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Ganjibakhsh M, Tkachenko Y, Knutsen RH, Kozel BA. Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies. Matrix Biol 2025; 138:8-21. [PMID: 40158781 DOI: 10.1016/j.matbio.2025.03.003] [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: 01/04/2025] [Revised: 03/07/2025] [Accepted: 03/23/2025] [Indexed: 04/02/2025]
Abstract
Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.
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Affiliation(s)
- Meysam Ganjibakhsh
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Yanina Tkachenko
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Russell H Knutsen
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA
| | - Beth A Kozel
- Institute of Genomic Medicine, Abigail Wexler Research Institute, Nationwide Children's Hospital, OH 43205, USA; Department of Pediatrics, The Ohio State University, OH 43210, USA.
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Gul MT, Khattak MNK, Qaisar R, Jayakumar MN, Samsudin ABR, Khan AA. The Effects of miR-22-3p on Differentiation of Human Dental Pulp Stem Cells into Neural Progenitor-Like Cells. Mol Neurobiol 2025; 62:7445-7468. [PMID: 39900772 DOI: 10.1007/s12035-025-04702-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/11/2025] [Indexed: 02/05/2025]
Abstract
Stem cell treatment shows promise in treating conditions such as neurodegenerative disorders and spinal injuries, but its effectiveness is hampered by cell death and apoptosis. Improving the differentiation of MSCs into neural cells could enhance their therapeutic potential. The role of miR-22-3p in human dental pulp stem cells (HDPSCs), a superior alternative to treat neurodegenerative disorders, and its molecular mechanisms during neural differentiation remain elusive. Therefore, we investigated the miR-22-3p transfections during HDPSC differentiation into neural progenitor-like cells (NPCs) and elucidated the molecular processes through transcriptomic analysis. HDPSCs were differentiated into NPCs after transfection with a miR-22-3p mimic and inhibitor; the differentiation process was assessed by cell viability and expression of Nestin protein. mRNA sequencing on days 1, 3, and 7 of the differentiation process identified several differentially expressed genes (DEGs). Cytoscape and functional enrichment analysis pinpointed central hub genes among the DEGs and uniquely expressed genes. miR-22-3p mimic hindered HDPSC differentiation by reducing proliferation and increasing apoptosis. It downregulated genes linked to extracellular matrix, synaptic and vesicle functions, lipid metabolism, JAK-STAT, and cell cycle pathways across all days while activating proteasome and digestion pathways. In contrast, miR-22-3p inhibition boosts NPC proliferation and elevates Nestin neural marker protein expression. Altogether, miR-22-3p disrupts synapse functioning and lipid metabolism pathways, resulting in apoptosis and death. Conversely, inhibiting miR-22-3p enhances neural differentiation and proliferation of HDPSCs, suggesting its potential application in generating a greater quantity of NPCs and neurons.
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Affiliation(s)
- Muhammad Tehsil Gul
- Department of Applied Biology, College of Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates
- Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Muhammad Nasir Khan Khattak
- Department of Study of Health in Pomerania/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Rizwan Qaisar
- Cardiovascualr Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates
- Space Medicine Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Manju Nidagodu Jayakumar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - A B Rani Samsudin
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates
| | - Amir Ali Khan
- Department of Applied Biology, College of Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates.
- Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, 27272, Sharjah, United Arab Emirates.
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Choi J, Kwak Y, Park M, Jo JY, Kang JH, Myeong-Cherl K, Kim HR, Kim G, Kong SH, Park DJ, Lee HS, Lee HJ, Kim JM, Kim SG, Yang HK, Ryu JK, Cho SJ. Cancer-associated fibroblast-derived fibulin-5 promotes epithelial-mesenchymal transition in diffuse-type gastric cancer via cAMP response element-binding protein pathway, showing poor prognosis. Exp Mol Med 2025:10.1038/s12276-025-01447-8. [PMID: 40369121 DOI: 10.1038/s12276-025-01447-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/27/2025] [Accepted: 02/23/2025] [Indexed: 05/16/2025] Open
Abstract
Diffuse-type gastric cancer (DGC), characterized by poorly cohesive cells within fibrotic stroma, is associated with advanced disease and poor prognosis. Here, to identify distinct biomarkers for DGC compared with intestinal-type gastric cancer, we constructed a comprehensive large-scale signaling network using RNA-sequencing data from three genomic databases (The Cancer Genome Atlas, GSE62254 and GSE26253), developed a mathematical model and conducted simulation analyses. For validation, we used tissue microarray blocks of gastric cancers with immunohistochemical staining, single-cell RNA sequencing, primary cultures of cancer-associated fibroblasts (CAFs) and organoids, and a co-culture system involving CAFs and cancer cells. Signaling network analysis identified six differentially activated signaling components across the database, including BIRC5, TTK, NEK2, FHL1, NR2F1 and FBLN5. Among the differentially activated signaling components, high tumoral expression of fibulin-5 protein encoded by FBLN5 correlated with poor overall and disease-specific survival rates in patients with DGC, even after adjusting for the tumor, node, metastases (TNM) stage. Fibulin-5, derived from CAFs within DGC stroma, promoted organoid growth and epithelial-mesenchymal transition (EMT) in DGC cell lines via the cAMP response element-binding protein (CREB) pathway in a CAF co-culture system. FBLN5 knockdown in CAFs reduced the aggressive phenotype of co-cultured DGC cells, while CREB inhibitors reversed EMT. Furthermore, levels of secreted FBLN5 in patient blood samples correlated with its expression in primary tumors. In summary, fibulin-5 secreted by CAFs and interacted with DGC cells promotes EMT and is clinically associated with poor patient outcomes. These findings suggest fibulin-5 as a potential prognostic marker and therapeutic target in patients with DGC.
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Affiliation(s)
- Jinju Choi
- Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Miree Park
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Yeon Jo
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyuk Kang
- Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Kook Myeong-Cherl
- Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Hang-Rae Kim
- Department of Biomedical Sciences, BK21 FOUR Biomedical Science Project, and Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gwanghun Kim
- Department of Biomedical Sciences, BK21 FOUR Biomedical Science Project, and Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seong-Ho Kong
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do-Joong Park
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyuk-Joon Lee
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Sang Gyun Kim
- Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Han-Kwang Yang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Kon Ryu
- Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo-Jeong Cho
- Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Suzuki Y, Nampei M, Kawakita F, Oinaka H, Nakajima H, Suzuki H. The effect of Fibulin-5 on early brain injury after subarachnoid hemorrhage in mice. Neurochem Int 2025; 187:105989. [PMID: 40339910 DOI: 10.1016/j.neuint.2025.105989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Early brain injury (EBI) is an important cause that determines outcomes after aneurysmal subarachnoid hemorrhage (SAH). Our recent clinical study reported that a high concentration of plasma fibulin-5 (FBLN5), one of matricellular proteins, was associated with poor outcomes after SAH. The aim of this study was to investigate whether and how FBLN5 was associated with EBI during an acute phase of SAH in mice. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or four dosages (0.001, 0.01, 0.1, and 1 μg) of short or long recombinant FBLN5 (rFBLN5) were randomly administrated by an intracerebroventricular injection. Neurobehavioral test, measurements of brain water content, immunohistochemical staining, and Western blotting were performed to evaluate EBI 24 h after SAH. Short rFBLN5 had no significant effects on EBI, but administration of long rFBLN5 containing an arginine-glycine-aspartic acid motif improved neurobehavior functions depending on the dosages, without affecting brain edema. Administration of long rFBLN5 also reduced cleaved caspase-3-dependent neuronal apoptosis, associated with the inhibition of post-SAH upregulation of transforming growth factor-β1, but no significant changes in the expression level of Smad 2/3, mitogen-activated protein kinases, and another matricellular protein tenascin-C. Although further research is required to clarify the detailed mechanism, this study demonstrated for the first time that FBLN5 played a protective role against neuronal apoptosis in an acute phase of experimental SAH.
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Affiliation(s)
- Yume Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Mai Nampei
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Fumihiro Kawakita
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hiroki Oinaka
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hideki Nakajima
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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Lynch WB, Miracle SA, Goldstein SI, Beierle JA, Bhandari R, Gerhardt ET, Farnan A, Nguyen BM, Wingfield KK, Kazerani I, Saavedra GA, Averin O, Baskin BM, Ferris MT, Reilly CA, Emili A, Bryant CD. Validation studies and multiomics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior. J Pharmacol Exp Ther 2025; 392:103557. [PMID: 40215834 DOI: 10.1016/j.jpet.2025.103557] [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: 09/09/2024] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 04/25/2025] Open
Abstract
Sensitivity to the subjective reinforcing properties of opioids has a genetic component and can predict addiction liability of opioid compounds. We previously identified Zhx2 as a candidate gene underlying increased brain concentration of the oxycodone (OXY) metabolite oxymorphone (OMOR) in BALB/cJ (J) versus BALB/cByJ (By) females that could increase OXY state-dependent reward. A large structural intronic variant is associated with a robust reduction of Zhx2 expression in J mice, which we hypothesized enhances OMOR levels and OXY addiction-like behaviors. We tested this hypothesis by restoring the Zhx2 loss-of-function in J mice (mouse endogenous retroviral element knockout) and modeling the loss-of-function variant through knocking out the Zhx2 coding exon (exon 3 knockout [E3KO]) in By mice and assessing brain OXY metabolite levels and behavior. Consistent with our hypothesis, Zhx2 E3KO females showed an increase in brain OMOR levels and OXY-induced locomotor activity. However, contrary to our hypothesis, state-dependent expression of OXY conditioned place preference decreased in E3KO females and increased in E3KO males. We also overexpressed Zhx2 in the livers and brains of J mice and observed Zhx2 overexpression in select brain regions that was associated with reduced OXY state-dependent learning. Integrative transcriptomic and proteomic analysis of E3KO mice identified astrocyte function, cell adhesion, extracellular matrix properties, and endothelial cell functions as pathways influencing brain OXY metabolite concentration and behavior. These results support Zhx2 as a quantitative trait gene underlying brain OMOR concentration that is associated with changes in OXY behavior and implicate potential quantitative trait mechanisms that together inform our overall understanding of Zhx2 in brain function. SIGNIFICANCE STATEMENT: This study validated Zhx2 as a gene whose dysfunction increases brain levels of a highly potent and addictive metabolite of oxycodone, oxymorphone, in a female-specific manner. This result has broad implications for understanding the role of oxycodone metabolism and brain oxymorphone levels in the addiction liability of oxycodone (the active ingredient in OxyContin) and highlights the need for the study of sex differences in opioid metabolism as it relates to the addiction liability of opioids and opioid use disorder.
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Affiliation(s)
- William B Lynch
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Graduate Program for Neuroscience, Graduate Medical Sciences, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts; Transformative Training Program in Addiction Science, Boston University, Boston, Massachusetts
| | - Sophia A Miracle
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Graduate Program for Neuroscience, Graduate Medical Sciences, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
| | - Stanley I Goldstein
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
| | - Jacob A Beierle
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Transformative Training Program in Addiction Science, Boston University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
| | - Rhea Bhandari
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts
| | - Ethan T Gerhardt
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Undergraduate Research Opportunity Program (UROP), Boston University, Boston, Massachusetts
| | - Ava Farnan
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts
| | - Binh-Minh Nguyen
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts
| | - Kelly K Wingfield
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
| | - Ida Kazerani
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Summer Research Internship Program, National Institute on Drug Abuse, North Bethesda, Maryland
| | - Gabriel A Saavedra
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Research in Science and Engineering Program, Boston University, Boston, Massachusetts
| | - Olga Averin
- Center for Human Toxicology, University of Utah Health, Salt Lake City, Utah
| | - Britahny M Baskin
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts; Training Program on Development of Medications for Substance Use Disorder, Northeastern University, Boston, Massachusetts
| | - Martin T Ferris
- Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
| | | | - Andrew Emili
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
| | - Camron D Bryant
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, Massachusetts.
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Tuli TR, Mia M, Habib A. Integrated bioinformatics approach for the identification and validation of novel biomarkers in ACC progression and prognosis. Biomarkers 2025:1-15. [PMID: 40183287 DOI: 10.1080/1354750x.2025.2489453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 03/29/2025] [Indexed: 04/05/2025]
Abstract
CONCLUSION In conclusion, the identified novel biomarkers and associated pathways, provides a comprehensive insight into the molecular mechanisms, prognosis, and potential clinical applications for the diagnosis and therapeutic interventions of ACC.
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Affiliation(s)
- Tonima Rahman Tuli
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
| | - Mijan Mia
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
| | - Ahsan Habib
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
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Ramachandra AB, Sharma P, De Man R, Nikola F, Guerrera N, Doddaballapur P, Cavinato C, Choi R, Raredon MSB, Szafron JM, Zhuang ZW, Barnthaler T, Justet A, Akingbesote ND, Abu Hussein NS, Diggs L, Perry RJ, Adams TS, Singh I, Kaminski N, Yan X, Tellides G, Humphrey JD, Manning EP. Hypoxia-Induced Cardiopulmonary Remodeling and Recovery: Critical Roles of the Proximal Pulmonary Artery, Macrophages, and Exercise. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.15.638455. [PMID: 40027757 PMCID: PMC11870459 DOI: 10.1101/2025.02.15.638455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.
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Elsayed OA, Cai J, Liu Y. Exfoliation syndrome genetics in the era of post-GWAS. Vision Res 2025; 226:108518. [PMID: 39549468 PMCID: PMC11624108 DOI: 10.1016/j.visres.2024.108518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/18/2024]
Abstract
Exfoliation syndrome (XFS), or pseudoexfoliation syndrome, is considered a systemic disorder that leads to glaucoma with progressive visual field loss. A better insight into the underlying pathogenic mechanism will help diagnose the disease and prevent and slow progression. Here, we provide an overview of disease pathogenesis in the light of GWAS and multi-omics research. We discuss possible environmental interactions related to XFS. We investigate the potential interactions in differentially expressed genes from RNA-Seq by using Ingenuity Pathway Analysis. MAPK pathway was identified as the top network of these genes. Further investigation is needed to verify our results in vivo. It is necessary to establish an animal model mimicking exfoliation syndrome phenotypes.
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Affiliation(s)
- Ola A Elsayed
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Jingwen Cai
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA
| | - Yutao Liu
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA; Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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Schofield C, Sarrigiannidis S, Moran‐Horowich A, Jackson E, Rodrigo‐Navarro A, van Agtmael T, Cantini M, Dalby MJ, Salmeron‐Sanchez M. An In Vitro Model of the Blood-Brain Barrier for the Investigation and Isolation of the Key Drivers of Barriergenesis. Adv Healthc Mater 2024; 13:e2303777. [PMID: 39101628 PMCID: PMC11670300 DOI: 10.1002/adhm.202303777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 07/24/2024] [Indexed: 08/06/2024]
Abstract
The blood-brain barrier (BBB) tightly regulates substance transport between the bloodstream and the brain. Models for the study of the physiological processes affecting the BBB, as well as predicting the permeability of therapeutic substances for neurological and neurovascular pathologies, are highly desirable. Existing models, such as Transwell utilizing-models, do not mimic the extracellular environment of the BBB with their stiff, semipermeable, non-biodegradable membranes. To help overcome this, we engineered electrospun membranes from poly L-lactic acid in combination with a nanometric coating of poly(ethyl acrylate) (PEA) that drives fibrillogenesis of fibronectin, facilitating the synergistic presentation of both growth factors and integrin binding sites. Compared to commercial semi-porous membranes, these membranes significantly improve the expression of BBB-related proteins in brain endothelial cells. PEA-coated membranes in combination with different growth factors and extracellular protein coatings reveal nerve growth factor (NGF) and fibroblast growth factor (FGF-2) caused formation of better barriers in vitro. This BBB model offers a robust platform for studying key biochemical factors influencing barrier formation that marries the simplicity of the Transwell model with the highly tunable electrospun PEA-fibronectin membranes. This enables the generation of high-throughput drug permeability models without the need of complicated co-culture conditions.
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Affiliation(s)
- Christina Schofield
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG11 6EWUK
| | | | | | - Emma Jackson
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG11 6EWUK
| | | | - Tom van Agtmael
- School of Cardiovascular and Metabolic HealthUniversity of GlasgowGlasgowG12 8TAUK
| | - Marco Cantini
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG11 6EWUK
| | - Matthew J. Dalby
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG11 6EWUK
| | - Manuel Salmeron‐Sanchez
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG11 6EWUK
- Institute for Bioengineering of Catalonia (IBEC)The Barcelona Institute for Science and Technology (BIST)Barcelona08028Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain
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Suzuki Y, Okada T, Oinaka H, Nakajima H, Nampei M, Kawakita F, Suzuki H. Independent elevation of plasma fibulin-5 proceeding chronic hydrocephalus development after aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 2024; 247:108634. [PMID: 39541611 DOI: 10.1016/j.clineuro.2024.108634] [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: 03/24/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Aneurysmal subarachnoid hemorrhage (aSAH) causes chronic hydrocephalus (CH) due to disturbance in the reabsorption of cerebrospinal fluid following subarachnoidal fibrosis via inflammatory reactions or blood clotting products. Fibulin-5 (FBLN5) is one of matricellular proteins associated with fibrosis processes. OBJECTIVE The aim of this study was to assess whether FBLN5 elevation is related to CH after aSAH. METHODS This study prospectively enrolled consecutive aSAH patients at 9 institutions in Japan from 2013 to 2016. Plasma FBLN5 levels at days 1-3, 4-6, 7-9, and 10-12 were measured. Relationships between plasma FBLN5 levels and incidence of CH were analyzed. Multivariate logistic regression analyses were performed on clinical variables with a p value of < 0.05 on univariate analyses and plasma FBLN5 levels with the highest area under the receiver-operating characteristic (ROC) curve. RESULTS A total of 229 aSAH patients were analyzed, and CH occurred in 67 patients. FBLN5 levels at days 4-6 from aSAH onset elevated in patients resulting in subsequent CH occurrence. The ROC curve analyses revealed that the area under the curve (AUC) at days 4-6 post-aSAH was the highest (AUC, 0.592; 95 % confidence interval, 0.514-0.671) among the four time points. Multivariate logistic regression analyses using clinical variables related to CH on univariate analyses and plasma FBLN5 levels at days 4-6 post-aSAH revealed that FBLN5 levels at days 4-6 post-aSAH ≥ 366.4 ng/mL (adjusted odds ratio, 3.14) were an independent determinant of subsequent CH development. CONCLUSION The elevation of plasma FBLN5 levels in a subacute phase of aSAH may contribute to the development of CH. FBLN5 may be a molecular target to develop a new therapy against post-aSAH CH.
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Affiliation(s)
- Yume Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Takeshi Okada
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hiroki Oinaka
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hideki Nakajima
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Mai Nampei
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Fumihiro Kawakita
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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11
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Niro F, Fernandes S, Cassani M, Apostolico M, Oliver-De La Cruz J, Pereira-Sousa D, Pagliari S, Vinarsky V, Zdráhal Z, Potesil D, Pustka V, Pompilio G, Sommariva E, Rovina D, Maione AS, Bersanini L, Becker M, Rasponi M, Forte G. Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis. Transl Res 2024; 273:58-77. [PMID: 39025226 PMCID: PMC11832458 DOI: 10.1016/j.trsl.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/14/2024] [Accepted: 07/14/2024] [Indexed: 07/20/2024]
Abstract
Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the activation of cardiac fibroblasts (cFbs) to myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments, as most of the cellular-based in vitro reductionist models do not take into account the leading role of ECM cues in driving the progression of the pathology. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α-SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere assembly, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.
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Affiliation(s)
- Francesco Niro
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno; Masaryk University, Faculty of Medicine, Department of Biomedical Sciences, Brno 62500, Czech Republic; School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, UK
| | - Soraia Fernandes
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno
| | - Marco Cassani
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno
| | - Monica Apostolico
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno
| | - Jorge Oliver-De La Cruz
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST), Barcelona, Spain
| | - Daniel Pereira-Sousa
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno; Masaryk University, Faculty of Medicine, Department of Biomedical Sciences, Brno 62500, Czech Republic
| | - Stefania Pagliari
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno; School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, UK
| | - Vladimir Vinarsky
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno
| | - Zbyněk Zdráhal
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
| | - David Potesil
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
| | - Vaclav Pustka
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy; Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Milan, Italy
| | - Elena Sommariva
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Davide Rovina
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | - Angela Serena Maione
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
| | | | | | - Marco Rasponi
- Department of Electronics, Informatics and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Giancarlo Forte
- International Clinical Research Center (ICRC), St Anne's University Hospital Brno; School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, UK.
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12
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Wong GYM, Li J, McKay M, Castaneda M, Bhimani N, Diakos C, Hugh TJ, Molloy MP. Proteogenomic Characterization of Early Intrahepatic Recurrence after Curative-Intent Treatment of Colorectal Liver Metastases. J Proteome Res 2024; 23:4523-4537. [PMID: 39264718 DOI: 10.1021/acs.jproteome.4c00440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024]
Abstract
Clinical and pathological factors are insufficient to accurately identify patients at risk of early recurrence after curative-intent treatment of colorectal liver metastases (CRLM). This study aimed to identify candidate prognostic proteogenomic biomarkers for early intrahepatic recurrence after curative-intent resection of CRLM. Patients diagnosed with intrahepatic recurrence within 6 months of liver resection were categorized as the "early recurrence" group, while those who achieved a recurrence-free status for 10 years were designated as "durable remission". Comprehensive genomic and proteomic profiling of fresh frozen samples from these prognostically distinct groups was performed using the TruSight Oncology 500 assay and label-free data-dependent acquisition liquid chromatography-mass spectrometry. Genetic alterations were identified in 117 of the 523 profiled genes in patients with early recurrence. The most common somatic mutations linked to early recurrence were TP53 (88%), APC (71%), KRAS (38%), and SMAD4 (21%). SMAD4 alterations were absent in samples from patients with a durable remission. Calponin-2, versican core protein, glutathione peroxidase 3, fibulin-5, and amyloid-β precursor protein were upregulated more than 2-fold in early recurrence. Exploratory analysis of these proteogenomic biomarkers suggests that SMAD4, calponin-2, and glutathione peroxidase 3 may have the potential to predict early recurrence, enabling improved prognostication and precision oncology in CRLM.
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Affiliation(s)
- Geoffrey Yuet Mun Wong
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
- Northern Clinical School, The University of Sydney, Sydney, New South Wales 2065, Australia
- Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, St Leonards, New South Wales 2065, Australia
| | - Jun Li
- Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, St Leonards, New South Wales 2065, Australia
| | - Matthew McKay
- Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, St Leonards, New South Wales 2065, Australia
| | - Miguel Castaneda
- Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, St Leonards, New South Wales 2065, Australia
| | - Nazim Bhimani
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales 2050, Australia
| | - Connie Diakos
- Northern Clinical School, The University of Sydney, Sydney, New South Wales 2065, Australia
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
| | - Thomas J Hugh
- Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia
- Northern Clinical School, The University of Sydney, Sydney, New South Wales 2065, Australia
| | - Mark P Molloy
- Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, St Leonards, New South Wales 2065, Australia
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13
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Burgess JK, Gosens R. Mechanotransduction and the extracellular matrix: Key drivers of lung pathologies and drug responsiveness. Biochem Pharmacol 2024; 228:116255. [PMID: 38705536 DOI: 10.1016/j.bcp.2024.116255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/19/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
The lung is a biomechanically active organ, with multiscale mechanical forces impacting the organ, tissue and cellular responses within this microenvironment. In chronic lung diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and others, the structure of the lung is drastically altered impeding gas exchange. These changes are, in part, reflected in alterations in the composition, amount and organization of the extracellular matrix within the different lung compartments. The transmission of mechanical forces within lung tissue are broadcast by this complex mix of extracellular matrix components, in particular the collagens, elastin and proteoglycans and the crosslinking of these components. At both a macro and a micro level, the mechanical properties of the microenvironment have a key regulatory role in ascertaining cellular responses and the function of the lung. Cells adhere to, and receive signals from, the extracellular matrix through a number of different surface receptors and complexes which are important for mechanotransduction. This review summarizes the multiscale mechanics in the lung and how the mechanical environment changes in lung disease and aging. We then examine the role of mechanotransduction in driving cell signaling events in lung diseases and finish with a future perspective of the need to consider how such forces may impact pharmacological responsiveness in lung diseases.
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Affiliation(s)
- Janette K Burgess
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
| | - Reinoud Gosens
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands
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14
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Krymchenko R, Coşar Kutluoğlu G, van Hout N, Manikowski D, Doberenz C, van Kuppevelt TH, Daamen WF. Elastogenesis in Focus: Navigating Elastic Fibers Synthesis for Advanced Dermal Biomaterial Formulation. Adv Healthc Mater 2024; 13:e2400484. [PMID: 38989717 DOI: 10.1002/adhm.202400484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/31/2024] [Indexed: 07/12/2024]
Abstract
Elastin, a fibrous extracellular matrix (ECM) protein, is the main component of elastic fibers that are involved in tissues' elasticity and resilience, enabling them to undergo reversible extensibility and to endure repetitive mechanical stress. After wounding, it is challenging to regenerate elastic fibers and biomaterials developed thus far have struggled to induce its biosynthesis. This review provides a comprehensive summary of elastic fibers synthesis at the cellular level and its implications for biomaterial formulation, with a particular focus on dermal substitutes. The review delves into the intricate process of elastogenesis by cells and investigates potential triggers for elastogenesis encompassing elastin-related compounds, ECM components, and other molecules for their potential role in inducing elastin formation. Understanding of the elastogenic processes is essential for developing biomaterials that trigger not only the synthesis of the elastin protein, but also the formation of a functional and branched elastic fiber network.
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Affiliation(s)
- Roman Krymchenko
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - Gizem Coşar Kutluoğlu
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
- MedSkin Solutions Dr. Suwelack AG, 48727, Billerbeck, Germany
| | - Noor van Hout
- Department of Dermatology, Radboud university medical center, Nijmegen, 6525 GA, The Netherlands
| | | | | | - Toin H van Kuppevelt
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - Willeke F Daamen
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud university medical center, PO Box 9101, Nijmegen, 6500 HB, The Netherlands
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15
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Huang M, Tabib T, Khanna D, Assassi S, Domsic R, Lafyatis R. Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis. Ann Rheum Dis 2024; 83:1335-1344. [PMID: 38754983 PMCID: PMC11442142 DOI: 10.1136/ard-2023-225415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/26/2024] [Indexed: 05/18/2024]
Abstract
OBJECTIVES Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved. METHODS Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs). RESULTS Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc. CONCLUSIONS This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.
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Affiliation(s)
- Mengqi Huang
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Tracy Tabib
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Dinesh Khanna
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Shervin Assassi
- Division of Rheumatology, The University of Texas Health Science Center, Houston, Texas, USA
| | - Robyn Domsic
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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16
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Eun K, Kim AY, Ryu S. Matricellular proteins in immunometabolism and tissue homeostasis. BMB Rep 2024; 57:400-416. [PMID: 38919018 PMCID: PMC11444987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/11/2023] [Accepted: 04/25/2024] [Indexed: 06/27/2024] Open
Abstract
Matricellular proteins are integral non-structural components of the extracellular matrix. They serve as essential modulators of immunometabolism and tissue homeostasis, playing critical roles in physiological and pathological conditions. These extracellular matrix proteins including thrombospondins, osteopontin, tenascins, the secreted protein acidic and rich in cysteine (SPARC) family, the Cyr61, CTGF, NOV (CCN) family, and fibulins have multi-faceted functions in regulating immune cell functions, metabolic pathways, and tissue homeostasis. They are involved in immune-metabolic regulation and influence processes such as insulin signaling, adipogenesis, lipid metabolism, and immune cell function, playing significant roles in metabolic disorders such as obesity and diabetes. Furthermore, their modulation of tissue homeostasis processes including cellular adhesion, differentiation, migration, repair, and regeneration is instrumental for maintaining tissue integrity and function. The importance of these proteins in maintaining physiological equilibrium is underscored by the fact that alterations in their expression or function often coincide with disease manifestation. This review contributes to our growing understanding of these proteins, their mechanisms, and their potential therapeutic applications. [BMB Reports 2024; 57(9): 400-416].
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Affiliation(s)
- Kyoungjun Eun
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Ah Young Kim
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Seungjin Ryu
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Institute of Natural Medicine, College of Medicine, Hallym Unviersity, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
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17
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Lynch WB, Miracle SA, Goldstein SI, Beierle JA, Bhandari R, Gerhardt ET, Farnan A, Nguyen BM, Wingfield KK, Kazerani I, Saavedra GA, Averin O, Baskin BM, Ferris MT, Reilly CA, Emili A, Bryant CD. Validation studies and multi-omics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.30.610534. [PMID: 39257803 PMCID: PMC11383981 DOI: 10.1101/2024.08.30.610534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
Sensitivity to the subjective reinforcing properties of opioids has a genetic component and can predict addiction liability of opioid compounds. We previously identified Zhx2 as a candidate gene underlying increased brain concentration of the oxycodone (OXY) metabolite oxymorphone (OMOR) in BALB/cJ (J) versus BALB/cByJ (By) females that could increase OXY state-dependent reward. A large structural intronic variant is associated with a robust reduction of Zhx2 expression in J mice, which we hypothesized enhances OMOR levels and OXY addiction-like behaviors. We tested this hypothesis by restoring the Zhx2 loss-of-function in Js (MVKO) and modeling the loss-of-function variant through knocking out the Zhx2 coding exon (E3KO) in Bys and assessing brain OXY metabolite levels and behavior. Consistent with our hypothesis, Zhx2 E3KO females showed an increase in brain OMOR levels and OXY-induced locomotor activity. However, contrary to our hypothesis, state-dependent expression of OXY-CPP was decreased in E3KO females and increased in E3KO males. We also overexpressed Zhx2 in the livers and brains of Js and observed Zhx2 overexpression in select brain regions that was associated with reduced OXY state-dependent learning. Integrative transcriptomic and proteomic analysis of E3KO mice identified astrocyte function, cell adhesion, extracellular matrix properties, and endothelial cell functions as pathways influencing brain OXY metabolite concentration and behavior. These results support Zhx2 as a quantitative trait gene underlying brain OMOR concentration that is associated with changes in OXY behavior and implicate potential quantitative trait mechanisms that together inform our overall understanding of Zhx2 in brain function.
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Affiliation(s)
- William B. Lynch
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Graduate Program for Neuroscience, Graduate Medical Sciences, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA
- Transformative Training Program in Addiction Science, Boston University, Boston, MA USA
| | - Sophia A. Miracle
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Graduate Program for Neuroscience, Graduate Medical Sciences, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA
| | - Stanley I. Goldstein
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA
| | - Jacob A. Beierle
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Transformative Training Program in Addiction Science, Boston University, Boston, MA USA
- Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA
| | - Rhea Bhandari
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
| | - Ethan T. Gerhardt
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Undergraduate Research Opportunity Program (UROP), Boston University, Boston, MA USA
| | - Ava Farnan
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
| | - Binh-Minh Nguyen
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
| | - Kelly K. Wingfield
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Graduate Program in Biomolecular Pharmacology, Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA
| | - Ida Kazerani
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Summer Research Internship Program, National Institute on Drug Abuse, North Bethesda, MD USA
| | - Gabriel A. Saavedra
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Research in Science and Engineering Program, Boston University, Boston, MA USA
| | - Olga Averin
- Center for Human Toxicology, University of Utah Health, Salt Lake City, UT USA
| | - Britahny M. Baskin
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
- Training Program on Development of Medications for Substance Use Disorder, Northeastern University, Boston, MA USA
| | - Martin T. Ferris
- Department of Genetics, University of North Carolina, Chapel Hill, NC USA
| | | | - Andrew Emili
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA
| | - Camron D. Bryant
- Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA
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18
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Song S, Li X, Xue X, Dong W, Li C. Progress in the Study of the Role and Mechanism of HTRA1 in Diseases Related to Vascular Abnormalities. Int J Gen Med 2024; 17:1479-1491. [PMID: 38650587 PMCID: PMC11034561 DOI: 10.2147/ijgm.s456912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
High temperature requirement A1 (HTRA1) is a member of the serine protease family, comprising four structural domains: IGFBP domain, Kazal domain, protease domain and PDZ domain. HTRA1 encodes a serine protease, a secreted protein that is widely expressed in the vasculature. HTRA1 regulates a wide range of physiological processes through its proteolytic activity, and is also involved in a variety of vascular abnormalities-related diseases. This article reviews the role of HTRA1 in the development of vascular abnormalities-related hereditary cerebral small vessel disease (CSVD), age-related macular degeneration (AMD), tumors and other diseases. Through relevant research advances to understand the role of HTRA1 in regulating signaling pathways or refolding, translocation, degradation of extracellular matrix (ECM) proteins, thus directly or indirectly regulating angiogenesis, vascular remodeling, and playing an important role in vascular homeostasis, further understanding the mechanism of HTRA1's role in vascular abnormality-related diseases is important for HTRA1 to be used as a therapeutic target in related diseases.
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Affiliation(s)
- Shina Song
- Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
- Department of Geriatrics, General Hospital of TISCO, Taiyuan, People’s Republic of China
| | - Xiaofeng Li
- Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Xuting Xue
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Wenping Dong
- Department of Geriatrics, General Hospital of TISCO, Taiyuan, People’s Republic of China
| | - Changxin Li
- Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
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19
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Tan J, Cai S, Luo X, Li Q, Chen Y, Chen Z, Mao Y, Liu G, Yang M, Liu X. Stop codon variant in EFEMP1 is associated with primary open-angle glaucoma due to impaired regulation of aqueous humor outflow. Exp Eye Res 2024; 241:109859. [PMID: 38467175 DOI: 10.1016/j.exer.2024.109859] [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: 01/01/2024] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 03/13/2024]
Abstract
It is known that the actin cytoskeleton and its associated cellular interactions in the trabecular meshwork (TM) and juxtacanalicular tissues mainly contribute to the formation of resistance to aqueous outflow of the eye. Fibulin-3, encoded by EFEMP1 gene, has a role in extracellular matrix (ECM) modulation, and interacts with enzymatic ECM regulators, but the effects of fibulin-3 on TM cells has not been explored. Here, we report a stop codon variant (c.T1480C, p.X494Q) of EFEMP1 that co-segregates with primary open angle glaucoma (POAG) in a Chinese pedigree. In the human TM cells, overexpression of wild-type fibulin-3 reduced intracellular actin stress fibers formation and the extracellular fibronectin levels by inhibiting Rho/ROCK signaling. TGFβ1 up-regulated fibulin-3 protein levels in human TM cells by activating Rho/ROCK signaling. In rat eyes, overexpression of wild-type fibulin-3 decreased the intraocular pressure and the fibronectin expression of TM, however, overexpression of mutant fibulin-3 (c.T1480C, p.X494Q) showed opposite effects in cells and rat eyes. Taken together, the EFEMP1 variant may impair the regulatory capacity of fibulin-3 which has a role for modulating the cell contractile activity and ECM synthesis in TM cells, and in turn may maintain normal resistance of aqueous humor outflow. This study contributes to the understanding of the important role of fibulin-3 in TM pathophysiology and provides a new possible POAG therapeutic approach.
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Affiliation(s)
- Junkai Tan
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China
| | - Suping Cai
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China
| | - Xiaolin Luo
- Department of Ophthalmology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China
| | - Qiang Li
- Department of Ophthalmology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China
| | - Yanbing Chen
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China
| | - Zijie Chen
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China
| | - Yukai Mao
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China
| | - Guo Liu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan Province, China
| | - Mingming Yang
- Department of Ophthalmology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China.
| | - Xuyang Liu
- Xiamen Eye Center, Xiamen University, Xiamen Research Center for Eye Diseases and Key Laboratory of Ophthalmology, Xiamen, 361000, Fujian, China; Department of Ophthalmology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China.
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20
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Mao A, Zhang K, Kan H, Gao M, Wang Z, Zhou T, Shao J, He D. Single-Cell RNA-Seq Reveals Coronary Heterogeneity and Identifies CD133 +TRPV4 high Endothelial Subpopulation in Regulating Flow-Induced Vascular Tone in Mice. Arterioscler Thromb Vasc Biol 2024; 44:653-665. [PMID: 38269590 PMCID: PMC10880935 DOI: 10.1161/atvbaha.123.319516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 01/10/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND Single-cell RNA-Seq analysis can determine the heterogeneity of cells between different tissues at a single-cell level. Coronary artery endothelial cells (ECs) are important to coronary blood flow. However, little is known about the heterogeneity of coronary artery ECs, and cellular identity responses to flow. Identifying endothelial subpopulations will contribute to the precise localization of vascular endothelial subpopulations, thus enabling the precision of vascular injury treatment. METHODS Here, we performed a single-cell RNA sequencing of 31 962 cells and functional assays of 3 branches of the coronary arteries (right coronary artery/circumflex left coronary artery/anterior descending left coronary artery) in wild-type mice. RESULTS We found a compendium of 7 distinct cell types in mouse coronary arteries, mainly ECs, granulocytes, cardiac myocytes, smooth muscle cells, lymphocytes, myeloid cells, and fibroblast cells, and showed spatial heterogeneity between arterial branches. Furthermore, we revealed a subpopulation of coronary artery ECs, CD133+TRPV4high ECs. TRPV4 (transient receptor potential vanilloid 4) in CD133+TRPV4high ECs is important for regulating vasodilation and coronary blood flow. CONCLUSIONS Our study elucidates the nature and range of coronary arterial cell diversity and highlights the importance of coronary CD133+TRPV4high ECs in regulating coronary vascular tone.
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Affiliation(s)
- Aiqin Mao
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
- School of Food Science and Technology (A.M., D.H.), Jiangnan University, China
| | - Ka Zhang
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Hao Kan
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Mengru Gao
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Zhiwei Wang
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Tingting Zhou
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Jing Shao
- Wuxi School of Medicine (A.M., K.Z., H.K., M.G., Z.W., T.Z., J.S.), Jiangnan University, China
| | - Dongxu He
- School of Food Science and Technology (A.M., D.H.), Jiangnan University, China
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21
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Wang T, Peng J, Fan J, Tang N, Hua R, Zhou X, Wang Z, Wang L, Bai Y, Quan X, Wang Z, Zhang L, Luo C, Zhang W, Kang X, Liu J, Li L, Li L. Single-cell multi-omics profiling of human preimplantation embryos identifies cytoskeletal defects during embryonic arrest. Nat Cell Biol 2024; 26:263-277. [PMID: 38238450 DOI: 10.1038/s41556-023-01328-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 12/01/2023] [Indexed: 02/16/2024]
Abstract
Human in vitro fertilized embryos exhibit low developmental capabilities, and the mechanisms that underlie embryonic arrest remain unclear. Here using a single-cell multi-omics sequencing approach, we simultaneously analysed alterations in the transcriptome, chromatin accessibility and the DNA methylome in human embryonic arrest due to unexplained reasons. Arrested embryos displayed transcriptome disorders, including a distorted microtubule cytoskeleton, increased genomic instability and impaired glycolysis, which were coordinated with multiple epigenetic reprogramming defects. We identified Aurora A kinase (AURKA) repression as a cause of embryonic arrest. Mechanistically, arrested embryos induced through AURKA inhibition resembled the reprogramming abnormalities of natural embryonic arrest in terms of the transcriptome, the DNA methylome, chromatin accessibility and H3K4me3 modifications. Mitosis-independent sequential activation of the zygotic genome in arrested embryos showed that YY1 contributed to human major zygotic genome activation. Collectively, our study decodes the reprogramming abnormalities and mechanisms of human embryonic arrest and the key regulators of zygotic genome activation.
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Affiliation(s)
- Teng Wang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Junhua Peng
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Jiaqi Fan
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Ni Tang
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
| | - Rui Hua
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Xueliang Zhou
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
| | - Zhihao Wang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Longfei Wang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Yanling Bai
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
| | - Xiaowan Quan
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Zimeng Wang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Li Zhang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China
| | - Chen Luo
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Weiqing Zhang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Xiangjin Kang
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
| | - Jianqiao Liu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China
| | - Lei Li
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
- Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
| | - Lin Li
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China.
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22
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Zhang R, Li Y, Zhang J. Molecular mechanisms of pelvic organ prolapse influenced by FBLN5 via FOSL1/miR-222/MEIS1/COL3A1 axis. Cell Signal 2024; 114:111000. [PMID: 38056607 DOI: 10.1016/j.cellsig.2023.111000] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/27/2023] [Accepted: 12/01/2023] [Indexed: 12/08/2023]
Abstract
This study delves into the role of FBLN5 in pelvic organ prolapse (POP) and its molecular mechanisms, focusing on the FOSL1/miR-222/MEIS1/COL3A1 axis. Gene relationships linked to POP were confirmed using bioinformatics databases like GEO and StarBase. Primary human uterosacral ligament fibroblasts (hUSLF) were extracted and subjected to mechanical stretching. Cellular cytoskeletal changes were examined via phalloidin staining, intracellular ROS levels with a ROS kit, cell apoptosis through flow cytometry, and cell senescence using β-galactosidase staining. FBLN5's downstream targets were identified, and the interaction between FOSL1 and miR-222 and miR-222 and MEIS1 were validated using assays. In rat models, the role of FBLN5 in POP was assessed using bladder pressure tests. Results indicated diminished FBLN5 expression in uterine prolapse. Enhanced FBLN5 countered mechanical damage in hUSLF cells by downregulating FOSL1. FOSL1 augmented miR-222, inhibiting MEIS1, which subsequently fostered COL3A1 transcription. In rat models, the absence of FBLN5 exacerbated POP by influencing the FOSL1/miR-222/MEIS1/COL3A1 pathway. FBLN5's protective role likely involves regulating the above axis and boosting COL3A1 expression. Further research is needed to validate the effectiveness and safety of this mechanism in human patients and to propose potential new treatment options.
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Affiliation(s)
- Rui Zhang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, PR China
| | - Ya Li
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, PR China
| | - Jin Zhang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, PR China.
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23
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Choi H, Miller MR, Nguyen HN, Surratt VE, Koch SR, Stark RJ, Lamb FS. Extracellular SOD modulates canonical TNFα signaling and α5β1 integrin transactivation in vascular smooth muscle cells. Free Radic Biol Med 2023; 209:152-164. [PMID: 37852546 PMCID: PMC10841345 DOI: 10.1016/j.freeradbiomed.2023.10.397] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/03/2023] [Accepted: 10/15/2023] [Indexed: 10/20/2023]
Abstract
TNFα activates NADPH oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs). The extracellular superoxide anion (O2•-) produced is essential for the pro-inflammatory effects of the cytokine but the specific contributions of O2•- to signal transduction remain obscure. Extracellular superoxide dismutase (ecSOD, SOD3 gene) is a secreted protein that binds to cell surface heparin sulfate proteoglycans or to Fibulin-5 (Fib-5, FBLN5 gene), an extracellular matrix protein that also associates with elastin and integrins. ecSOD converts O2•- to hydrogen peroxide (H2O2) which prevents NO• inactivation, limits generation of hydroxyl radical (OH•), and creates high local concentrations of H2O2. We hypothesized that ecSOD modifies TNFα signaling in VSMCs. Knockdown of ecSOD (siSOD3) suppressed downstream TNFα signals including MAPK (JNK and ERK phosphorylation) and NF-κB activation (luciferase reporter and IκB phosphorylation), interleukin-6 (IL-6) secretion, iNOS and VCAM expression, and proliferation (Sulforhodamine B assay, PCNA western blot). These effects were associated with significant reductions in the expression of both Type1 and 2 TNFα receptors. Reduced Fib-5 expression (siFBLN5) similarly impaired NF-κB activation by TNFα, but potentiated FAK phosphorylation at Y925. siSOD3 also increased both resting and TNFα-induced phosphorylation of FAK and of glycogen synthase kinase-3β (GSK3β), a downstream target of integrin linked kinase (ILK). These effects were dependent upon α5β1 integrins and siSOD3 increased resting sulfenylation (oxidation) of both integrin subunits, while preventing TNFα-induced increases in sulfenylation. To determine how ecSOD modified TNFα-induced inflammation in intact blood vessels, mesenteric arteries from VSMC-specific ecSOD knockout (KO) mice were exposed to TNFα (10 ng/ml) in culture for 48 h. Relaxation to acetylcholine and sodium nitroprusside was impaired in WT but not ecSOD KO vessels. Thus, ecSOD association with Fib-5 supports pro-inflammatory TNFα signaling while tonically inhibiting α5β1 integrin activation.
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Affiliation(s)
- Hyehun Choi
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
| | - Michael R Miller
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Hong-Ngan Nguyen
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Victoria E Surratt
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Stephen R Koch
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Ryan J Stark
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Fred S Lamb
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
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24
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Chen T, Li D, Wang Y, Shen X, Dong A, Dong C, Duan K, Ren J, Li W, Shu G, Yang J, Xie Y, Qian F, Zhou J. Loss of NDUFS1 promotes gastric cancer progression by activating the mitochondrial ROS-HIF1α-FBLN5 signaling pathway. Br J Cancer 2023; 129:1261-1273. [PMID: 37644092 PMCID: PMC10575981 DOI: 10.1038/s41416-023-02409-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 08/09/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Recent studies suggested that NDUFS1 has an important role in human cancers; however, the effects of NDUFS1 on gastric cancer (GC) are still not fully understood. METHODS We confirmed that NDUFS1 is downregulated in GC cells through western blot immunohistochemistry and bioinformation analysis. The effect of NDUFS1 on GC was studied by CCK-8, colony formation, transwell assay in vitro and Mouse xenograft assay in vivo. Expression and subcellular localization of NDUFS1 and the content of mitochondrial reactive oxygen species (mROS) was observed by confocal reflectance microscopy. RESULTS Reduced expression of NDUFS1 was found in GC tissues and cell lines. Also, NDUFS1 overexpression inhibited GC cell proliferation, migration, and invasion in vitro as well as growth and metastasis in vivo. Mechanistically, NDUFS1 reduction led to the activation of the mROS-hypoxia-inducible factor 1α (HIF1α) signaling pathway. We further clarified that NDUFS1 reduction upregulated the expression of fibulin 5 (FBLN5), a transcriptional target of HIF1α, through activation of mROS-HIF1α signaling in GC cells. CONCLUSIONS The results of this study indicate that NDUFS1 downregulation promotes GC progression by activating an mROS-HIF1α-FBLN5 signaling pathway.
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Affiliation(s)
- Tao Chen
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Dongbao Li
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Yunliang Wang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Xiaochun Shen
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Anqi Dong
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Chao Dong
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Kaipeng Duan
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Jiayu Ren
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Weikang Li
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Gege Shu
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Jiaoyang Yang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China
| | - Yufeng Xie
- Department of Thoracic Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.
| | - Fuliang Qian
- Center for Systems Biology, Suzhou Medical College of Soochow University, 215123, Suzhou, China.
- Medical Center of Soochow University, 215123, Suzhou, China.
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, 215123, Suzhou, China.
| | - Jin Zhou
- Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.
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25
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Frazel PW, Labib D, Fisher T, Brosh R, Pirjanian N, Marchildon A, Boeke JD, Fossati V, Liddelow SA. Longitudinal scRNA-seq analysis in mouse and human informs optimization of rapid mouse astrocyte differentiation protocols. Nat Neurosci 2023; 26:1726-1738. [PMID: 37697111 PMCID: PMC10763608 DOI: 10.1038/s41593-023-01424-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 08/08/2023] [Indexed: 09/13/2023]
Abstract
Macroglia (astrocytes and oligodendrocytes) are required for normal development and function of the central nervous system, yet many questions remain about their emergence during the development of the brain and spinal cord. Here we used single-cell/single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) to analyze over 298,000 cells and nuclei during macroglia differentiation from mouse embryonic and human-induced pluripotent stem cells. We computationally identify candidate genes involved in the fate specification of glia in both species and report heterogeneous expression of astrocyte surface markers across differentiating cells. We then used our transcriptomic data to optimize a previous mouse astrocyte differentiation protocol, decreasing the overall protocol length and complexity. Finally, we used multi-omic, dual single-nuclei (sn)RNA-seq/snATAC-seq analysis to uncover potential genomic regulatory sites mediating glial differentiation. These datasets will enable future optimization of glial differentiation protocols and provide insight into human glial differentiation.
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Affiliation(s)
- Paul W Frazel
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA.
| | - David Labib
- The New York Stem Cell Foundation Research Institute, New York City, NY, USA
| | - Theodore Fisher
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA
| | - Ran Brosh
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York City, NY, USA
| | - Nicolette Pirjanian
- The New York Stem Cell Foundation Research Institute, New York City, NY, USA
| | - Anne Marchildon
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA
| | - Jef D Boeke
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York City, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA
- Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY, USA
| | - Valentina Fossati
- The New York Stem Cell Foundation Research Institute, New York City, NY, USA
| | - Shane A Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA.
- Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York City, NY, USA.
- Department of Ophthalmology, NYU Grossman School of Medicine, New York City, NY, USA.
- Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York City, NY, USA.
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26
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Ding Y, Wu X, Yang X. Identification of miRNAs and target genes associated with lymph node metastasis in cervical cancer using bioinformatics analysis. Toxicol Mech Methods 2023; 33:625-635. [PMID: 37125668 DOI: 10.1080/15376516.2023.2207644] [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: 01/07/2023] [Revised: 04/19/2023] [Accepted: 04/23/2023] [Indexed: 05/02/2023]
Abstract
This study was designed to identify the differentially expressed miRNAs (DEMs) and genes (DEGs) in metastatic cervical cancer using bioinformatic tools. In this study, fifty-seven DEMs (48 downregulated and 9 upregulated) were identified, among which miR-4459 and miR-3195 expression was negatively associated with overall survival of cervical cancer patients. Then, 476 target DEGs were determined, and protein-protein interaction (PPI) network was constructed. Seventeen hub genes (LONRF2, CCNE2, AURKA, SYT1, NEGR1, PPP1R12B, GABRP, RAD51, CDK1, FBLN5, PRKG1, CDC6, CACNA1C, MEOX2, ANLN, MYLK, and EDNRB) were finally selected to construct the miRNA-hub gene network. Overall, our study discovered the key miRNAs and mRNAs related to lymph node metastasis (LNM) in cervical cancer, which helps discover candidate therapeutic targets for cervical cancer.
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Affiliation(s)
- Yishan Ding
- Department of Gynecology, Ankang City Central Hospital, Ankang, PR China
| | - Xiaorong Wu
- Ankang City Central Hospital, Ankang, PR China
| | - Xiaofeng Yang
- Department of Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China
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27
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Halsey G, Sinha D, Dhital S, Wang X, Vyavahare N. Role of elastic fiber degradation in disease pathogenesis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166706. [PMID: 37001705 PMCID: PMC11659964 DOI: 10.1016/j.bbadis.2023.166706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023]
Abstract
Elastin is a crucial extracellular matrix protein that provides structural integrity to tissues. Crosslinked elastin and associated microfibrils, named elastic fiber, contribute to biomechanics by providing the elasticity required for proper function. During aging and disease, elastic fiber can be progressively degraded and since there is little elastin synthesis in adults, degraded elastic fiber is not regenerated. There is substantial evidence linking loss or damage of elastic fibers to the clinical manifestation and pathogenesis of a variety of diseases. Disruption of elastic fiber networks by hereditary mutations, aging, or pathogenic stimuli results in systemic ailments associated with the production of elastin degradation products, inflammatory responses, and abnormal physiology. Due to its longevity, unique mechanical properties, and widespread distribution in the body, elastic fiber plays a central role in homeostasis of various physiological systems. While pathogenesis related to elastic fiber degradation has been more thoroughly studied in elastic fiber rich tissues such as the vasculature and the lungs, even tissues containing relatively small quantities of elastic fibers such as the eyes or joints may be severely impacted by elastin degradation. Elastic fiber degradation is a common observation in certain hereditary, age, and specific risk factor exposure induced diseases representing a converging point of pathological clinical phenotypes which may also help explain the appearance of co-morbidities. In this review, we will first cover the role of elastic fiber degradation in the manifestation of hereditary diseases then individually explore the structural role and degradation effects of elastic fibers in various tissues and organ systems. Overall, stabilizing elastic fiber structures and repairing lost elastin may be effective strategies to reverse the effects of these diseases.
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Affiliation(s)
- Gregory Halsey
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Dipasha Sinha
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Saphala Dhital
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Xiaoying Wang
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Naren Vyavahare
- Department of Bioengineering, Clemson University, SC 29634, United States of America.
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Genetic variants and haplotypes in fibulin-5 (FBLN5) are associated with pseudoexfoliation glaucoma but not with pseudoexfoliation syndrome. Biosci Rep 2023; 43:232571. [PMID: 36794549 PMCID: PMC9995586 DOI: 10.1042/bsr20221622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Pseudoexfoliation (PEX) is a multifactorial age-related disease involving deposition of extracellular proteinaceous aggregates on anterior ocular tissues. The present study aims to identify functional variants in fibulin-5 (FBLN5) as risk factors for the development of PEX. Thirteen tag single-nucleotide polymorphisms (SNPs) in FBLN5 were genotyped using TaqMan SNP genotyping technology to identify association between SNPs of FBLN5 and PEX in an Indian cohort comprising 200 control and 273 PEX patients (169 PEXS and 104 PEXG). Functional analysis of risk variants was done through luciferase reporter assays and electrophoretic mobility shift assay (EMSA) using human lens epithelial cells. Genetic association and risk haplotype analysis showed a significant association of rs17732466:G>A (NC_000014.9:g.91913280G>A) and rs72705342:C>T (NC_000014.9:g.91890855C>T) within FBLN5 as risk factors with the advanced severe stage of the disease, pseudoexfoliation glaucoma (PEXG). Reporter assays showed allele-specific regulatory effect of rs72705342:C>T on gene expression, wherein, construct containing the risk allele showed a significant decrease in the reporter activity compared with the one with protective allele. EMSA further validated higher binding affinity of the risk variant to nuclear protein. In silico analysis predicted binding sites for two transcription factors, GR-α and TFII-I with risk allele at rs72705342:C>T, which were lost in the presence of protective allele. The EMSA showed probable binding of both these proteins to rs72705342. In conclusion, the present study identified the novel association of two genetic variants in FBLN5 with PEXG but not with PEXS, distinguishing between the early and the later forms of PEX. Further, rs72705342:C>T was found to be a functional variant.
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Wang K, Wen D, Xu X, Zhao R, Jiang F, Yuan S, Zhang Y, Gao Y, Li Q. Extracellular matrix stiffness-The central cue for skin fibrosis. Front Mol Biosci 2023; 10:1132353. [PMID: 36968277 PMCID: PMC10031116 DOI: 10.3389/fmolb.2023.1132353] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/20/2023] [Indexed: 03/29/2023] Open
Abstract
Skin fibrosis is a physiopathological process featuring the excessive deposition of extracellular matrix (ECM), which is the main architecture that provides structural support and constitutes the microenvironment for various cellular behaviors. Recently, increasing interest has been drawn to the relationship between the mechanical properties of the ECM and the initiation and modulation of skin fibrosis, with the engagement of a complex network of signaling pathways, the activation of mechanosensitive proteins, and changes in immunoregulation and metabolism. Simultaneous with the progression of skin fibrosis, the stiffness of ECM increases, which in turn perturbs mechanical and humoral homeostasis to drive cell fate toward an outcome that maintains and enhances the fibrosis process, thus forming a pro-fibrotic "positive feedback loop". In this review, we highlighted the central role of the ECM and its dynamic changes at both the molecular and cellular levels in skin fibrosis. We paid special attention to signaling pathways regulated by mechanical cues in ECM remodeling. We also systematically summarized antifibrotic interventions targeting the ECM, hopefully enlightening new strategies for fibrotic diseases.
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Affiliation(s)
- Kang Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dongsheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuewen Xu
- Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rui Zhao
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Feipeng Jiang
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Shengqin Yuan
- School of Public Administration, Sichuan University, Chengdu, Sichuan, China
| | - Yifan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yifan Zhang, ; Ya Gao, ; Qingfeng Li,
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Sugiura H, Tsunezumi J, Yanagisawa H, Futaya M, Nitta K, Tsuchiya K. Fibulin7 aggravates calcium oxalate-induced acute kidney injury by binding to calcium oxalate crystals. J Cell Physiol 2023; 238:165-178. [PMID: 36370444 DOI: 10.1002/jcp.30914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022]
Abstract
Fibulin7 (Fbln7) is a matricellular protein that is structurally similar to short fibulins but does not possess elastogenic abilities. Fbln7 is localized on the cell surface of the renal tubular epithelium in the adult kidney. We previously reported that Fbln7 binds artificial calcium phosphate particles in vitro, and that heparin counteracts this binding by releasing Fbln7 from the cell surface. Fbln7 gene (Fbln7) deletion in vivo decreased interstitial fibrosis and improved renal function in a high phosphate diet-induced chronic kidney disease mouse model. However, the contribution of Fbln7 during acute injury response remains largely unknown. We hypothesized that Fbln7 serves as an exacerbating factor in acute kidney injury (AKI). We employed three AKI models in vivo and in vitro, including unilateral ureteral obstruction (UUO), cisplatin-induced AKI, and calcium oxalate (CaOx)-induced AKI. Here, we report that Fbln7KO mice were protected from kidney damage in a CaOx-induced AKI model. Using HEK293T cells, we found that Fbln7 overexpression enhanced the CaOx-induced upregulation of EGR1 and LAMB3, and that heparin treatment canceled this effect. Interestingly, the protective function observed in Fbln7KO kidneys was limited to the CaOx-induced AKI model, while Fbln7KO mice were not protected against UUO-induced renal fibrosis or cisplatin-induced renal tubular damage. Taken together, our study indicates that Fbln7 mediates the local deposition of CaOx and damages the renal tubular epithelium. Releasing Fbln7 from the cell surface via heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a general strategy to mitigate calcium crystal-induced kidney injuries.
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Affiliation(s)
- Hidekazu Sugiura
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.,Department of Nephrology, Division of Medicine, Saiseikai Kazo Hospital, Kazo, Saitama, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Jun Tsunezumi
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.,Department of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Miyazaki, Japan
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.,Department of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Mayuko Futaya
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Kosaku Nitta
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Ken Tsuchiya
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.,Department of Blood Purification, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
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Suzuki Y, Oinaka H, Nakajima H, Nampei M, Kawakita F, Miura Y, Yasuda R, Toma N, Suzuki H, pSEED Group. Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci 2022; 23:ijms232315184. [PMID: 36499510 PMCID: PMC9740042 DOI: 10.3390/ijms232315184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/27/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5's roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3-6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4-6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7-9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients' and non-severe patients' analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hidenori Suzuki
- Correspondence: ; Tel.: +81-59-232-1111; Fax: +81-59-231-5212
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Roy TK, Uniyal A, Tiwari V. Multifactorial pathways in burn injury-induced chronic pain: novel targets and their pharmacological modulation. Mol Biol Rep 2022; 49:12121-12132. [PMID: 35842856 DOI: 10.1007/s11033-022-07748-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/30/2022]
Abstract
Burn injuries are among the highly prevalent medical conditions worldwide that occur mainly in children, military veterans and victims of fire accidents. It is one of the leading causes of temporary as well as permanent disabilities in patients. Burn injuries are accompanied by pain that persists even after recovery from tissue damage which puts immense pressure on the healthcare system. The pathophysiology of burn pain is poorly understood due to its complex nature and lack of considerable preclinical and clinical shreds of evidence, that creates a substantial barrier to the development of new analgesics. Burns damage the skin layers supplied with nociceptors such as NAV1.7, TRPV1, and TRPA1. Burn injury-mediated co-localization and simultaneous activation of TRPA1 and TRPV1 in nociceptive primary afferent C-fibers which contributes to the development and maintenance of chronic pain. Burn injuries are accompanied by central sensitization, a key feature of pain pathophysiology mainly driven by a series of cascades involving aberrations in the glutamatergic system, microglial activation, release of neuropeptides, cytokines, and chemokines. Activation of p38 mitogen-activated protein kinase, altered endogenous opioid signaling, and distorted genomic expression are other pathophysiological factors responsible for the development and maintenance of burn pain. Here we discuss comprehensive literature on molecular mechanisms of burn pain and potential targets that could be translated into near future therapeutics.
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Affiliation(s)
- Tapas Kumar Roy
- Neuroscience & Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, 221005, Varanasi, U.P, India
| | - Ankit Uniyal
- Neuroscience & Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, 221005, Varanasi, U.P, India
| | - Vinod Tiwari
- Neuroscience & Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, 221005, Varanasi, U.P, India.
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33
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Li Y, Yang X, Lu D. Knockdown of ubiquitin-conjugating enzyme E2T (UBE2T) suppresses lung adenocarcinoma progression via targeting fibulin-5 (FBLN5). Bioengineered 2022; 13:11867-11880. [PMID: 35543375 PMCID: PMC9275889 DOI: 10.1080/21655979.2022.2060162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Accumulating evidence has displayed that UBE2T is related to tumor progression. However, its role in LUAD has not been fully elucidated. The expression of UBE2T was detected in LUAD tissues by qRT-PCR, western blotting, and immunohistochemistry. UBE2T shRNAs were transfected into LUAD cells to analyze the consequent alteration in function through CCK-8 assay, Edu assay, transwell assay, and TUNEL staining. The potential mechanism of UBE2T was analyzed through GEPIA and verified using ChIP, EMSA, and GST pull-down assays. Furthermore, a xenograft mouse model was used to assess UBE2T function in vivo. Results showed that UBE2T level was significantly elevated in LUAD tissues and high UBE2T expression was associated with poor overall survival and disease-free survival. Results from the loss-of-function experiments in vitro showed that UBE2T modulated LUAD cell proliferation, migration, invasion, and apoptosis. The mechanism analysis demonstrated that silence of UBE2T increased FBLN5 expression and inhibited the activation of p-ERK, p-GSK3β, and β-catenin. Moreover, following knockdown of UBE2T, the cell proliferation, migration, and invasion were decreased, and sh-FBLN5 partially reverse the decrease. In in vivo experiments, it was found that UBE2T knockdown inhibits the tumor growth in LUAD. Immunohistochemically, there was a reduction in Ki67 and an increase in FBLN5 in UBE2T shRNA-treated tumor tissues. In conclusion, UBE2T might be a potential biomarker of LUAD, and targeting the UBE2T/FBLN5 axis might be a novel treatment strategy for LUAD.
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Affiliation(s)
- Yi Li
- Department of Respiration Medicine, People's Hospital of Shanxi Province, Taiyuan City, PR China
| | - Xiaojuan Yang
- Department of Respiration Medicine, People's Hospital of Shanxi Province, Taiyuan City, PR China
| | - Dan Lu
- Department of Respiratory Medicine, Shanxi Medical University, Taiyuan City, PR China
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34
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Melin LG, Dall JH, Lindholt JS, Steffensen LB, Beck HC, Elkrog SL, Clausen PD, Rasmussen LM, Stubbe J. Cycloastragenol Inhibits Experimental Abdominal Aortic Aneurysm Progression. Biomedicines 2022; 10:biomedicines10020359. [PMID: 35203568 PMCID: PMC8962318 DOI: 10.3390/biomedicines10020359] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/30/2022] [Indexed: 02/04/2023] Open
Abstract
The pathogenesis of abdominal aortic aneurysm involves vascular inflammation and elastin degradation. Astragalusradix contains cycloastragenol, which is known to be anti-inflammatory and to protect against elastin degradation. We hypothesized that cycloastragenol supplementation inhibits abdominal aortic aneurysm progression. Abdominal aortic aneurysm was induced in male rats by intraluminal elastase infusion in the infrarenal aorta and treated daily with cycloastragenol (125 mg/kg/day). Aortic expansion was followed weekly by ultrasound for 28 days. Changes in aneurysmal wall composition were analyzed by mRNA levels, histology, zymography and explorative proteomic analyses. At day 28, mean aneurysm diameter was 37% lower in the cycloastragenol group (p < 0.0001). In aneurysm cross sections, elastin content was insignificantly higher in the cycloastragenol group (10.5% ± 5.9% vs. 19.9% ± 16.8%, p = 0.20), with more preserved elastin lamellae structures (p = 0.0003) and without microcalcifications. Aneurysmal matrix metalloprotease-2 activity was reduced by the treatment (p = 0.022). Messenger RNA levels of inflammatory- and anti-oxidative markers did not differ between groups. Explorative proteomic analysis showed no difference in protein levels when adjusting for multiple testing. Among proteins displaying nominal regulation were fibulin-5 (p = 0.02), aquaporin-1 (p = 0.02) and prostacyclin synthase (p = 0.007). Cycloastragenol inhibits experimental abdominal aortic aneurysm progression. The suggested underlying mechanisms involve decreased matrix metalloprotease-2 activity and preservation of elastin and reduced calcification, thus, cycloastragenol could be considered for trial in abdominal aortic aneurysm patients.
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Affiliation(s)
- Leander Gaarde Melin
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, 5000 Odense, Denmark
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
| | - Julie Husted Dall
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, 5000 Odense, Denmark
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
| | - Jes S. Lindholt
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, 5000 Odense, Denmark
| | - Lasse B. Steffensen
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
| | - Hans Christian Beck
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark
| | - Sophie L. Elkrog
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
| | - Pernille D. Clausen
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
| | - Lars Melholt Rasmussen
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark
| | - Jane Stubbe
- Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital (OUH), 5000 Odense, Denmark; (L.G.M.); (J.H.D.); (J.S.L.); (H.C.B.); (L.M.R.)
- Cardiovascular and Renal Research Unit, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (L.B.S.); (S.L.E.); (P.D.C.)
- Correspondence: ; Tel.: +45-6550-3709
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Huang M, Liao X, Li L, Li G, Chen M. MiR-552-3p facilitated cell proliferation, migration and invasion by sponging Fibulin 5 in non-small cell lung cancer via activation of ERK/GSK3β/β-catenin signaling pathway. Tissue Cell 2021; 73:101672. [PMID: 34736163 DOI: 10.1016/j.tice.2021.101672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 10/09/2021] [Accepted: 10/22/2021] [Indexed: 12/24/2022]
Abstract
Apart from the fact that miR-552-3p is known to promote cell progression among various cancers, its function on non-small cell lung cancer (NSCLC) is unknown which therefore emerges as the purpose of this research. TargetScan, Starbase, miRWalk, miRDB and the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) were utilized to analyze the target genes of miR-552-3p. NSCLC cells were transfected with miR-552-3p mimic, miR-552-3p inhibitor, Fibulin 5 (FBLN5) overexpression plasmid, and small interfering FBLN5 (siFBLN5) and treated with extracellular regulated protein kinases (ERK) pathway inhibitor PD98059. MiR-552-3p, FBLN5, p-ERK, ERK, p-glycogen synthase kinase 3β (GSK3β) and β-catenin levels were detected through quantitative reverse transcription-polymerase chain reaction and western blot. The binding sites between miR-552-3p and FBLN5 were predicted by TargetScan, which was tested through dual luciferase reporter analysis. Cell viability, migration and invasion were determined by cell counting kit-8 (CCK-8) assay, wound healing assay and transwell assay, respectively. MiR-552-3p expression was upregulated in NSCLC and FBLN5 functioned as its target. MiR-552-3p mimic promoted proliferation, migration, invasion, p-ERK, p-GSK3β and β-catenin expressions in NSCLC cells while miR-552-3p inhibitor did the opposite. Overexpressed FBLN5 suppressed proliferation, migration, invasion, p-ERK, p-GSK3β and β-catenin expressions in NSCLC cells whereas siFBLN5 exerted the effects opposite to overexpressed FBLN5. PD98059 enhanced the effect of overexpressed FBLN5 on NSCLC cell migration and invasion while reversing the effect of siFBLN5. MiR-552-3p facilitated cell proliferation, migration and invasion in NSCLC through sponging FBLN5 via activation of ERK/GSK3β/β-catenin pathway.
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Affiliation(s)
- Mingfang Huang
- Thoracic Surgery Department, Hainan General Hospital, China
| | - Xuqiang Liao
- Thoracic Surgery Department, Hainan General Hospital, China
| | - Liang Li
- Thoracic Surgery Department, Hainan General Hospital, China
| | - Gao Li
- Thoracic Surgery Department, Hainan General Hospital, China
| | - Minbiao Chen
- Thoracic Surgery Department, Hainan General Hospital, China.
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Halper J. Basic Components of Connective Tissues and Extracellular Matrix: Fibronectin, Fibrinogen, Laminin, Elastin, Fibrillins, Fibulins, Matrilins, Tenascins and Thrombospondins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:105-126. [PMID: 34807416 DOI: 10.1007/978-3-030-80614-9_4] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Collagens are the most abundant components of the extracellular matrix (ECM) and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. It is an insoluble polymer of the monomeric soluble precursor tropoelastin, and the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of transforming growth factors β (TGFβ) through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Many other molecules, though lower in quantity, function as essential, structural and/or functional components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its multidomain structure plays a role of "master organizer" in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin it also binds to a variety of compounds, particularly to various growth factors, and as such, fibrinogen is a player in cardiovascular and extracellular matrix physiology. Laminins contribute to the structure of the ECM and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Fibrillins represent the predominant core of microfibrils in elastic as well as non-elastic extracellular matrixes, and interact closely with tropoelastin and integrins. Not only do microfibrils provide structural integrity of specific organ systems, but they also provide basis for elastogenesis in elastic tissues. Fibrillin is important for the assembly of elastin into elastic fibers. Mutations in the fibrillin-1 gene are closely associated with Marfan syndrome. Latent TGFβ binding proteins (LTBPs) are included here as their structure is similar to fibrillins. Several categories of ECM components described after fibrillins are sub-classified as matricellular proteins, i.e., they are secreted into ECM, but do not provide structure. Rather they interact with cell membrane receptors, collagens, proteases, hormones and growth factors, communicating and directing cell-ECM traffic. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers. Matrilins have been emerging as a new group of supporting actors, and their role in connective tissue physiology and pathophysiology has not been fully characterized. Tenascins are ECM polymorphic glycoproteins found in many connective tissues in the body. Their expression is regulated by mechanical stress both during development and in adulthood. Tenascins mediate both inflammatory and fibrotic processes to enable effective tissue repair and play roles in pathogenesis of Ehlers-Danlos, heart disease, and regeneration and recovery of musculo-tendinous tissue. One of the roles of thrombospondin 1 is activation of TGFβ. Increased expression of thrombospondin and TGFβ activity was observed in fibrotic skin disorders such as keloids and scleroderma. Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 is primarily present in the cartilage. High levels of COMP are present in fibrotic scars and systemic sclerosis of the skin, and in tendon, especially with physical activity, loading and post-injury. It plays a role in vascular wall remodeling and has been found in atherosclerotic plaques as well.
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Affiliation(s)
- Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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37
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Role of Fibulins in Embryonic Stage Development and Their Involvement in Various Diseases. Biomolecules 2021; 11:biom11050685. [PMID: 34063320 PMCID: PMC8147605 DOI: 10.3390/biom11050685] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/24/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in the evolution of early metazoans, as it provides structural and biochemical support to the surrounding cells through the cell–cell and cell–matrix interactions. In multi-cellular organisms, ECM plays a pivotal role in the differentiation of tissues and in the development of organs. Fibulins are ECM glycoproteins, found in a variety of tissues associated with basement membranes, elastic fibers, proteoglycan aggregates, and fibronectin microfibrils. The expression profile of fibulins reveals their role in various developmental processes such as elastogenesis, development of organs during the embryonic stage, tissue remodeling, maintenance of the structural integrity of basement membrane, and elastic fibers, as well as other cellular processes. Apart from this, fibulins are also involved in the progression of human diseases such as cancer, cardiac diseases, congenital disorders, and chronic fibrotic disorders. Different isoforms of fibulins show a dual role of tumor-suppressive and tumor-promoting activities, depending on the cell type and cellular microenvironment in the body. Knockout animal models have provided deep insight into their role in development and diseases. The present review covers details of the structural and expression patterns, along with the role of fibulins in embryonic development and disease progression, with more emphasis on their involvement in the modulation of cancer diseases.
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Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z, Miao H, Ren T, Yang Y, Li G, Song X, Hu Y, Wang X, Huang Y, Liu Y. LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:797-810. [PMID: 33614230 PMCID: PMC7868718 DOI: 10.1016/j.omtn.2021.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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Affiliation(s)
- Ruiyan Yuan
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bo Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China
| | - Zhaohui Jin
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jiacheng Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Ziyu Shao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huijie Miao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tai Ren
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoqiang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaoling Song
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunping Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu’an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Ying Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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Gharesouran J, Hosseinzadeh H, Ghafouri-Fard S, Jabbari Moghadam Y, Ahmadian Heris J, Jafari-Rouhi AH, Taheri M, Rezazadeh M. New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa. Orphanet J Rare Dis 2021; 16:51. [PMID: 33509220 PMCID: PMC7845118 DOI: 10.1186/s13023-021-01696-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background FBLN5-related cutis laxa (CL) is a rare disorder that involves elastic fiber-enriched tissues and is characterized by lax skin and variable systemic involvement such as pulmonary emphysema, arterial involvement, inguinal hernias, hollow viscus diverticula and pyloric stenosis. This type of CL follows mostly autosomal recessive (AR) and less commonly autosomal dominant patterns of inheritance. Results In this study, we detected a novel homozygous missense variant in exon 6 of FBLN5 gene (c.G544C, p.A182P) by using whole exome sequencing in a consanguineous Iranian family with two affected members. Our twin patients showed some of the clinical manifestation of FBLN5-related CL but they did not present pulmonary complications, gastrointestinal and genitourinary abnormalities. The notable thing about this monozygotic twin sisters is that only one of them showed ventricular septal defect, suggesting that this type of CL has intrafamilial variability. Co-segregation analysis showed the patients’ parents and relatives were heterozygous for detected variation suggesting AR form of the CL. In silico prediction tools showed that this mutation is pathogenic and 3D modeling of the normal and mutant protein revealed relative structural alteration of fibulin-5 suggesting that the A182P can contribute to the CL phenotype via the combined effect of lack of protein function and partly misfolding-associated toxicity. Conclusion We underlined the probable roles and functions of the involved domain of fibulin-5 and proposed some possible mechanisms involved in AR form of FBLN5-related CL. However, further functional studies and subsequent clinical and molecular investigations are needed to confirm our findings.
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Affiliation(s)
- Jalal Gharesouran
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Hosseinzadeh
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yalda Jabbari Moghadam
- Department of Otorhinolaryngology, School of Medicine, Sina Medical Research and Training Hospital, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Pediatrics, School of Medicine, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Rezazadeh
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.
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García-Valero J, Olloquequi J, Rodríguez E, Martín-Satué M, Texidó L, Ferrer J. Decreased Expression of EC-SOD and Fibulin-5 in Alveolar Walls of Lungs From COPD Patients. Arch Bronconeumol 2021; 58:S0300-2896(21)00016-8. [PMID: 33640211 DOI: 10.1016/j.arbres.2020.12.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION The aim of this study is to analyze the expression of the main oxidant scavenger superoxide dismutase (EC-SOD), its main binding protein Fibulin-5 and several oxidative and nitrosative-derived products in the lung of COPD patients and controls. MATERIALS AND METHODS Lung tissue samples from 19 COPD patients and 20 control subjects were analyzed. The architecture of elastic fibres was assessed by light and electron microscope histochemical techniques, and levels of EC-SOD and fibulin-5 were analyzed by immunohistochemistry and RT-PCR. The impact of oxidative stress on the extracellular matrix was estimated by immunolocalization of 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) and 3-nitrotyrosine (3-NYT) adducts. RESULTS Alveolar walls of COPD patients exhibited abnormal accumulations of collapsing elastic fibres, showing a pierced pattern in the amorphous component. The semiquantitative analysis revealed that COPD patients have a significantly reduced expression of both EC-SOD and fibulin-5 (0.59±0.64 and 0.62±0.61, respectively) in alveolar, bronchiolar and arteriolar walls compared to control subjects (1.39±0.63 and 1.55±0.52, respectively, p<0.05). No significant changes in mRNA levels of these proteins were observed between groups. Among the oxidation markers, malondialdehyde was the best in distinguishing COPD patients. CONCLUSIONS COPD patients show a reduced expression of EC-SOD and fibulin-5 in the lung interstitium. Paralleling the reduction of EC-SOD levels, the decrease of fibulin-5 expression in COPD lungs supports the hypothesis of an impaired pulmonary antioxidant response in COPD patients.
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Affiliation(s)
- José García-Valero
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Esther Rodríguez
- Department of Pneumology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
| | - Mireia Martín-Satué
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Laura Texidó
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Jaume Ferrer
- Department of Pneumology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona and CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.
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Eekhoff JD, Steenbock H, Berke IM, Brinckmann J, Yanagisawa H, Wagenseil JE, Lake SP. Dysregulated assembly of elastic fibers in fibulin-5 knockout mice results in a tendon-specific increase in elastic modulus. J Mech Behav Biomed Mater 2021; 113:104134. [PMID: 33045519 PMCID: PMC8146012 DOI: 10.1016/j.jmbbm.2020.104134] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 12/15/2022]
Abstract
Elastic fiber assembly is coordinated in part by fibulin-5, a matricellular protein. When fibulin-5 is not available to guide elastogenesis, elastin forms into disconnected globules instead of the dense elastic fiber core found in healthy tissues. Despite the growing evidence for a significant role of elastic fibers in tendon mechanics and the clinical relevance to cutis laxa, a human disease which can be caused by a mutation in the gene encoding fibulin-5, it is unknown how malformed elastic fibers affect tendon function. Therefore, this study investigated the effects of dysregulated elastic fiber assembly in tendons from fibulin-5 knockout mice in comparison to wild-type controls. Due to evidence for a more prominent role of elastic fibers in tendons with higher functional demands, both the energy-storing Achilles tendon and the more positional tibialis anterior tendon were evaluated. The linear modulus of knockout Achilles tendons was increased compared to controls, yet there was no discernible change in mechanical properties of the tibialis anterior tendon across genotypes. Transmission electron microscopy confirmed the presence of malformed elastic fibers in knockout tendons while no other changes to tendon composition or structure were found. The mechanism behind the increase in linear modulus in fibulin-5 knockout Achilles tendons may be greater collagen engagement due to decreased regulation of strain-induced structural reorganization. These findings support the theory of a significant, functionally distinct role of elastic fibers in tendon mechanics.
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Affiliation(s)
- Jeremy D Eekhoff
- Department of Biomedical Engineering, Washington University in St. Louis, USA
| | - Heiko Steenbock
- Institute of Virology and Cell Biology, University of Lübeck, Germany
| | - Ian M Berke
- Department of Biomedical Engineering, Washington University in St. Louis, USA
| | - Jürgen Brinckmann
- Institute of Virology and Cell Biology, University of Lübeck, Germany; Department of Dermatology, University of Lübeck, Germany
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan
| | - Jessica E Wagenseil
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, USA
| | - Spencer P Lake
- Department of Biomedical Engineering, Washington University in St. Louis, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, USA; Department of Orthopaedic Surgery, Washington University in St. Louis, USA.
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Blokland K, Pouwels S, Schuliga M, Knight D, Burgess J. Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases. Clin Sci (Lond) 2020; 134:2681-2706. [PMID: 33084883 PMCID: PMC7578566 DOI: 10.1042/cs20190893] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM-senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.
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Affiliation(s)
- Kaj E.C. Blokland
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
- University of Newcastle, School of Biomedical Sciences and Pharmacy, Callaghan, NSW, Australia
- National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Sydney, NSW, Australia
| | - Simon D. Pouwels
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
- Department of Lung Diseases, University Medical Center Groningen, Groningen, The Netherlands
| | - Michael Schuliga
- University of Newcastle, School of Biomedical Sciences and Pharmacy, Callaghan, NSW, Australia
| | - Darryl A. Knight
- University of Newcastle, School of Biomedical Sciences and Pharmacy, Callaghan, NSW, Australia
- National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Sydney, NSW, Australia
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Providence Health Care Research Institute, Vancouver, BC, Canada
| | - Janette K. Burgess
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
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Won SY, Kwon S, Jeong HS, Chung KW, Choi B, Chang JW, Lee JE. Fibulin 5, a human Wharton's jelly-derived mesenchymal stem cells-secreted paracrine factor, attenuates peripheral nervous system myelination defects through the Integrin-RAC1 signaling axis. Stem Cells 2020; 38:1578-1593. [PMID: 33107705 PMCID: PMC7756588 DOI: 10.1002/stem.3287] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/15/2020] [Accepted: 09/22/2020] [Indexed: 04/25/2023]
Abstract
In the peripheral nervous system (PNS), proper development of Schwann cells (SCs) contributing to axonal myelination is critical for neuronal function. Impairments of SCs or neuronal axons give rise to several myelin-related disorders, including dysmyelinating and demyelinating diseases. Pathological mechanisms, however, have been understood at the elementary level and targeted therapeutics has remained undeveloped. Here, we identify Fibulin 5 (FBLN5), an extracellular matrix (ECM) protein, as a key paracrine factor of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) to control the development of SCs. We show that co-culture with WJ-MSCs or treatment of recombinant FBLN5 promotes the proliferation of SCs through ERK activation, whereas FBLN5-depleted WJ-MSCs do not. We further reveal that during myelination of SCs, FBLN5 binds to Integrin and modulates actin remodeling, such as the formation of lamellipodia and filopodia, through RAC1 activity. Finally, we show that FBLN5 effectively restores the myelination defects of SCs in the zebrafish model of Charcot-Marie-Tooth (CMT) type 1, a representative demyelinating disease. Overall, our data propose human WJ-MSCs or FBLN5 protein as a potential treatment for myelin-related diseases, including CMT.
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Affiliation(s)
- So Yeon Won
- Department of Health Sciences and TechnologySamsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan UniversitySeoulSouth Korea
| | - Soojin Kwon
- Stem Cell & Regenerative Medicine Institute, Samsung Medical CenterSeoulSouth Korea
- Stem Cell Institute, ENCell Co. LtdSeoulSouth Korea
| | - Hui Su Jeong
- Department of Health Sciences and TechnologySamsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan UniversitySeoulSouth Korea
| | - Ki Wha Chung
- Department of Biological SciencesKongju National UniversityKongjuSouth Korea
| | - Byung‐Ok Choi
- Department of NeurologySungkyunkwan University School of MedicineSeoulSouth Korea
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Institute, Samsung Medical CenterSeoulSouth Korea
- Stem Cell Institute, ENCell Co. LtdSeoulSouth Korea
| | - Ji Eun Lee
- Department of Health Sciences and TechnologySamsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan UniversitySeoulSouth Korea
- Samsung Biomedical Research Institute, Samsung Medical CenterSeoulSouth Korea
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O'Neill Moore S, Grubb TJ, Kothapalli CR. Insights into the biophysical forces between proteins involved in elastic fiber assembly. J Mater Chem B 2020; 8:9239-9250. [PMID: 32966543 DOI: 10.1039/d0tb01591a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Elastogenesis is a complex process beginning with transcription, translation, and extracellular release of precursor proteins leading to crosslinking, deposition, and assembly of ubiquitous elastic fibers. While the biochemical pathways by which elastic fibers are assembled are known, the biophysical forces mediating the interactions between the constituent proteins are unknown. Using atomic force microscopy, we quantified the adhesive forces among the elastic fiber components, primarily between tropoelastin, elastin binding protein (EBP), fibrillin-1, fibulin-5, and lysyl oxidase-like 2 (LOXL2). The adhesive forces between tropoelastin and other tissue-derived proteins such as insoluble elastin, laminin, and type I collagens were also assessed. The adhesive forces between tropoelastin and laminin were strong (1767 ± 126 pN; p < 10-5vs. all others), followed by forces (≥200 pN) between tropoelastin and human collagen, mature elastin, or tropoelastin. The adhesive forces between tropoelastin and rat collagen, EBP, fibrillin-1, fibulin-5, and LOXL2 coated on fibrillin-1 were in the range of 100-200 pN. The forces between tropoelastin and LOXL2, LOXL2 and fibrillin-1, LOXL2 and fibulin-5, and fibrillin-1 and fibulin-5 were less than 100 pN. Introducing LOXL2 decreased the adhesive forces between the tropoelastin monomers by ∼100 pN. The retraction phase of force-deflection curves was fitted to the worm-like chain model to calculate the rigidity and flexibility of these proteins as they unfolded. The results provided insights into how each constituent's stretching under deformation contributes to structural and mechanical characteristics of these fibers and to elastic fiber assembly.
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Affiliation(s)
- Sean O'Neill Moore
- Department of Chemical and Biomedical Engineering, FH 460, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
| | - Tyler Jacob Grubb
- Department of Chemical and Biomedical Engineering, FH 460, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
| | - Chandrasekhar R Kothapalli
- Department of Chemical and Biomedical Engineering, FH 460, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
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Wurmser M, Chaverot N, Madani R, Sakai H, Negroni E, Demignon J, Saint-Pierre B, Mouly V, Amthor H, Tapscott S, Birchmeier C, Tajbakhsh S, Le Grand F, Sotiropoulos A, Maire P. SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis. Development 2020; 147:dev.185975. [PMID: 32591430 DOI: 10.1242/dev.185975] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 06/18/2020] [Indexed: 01/09/2023]
Abstract
Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the sine oculis-related homeobox Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here, we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 knockout mice (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior muscle. Mutant stem cells contribute to hypotrophic myofibers that are not innervated but retain the ability to self-renew.
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Affiliation(s)
- Maud Wurmser
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Nathalie Chaverot
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Rouba Madani
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Hiroshi Sakai
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, Ehime, 791-0295, Japan.,Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris, France.,CNRS UMR 3738, Institut Pasteur, 75015 Paris, France
| | - Elisa Negroni
- Sorbonne Université, Institut de Myologie, INSERM, 75013 Paris, France
| | - Josiane Demignon
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Benjamin Saint-Pierre
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Vincent Mouly
- Sorbonne Université, Institut de Myologie, INSERM, 75013 Paris, France
| | - Helge Amthor
- INSERM U1179, LIA BAHN CSM, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France
| | | | | | - Shahragim Tajbakhsh
- Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris, France.,CNRS UMR 3738, Institut Pasteur, 75015 Paris, France
| | - Fabien Le Grand
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France.,Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS, INSERM, 69008 Lyon, France
| | - Athanassia Sotiropoulos
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
| | - Pascal Maire
- Université de Paris, Institut Cochin, INSERM, CNRS, 24 rue du Fg St Jacques, F-75014 Paris, France
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Smith TA, Ghergherehchi CL, Tucker HO, Bittner GD. Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts. J Neuroinflammation 2020; 17:287. [PMID: 33008419 PMCID: PMC7532577 DOI: 10.1186/s12974-020-01953-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 09/16/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Current methods to repair ablation-type peripheral nerve injuries (PNIs) using peripheral nerve allografts (PNAs) often result in poor functional recovery due to immunological rejection as well as to slow and inaccurate outgrowth of regenerating axonal sprouts. In contrast, ablation-type PNIs repaired by PNAs, using a multistep protocol in which one step employs the membrane fusogen polyethylene glycol (PEG), permanently restore sciatic-mediated behaviors within weeks. Axons and cells within PEG-fused PNAs remain viable, even though outbred host and donor tissues are neither immunosuppressed nor tissue matched. PEG-fused PNAs exhibit significantly reduced T cell and macrophage infiltration, expression of major histocompatibility complex I/II and consistently low apoptosis. In this study, we analyzed the coding transcriptome of PEG-fused PNAs to examine possible mechanisms underlying immunosuppression. METHODS Ablation-type sciatic PNIs in adult Sprague-Dawley rats were repaired using PNAs and a PEG-fusion protocol combined with neurorrhaphy. Electrophysiological and behavioral tests confirmed successful PEG-fusion of PNAs. RNA sequencing analyzed differential expression profiles of protein-coding genes between PEG-fused PNAs and negative control PNAs (not treated with PEG) at 14 days PO, along with unoperated control nerves. Sequencing results were validated by quantitative reverse transcription PCR (RT-qPCR), and in some cases, immunohistochemistry. RESULTS PEG-fused PNAs display significant downregulation of many gene transcripts associated with innate and adaptive allorejection responses. Schwann cell-associated transcripts are often upregulated, and cellular processes such as extracellular matrix remodeling and cell/tissue development are particularly enriched. Transcripts encoding several potentially immunosuppressive proteins (e.g., thrombospondins 1 and 2) also are upregulated in PEG-fused PNAs. CONCLUSIONS This study is the first to characterize the coding transcriptome of PEG-fused PNAs and to identify possible links between alterations of the extracellular matrix and suppression of the allorejection response. The results establish an initial molecular basis to understand mechanisms underlying PEG-mediated immunosuppression.
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Affiliation(s)
- Tyler A Smith
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
| | | | - Haley O Tucker
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
| | - George D Bittner
- Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA.
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Boezio GL, Bensimon-Brito A, Piesker J, Guenther S, Helker CS, Stainier DY. Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract. eLife 2020; 9:57603. [PMID: 32990594 PMCID: PMC7524555 DOI: 10.7554/elife.57603] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which are frequently associated with impaired TGF-β signaling. To better understand the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT: alk5-/- OFTs exhibit increased EC numbers as well as extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5-/- rescues the EC, ECM, and SMC defects. Transcriptomic analyses reveal downregulation of the ECM gene fibulin-5, which when overexpressed in ECs ameliorates OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.
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Affiliation(s)
- Giulia Lm Boezio
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Anabela Bensimon-Brito
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Janett Piesker
- Scientific Service Group Microscopy, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Stefan Guenther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Christian Sm Helker
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Didier Yr Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Li R, Wu H, Jiang H, Wang Q, Dou Z, Ma H, Yan S, Yuan C, Yang N, Kong B. FBLN5 is targeted by microRNA‑27a‑3p and suppresses tumorigenesis and progression in high‑grade serous ovarian carcinoma. Oncol Rep 2020; 44:2143-2151. [PMID: 32901854 PMCID: PMC7550983 DOI: 10.3892/or.2020.7749] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological malignancies; however, the precise molecular mechanisms have not been fully characterized. Fibulin-5 (FBLN-5) is an extracellular matrix (ECM) glycoprotein, and plays a crucial role in maintaining the stability of ECM structures, regulating cell proliferation and tumorigenesis. In the present study, the expression of FBLN-5, as determined by western blot analysis and immunohistochemistry, was significantly increased in normal fallopian tube (FT) samples compared with that in HGSOC samples, and decreased FBLN5 expression was associated with unfavorable prognosis of HGSOC. Functional characterization revealed that FBLN5 overexpression significantly inhibited migration, invasion and proliferation abilities of ovarian cancer cells in vitro. Furthermore, micro (mi)RNA-27a-3p (miR-27a-3p) was revealed to be increased in HGSOC, and dual-luciferase reporter assay indicated that miR-27a-3p was functioned as a negative regulator of FBLN5 by directly binding with its 3′-untranslated region. Collectively, FBLN5 expression was associated with prognosis, proliferation, and metastasis in HGSOC. We hypothesized that FBLN5 was targeted by miR-27a-3p and may serve as a biomarker and provide a new therapeutic approach for the treatment of HGSOC.
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Affiliation(s)
- Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Huan Wu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Huiyang Jiang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qiuman Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhiyuan Dou
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Shi Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ning Yang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Kazamel M, Lopez MA, Bebin M, Bowling K, Korf BR, Barsh GS, Cooper GM, Hurst ACE, Ubogu EE. Fibulin-5 mutation featuring Charcot-Marie-Tooth disease, joint hyperlaxity, and scoliosis. Neurol Genet 2020; 6:e476. [PMID: 32802946 PMCID: PMC7413605 DOI: 10.1212/nxg.0000000000000476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/01/2020] [Indexed: 11/25/2022]
Affiliation(s)
- Mohamed Kazamel
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Michael A Lopez
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Martina Bebin
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Kevin Bowling
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Bruce R Korf
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Gregory S Barsh
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Gregory M Cooper
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Anna C E Hurst
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
| | - Eroboghene E Ubogu
- Department of Neurology (M.K., M.B., E.E.U.), University of Alabama at Birmingham (UAB); Department of Pediatrics (M.A.L., M.B.), Children's of Alabama | UAB; HudsonAlpha Institute for Biotechnology (K.B., G.S.B., G.M.C.), Huntsville, AL; and Department of Genetics (B.R.K., A.C.E.H.), UAB
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Paula MVBD, Lira Júnior MADF, Monteiro VCESC, Souto RP, Fernandes CE, Oliveira ED. Evaluation of the fibulin 5 gene polymorphism as a factor related to the occurrence of pelvic organ prolapse. ACTA ACUST UNITED AC 2020; 66:680-686. [PMID: 32638975 DOI: 10.1590/1806-9282.66.5.680] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 12/08/2019] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Pelvic organ prolapse (POP) is a very frequent situation in our population that may lead to a significant decrease in patients' quality of life. Currently, we are looking for predictive factors for the development of POPs; thus, this study seeks to evaluate whether the Fibulin 5 polymorphism (FBLN5) is associated with the occurrence of POP. METHODS This is a cohort study with postmenopausal women who were divided into groups by POP stage: POP stages 0 and I (control group) and POP stages III and IV (case group). Subsequently, analyses of genetic polymorphisms of FBLN5 were performed using the Restriction Fragment Length Polymorphism (RFLP) technique. RESULTS A total of 292 women were included in the study. Pregnancy, parity and vaginal delivery in the patients, as well as in data described in the literature, were related to the occurrence of POP in the univariate analysis. However, after binary logistic regression, home birth and age remained independent risk factors for POP. We found no association between the FBLN5 polymorphism and the occurrence of POP (p = 0.371). CONCLUSION There was no association between the FBLN5 polymorphism and the occurrence of POP in Brazilian women.
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Affiliation(s)
| | | | | | - Ricardo Peres Souto
- Departamento de Morfologia e Psicologia, Faculdade de Medicina do ABC, Santo André, SP, Brasil
| | - César Eduardo Fernandes
- Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina do ABC, Santo André, SP, Brasil
| | - Emerson de Oliveira
- Departamento de Ginecologia e Obstetrícia, Faculdade de medicina do ABC, Santo André, SP, Brasil
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