogenesis. Thus, this review proposes and emphasizes that these molecules are the emerging sarcopenia biomarkers.
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Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol 2014; 76:325-37. [PMID: 25043204 DOI: 10.1002/ana.24217] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 07/01/2014] [Accepted: 07/01/2014] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. METHODS Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. RESULTS We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. INTERPRETATION A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.
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Affiliation(s)
- Emanuela Colombo
- Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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Tomellini E, Lagadec C, Polakowska R, Le Bourhis X. Role of p75 neurotrophin receptor in stem cell biology: more than just a marker. Cell Mol Life Sci 2014; 71:2467-81. [PMID: 24481864 PMCID: PMC11113797 DOI: 10.1007/s00018-014-1564-9] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/20/2013] [Accepted: 01/14/2014] [Indexed: 01/02/2023]
Abstract
p75(NTR), the common receptor for both neurotrophins and proneurotrophins, has been widely studied because of its role in many tissues, including the nervous system. More recently, a close relationship between p75(NTR) expression and pluripotency has been described. p75(NTR) was shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. Here, we give an overview of the current knowledge on p75(NTR) in stem cells, ranging from embryonic to adult stem cells, and cancer stem cells. In an attempt to address its potential role in the control of stem cell biology, the molecular mechanisms underlying p75(NTR) signaling in different models are also highlighted. p75(NTR)-mediated functions include survival, apoptosis, migration, and differentiation, and depend on cell type, (pro)neurotrophin binding, interacting transmembrane co-receptors expression, intracellular adaptor molecule availability, and post-translational modifications, such as regulated proteolytic processing. It is therefore conceivable that p75(NTR) can modulate cell-fate decisions through its highly ramified signaling pathways. Thus, elucidating the potential implications of p75(NTR) activity as well as the underlying molecular mechanisms of p75(NTR) will shed new light on the biology of both normal and cancer stem cells.
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Affiliation(s)
- Elisa Tomellini
- Université Lille 1, 59655 Villeneuve d’Ascq, France
- Inserm U908, 59655 Villeneuve d’Ascq, France
- SIRIC ONCOLille, Lille, France
| | - Chann Lagadec
- Université Lille 1, 59655 Villeneuve d’Ascq, France
- Inserm U908, 59655 Villeneuve d’Ascq, France
- SIRIC ONCOLille, Lille, France
| | - Renata Polakowska
- Inserm U837 Jean-Pierre Aubert Research Center, Institut pour la Recherche sur le Cancer de Lille (IRCL), 59045 Lille, France
- SIRIC ONCOLille, Lille, France
| | - Xuefen Le Bourhis
- Université Lille 1, 59655 Villeneuve d’Ascq, France
- Inserm U908, 59655 Villeneuve d’Ascq, France
- Inserm U908, Université Lille 1, Batiment SN3, 59655 Villeneuve d’Ascq, France
- SIRIC ONCOLille, Lille, France
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Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide. PLoS One 2014; 9:e99378. [PMID: 24905361 PMCID: PMC4048316 DOI: 10.1371/journal.pone.0099378] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 05/13/2014] [Indexed: 02/06/2023] Open
Abstract
Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.
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Cellular players in skeletal muscle regeneration. BIOMED RESEARCH INTERNATIONAL 2014; 2014:957014. [PMID: 24779022 PMCID: PMC3980925 DOI: 10.1155/2014/957014] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 01/12/2014] [Accepted: 01/28/2014] [Indexed: 12/12/2022]
Abstract
Skeletal muscle, a tissue endowed with remarkable endogenous regeneration potential, is still under focused experimental investigation mainly due to treatment potential for muscle trauma and muscular dystrophies. Resident satellite cells with stem cell features were enthusiastically described quite a long time ago, but activation of these cells is not yet controlled by any medical interventions. However, after thorough reports of their existence, survival, activation, and differentiation there are still many questions to be answered regarding the intimate mechanism of tissue regeneration. This review delivers an up-to-date inventory of the main known key players in skeletal muscle repair, revealed by various models of tissue injuries in mechanical trauma, toxic lesions, and muscular dystrophy. A better understanding of the spatial and temporal relationships between various cell populations, with different physical or paracrine interactions and phenotype changes induced by local or systemic signalling, might lead to a more efficient approach for future therapies.
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Colombo E, Bedogni F, Lorenzetti I, Landsberger N, Previtali SC, Farina C. Autocrine and immune cell-derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration. J Pathol 2013; 231:190-8. [PMID: 23775641 DOI: 10.1002/path.4228] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 06/05/2013] [Accepted: 06/11/2013] [Indexed: 01/03/2023]
Abstract
The neurotrophin system has a role in skeletal muscle biology. Conditional depletion of BDNF in mouse muscle precursor cells alters myogenesis and regeneration in vivo. However, the expression, localization and function of BDNF in human skeletal muscle tissue is not known, so the relevance of the rodent findings for human muscle are unknown. Here we address this by combining ex vivo histological investigations on human biopsies with in vitro analyses of human primary myocytes. We found that BDNF was expressed by precursor and differentiated cells both in vitro and in vivo. Differential analysis of BDNF receptors showed expression of p75NTR and not of TrkB in myocytes, suggesting that the BDNF-p75NTR axis is predominant in human skeletal muscle cells. Several in vitro functional experiments demonstrated that BDNF gene silencing or protein blockade in myoblast cultures hampered myogenesis. Finally, histological investigations of inflammatory myopathy biopsies revealed that infiltrating immune cells localized preferentially near p75NTR-positive regenerating fibres and that they produced BDNF. In conclusion, BDNF is an autocrine factor for skeletal muscle cells and may regulate human myogenesis. Furthermore, the preferential localization of BDNF-producing immune cells near p75NTR-positive regenerating myofibres suggests that immune cell-derived BDNF may sustain tissue repair in inflamed muscle.
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Affiliation(s)
- Emanuela Colombo
- Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
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Colombo E, Romaggi S, Blasevich F, Mora M, Falcone C, Lochmüller H, Morandi L, Farina C. The neurotrophin receptor p75NTR is induced on mature myofibres in inflammatory myopathies and promotes myotube survival to inflammatory stress. Neuropathol Appl Neurobiol 2012; 38:367-78. [PMID: 21851375 DOI: 10.1111/j.1365-2990.2011.01212.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
AIMS Recent studies propose the neurotrophin receptor p75NTR as a marker for muscle satellite cells and a key regulator of regenerative processes after injury. Here, we investigated the contribution of cellular compartments other than satellite cells and regenerating myofibres to p75NTR signal in diseased skeletal muscle. METHODS We checked regulation of p75NTR expression in muscle biopsies from patients with inflammatory myopathies (polymyositis, dermatomyositis and inclusion body myositis), or Becker muscular dystrophy, and in nonmyopathic tissues. Quantitative PCR, immunohistochemistry, immunofluorescence or electron microscopy were used. RNA interference approaches were applied to myotubes to explore p75NTR function. RESULTS We found p75NTR transcript and protein upregulation in all inflammatory myopathies but not in dystrophic muscle, suggesting a role for inflammatory mediators in induction of p75NTR expression. In inflamed muscle p75NTR was localized on distinct cell types, including immune cells and mature myofibres. In vitro assays on human myotubes confirmed that inflammatory factors such as IL-1 could induce p75NTR. Finally, RNA interference experiments in differentiated cells showed that, in the absence of p75NTR, myotubes were more susceptible to apoptosis when exposed to inflammatory stimuli. CONCLUSIONS Our observations that p75NTR is upregulated on skeletal myofibres in inflammatory myopathies in vivo and promotes resistance to inflammatory mediators in vitro suggest that neurotrophin signalling through p75NTR may mediate a tissue-protective response to inflammation in skeletal myofibres.
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Affiliation(s)
- E Colombo
- Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy
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Colombo E, Cordiglieri C, Melli G, Newcombe J, Krumbholz M, Parada LF, Medico E, Hohlfeld R, Meinl E, Farina C. Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. ACTA ACUST UNITED AC 2012; 209:521-35. [PMID: 22393127 PMCID: PMC3302220 DOI: 10.1084/jem.20110698] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.
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Affiliation(s)
- Emanuela Colombo
- Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
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Colombo E, Romaggi S, Mora M, Morandi L, Farina C. A role for inflammatory mediators in the modulation of the neurotrophin receptor p75NTR on human muscle precursor cells. J Neuroimmunol 2012; 243:100-2. [DOI: 10.1016/j.jneuroim.2011.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 11/25/2011] [Accepted: 12/01/2011] [Indexed: 12/01/2022]
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