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RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms
Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene exp...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9777098/ https://www.ncbi.nlm.nih.gov/pubmed/36552803 http://dx.doi.org/10.3390/cells11244040 |
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author | Ritelli, Marco Chiarelli, Nicola Cinquina, Valeria Zoppi, Nicoletta Bertini, Valeria Venturini, Marina Colombi, Marina |
author_facet | Ritelli, Marco Chiarelli, Nicola Cinquina, Valeria Zoppi, Nicoletta Bertini, Valeria Venturini, Marina Colombi, Marina |
author_sort | Ritelli, Marco |
collection | PubMed |
description | Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders. |
format | Online Article Text |
id | pubmed-9777098 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97770982022-12-23 RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms Ritelli, Marco Chiarelli, Nicola Cinquina, Valeria Zoppi, Nicoletta Bertini, Valeria Venturini, Marina Colombi, Marina Cells Article Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders. MDPI 2022-12-14 /pmc/articles/PMC9777098/ /pubmed/36552803 http://dx.doi.org/10.3390/cells11244040 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ritelli, Marco Chiarelli, Nicola Cinquina, Valeria Zoppi, Nicoletta Bertini, Valeria Venturini, Marina Colombi, Marina RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title | RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title_full | RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title_fullStr | RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title_full_unstemmed | RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title_short | RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms |
title_sort | rna-seq of dermal fibroblasts from patients with hypermobile ehlers–danlos syndrome and hypermobility spectrum disorders supports their categorization as a single entity with involvement of extracellular matrix degrading and proinflammatory pathomechanisms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9777098/ https://www.ncbi.nlm.nih.gov/pubmed/36552803 http://dx.doi.org/10.3390/cells11244040 |
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