Gene expression profile of collagen VI deficient human fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56741 | GEO | 2015/12/18
SECONDARY ACCESSION(S): PRJNA244398
REPOSITORIES: GEO
Similar Datasets
Project description:Objectives: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies, but the pathogenesis, including the role of mutant collagen VI in the matrix is poorly understood. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD patients from controls. Methods: We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD patients (8 dominant negative and 5 null) and 6 controls. Sequence reads were analyzed using the TopHat/Cufflinks pipeline. Results: Differentially expressed transcripts between COL6-RD patient and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples
2017-12-04 | GSE103270 | GEO
Project description:Collagen VI-related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes. ¬¬Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. Collagen VI absence or mislocalization in the skeletal muscle ECM underlies the non-cell autonomous dystrophic changes and dysfunction in skeletal muscle in COL6-RDs with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we derive a novel mouse model of COL6-RD, Col6a2-/- mice, and conduct a comprehensive natural history study in male and female animals aged to 60 weeks of age. Col6a2-/- mice have a normal lifespan but develop muscle weakness based on standardized behavioral tests (grip and hanging wire test), muscle atrophy with histologic hallmarks of muscular dystrophy, and reduced muscle force prodcution on physiologic parameters. We also report a robust dysregulation of TGFβ pathway early in the disease process and thus propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGFβ with downstream skeletal muscle abnormalities, paving the way for developing therapeutics that target this pathway.
2023-12-04 | GSE228223 | GEO
Project description:Proteomic analysis of Collagen VI-deficient fibroblasts at the level of secretome and extracellular vesicles
2023-10-24 | PXD018765 | Pride
Project description:Collagen VI-related muscular dystrophies (COL6RD) are a rare, inherited group of congenital muscular dystrophies. The phenotype spans from an early-onset, severe, and rapidly progressive clinical course in Ullrich congenital muscular dystrophy (UCMD), to a late-onset, mild and slowly progressive form in Bethlem muscular dystrophy (BM). COL6RD are caused by pathogenic variants in any of the three collagen type VI genes (COL6A1, COL6A2, COL6A3), which cause absence, reduction, mislocalization, or dysfunction of the collagen VI microfibrils in the skeletal muscle extracellular matrix (myomatrix), leading to yet incompletely understood downstream effects. Pathologic alterations in muscle biopsies of COL6RD varies, ranging from severely dystrophic changes, to mildly myopathic, represented by isolated myofiber atrophy. In this study, we aim to define the pathophysiologic events responsible for the histologic alterations of muscle and their progression in COL6RD. Aided by automated image analysis, we reviewed COL6RD patient muscle biopsies (n=22) and stratified them to three groups based on the degree of fibrosis and muscle fiber atrophy. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared it with controls (n=14). Different histologic groups were characterized by similar transcriptional signatures predominantly featuring the upregulation of myomatrix component genes and downregulation of skeletal muscle and mitochondrion-specific genes. Our results also identified the TGFβ1 pathway in strong correlation with the development of COL6RD pathology at the histologic level, beginning early in the disease process, preceding fibrosis, and increasing in direct correlation with increased histologic severity. Overall, our study identifies COL6RD as a primary disorder of the myomatrix and posits dysregulation of TGFβ1-dependent pathways as a potential factor in pathogenesis of the disease.
2022-03-22 | GSE103972 | GEO
Project description:Collagen VI-related muscular dystrophies (COL6RD) are a rare, inherited group of congenital muscular dystrophies. The phenotype spans from an early-onset, severe, and rapidly progressive clinical course in Ullrich congenital muscular dystrophy (UCMD), to a late-onset, mild and slowly progressive form in Bethlem muscular dystrophy (BM). COL6RD are caused by pathogenic variants in any of the three collagen type VI genes (COL6A1, COL6A2, COL6A3), which cause absence, reduction, mislocalization, or dysfunction of the collagen VI microfibrils in the skeletal muscle extracellular matrix (myomatrix), leading to yet incompletely understood downstream effects. Pathologic alterations in muscle biopsies of COL6RD varies, ranging from severely dystrophic changes, to mildly myopathic, represented by isolated myofiber atrophy. In this study, we aim to define the pathophysiologic events responsible for the histologic alterations of muscle and their progression in COL6RD. Aided by automated image analysis, we reviewed COL6RD patient muscle biopsies (n=22) and stratified them to three groups based on the degree of fibrosis and muscle fiber atrophy. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared it with controls (n=14). Different histologic groups were characterized by similar transcriptional signatures predominantly featuring the upregulation of myomatrix component genes and downregulation of skeletal muscle and mitochondrion-specific genes. Our results also identified the TGFβ1 pathway in strong correlation with the development of COL6RD pathology at the histologic level, beginning early in the disease process, preceding fibrosis, and increasing in direct correlation with increased histologic severity. Overall, our study identifies COL6RD as a primary disorder of the myomatrix and posits dysregulation of TGFβ1-dependent pathways as a potential factor in pathogenesis of the disease.
2022-03-22 | GSE103608 | GEO
Project description:Single cell analysis of PDL cells in ligature-induced periodontitis: The periodontal ligament (PDL) is a fibrillar connective tissue that lies between the alveolar bone and the tooth and is composed of highly specialized extracellular matrix (ECM) molecules and a heterogeneous population of cells that are responsible for collagen formation, immune response, bone formation, and chewing force sensation. Type VI collagen (COL6), a widely distributed ECM molecule, plays a critical role in the structural integrity and mechanical properties of various tissues including muscle, tendon, bone, cartilage, and skin. However, its role in the PDL remains largely unknown. Our study shows that deficiency of COL6 impairs PDL fibrogenesis and exacerbates tissue destruction in ligature-induced periodontitis (LIP). We found that COL6 deficient mice exhibited increased bone loss and degraded PDL in LIP and that fibroblasts expressing high levels of Col6α2 are pivotal in ECM organization and cell-ECM interactions. Moreover, COL6 deficiency in the PDL led to an increased number of fibroblasts geared towards the inflammatory response. We also observed that cultured COL6 deficient fibroblasts from the PDL exhibited decreased expression of genes related to collagen fiber metabolism and ECM organization, and migration and proliferation. Our findings suggest that COL6 plays a crucial role in the PDL, influencing fibroblast function in fibrogenesis and affecting the immune response in periodontitis. These insights could advance our understanding of the molecular mechanisms underlying PDL maturation and periodontal disease.
2024-06-24 | GSE255695 | GEO
Project description:We compared by quantitative proteomics the protein cargo of EVs as well as the secretome from fibroblasts from patients with collagen VI deficiency
2024-08-22 | PXD042327 | JPOST Repository
Project description:Dermal fibroblasts deposit type I collagen, the dominant extracellular matrix molecule found in skin, during early postnatal development. Coincident with this biosynthetic program, fibroblasts proteolytically remodel pericellular collagen fibrils by mobilizing the membrane-anchored matrix metalloproteinase, Mmp14. Unexpectedly, dermal fibroblasts in Mmp14-/- mice commit to a large-scale apoptotic program that leaves skin tissues replete with dying cells. A requirement for Mmp14 in dermal fibroblast survival is recapitulated in vitro when cells are embedded within, but not cultured atop, 3-dimensional hydrogels of cross-linked type I collagen. In the absence of Mmp14-dependent pericellular proteolysis, dermal fibroblasts fail to trigger β1 integrin activation and instead actuate a TGF-β1/phospho-JNK stress response that leads to apoptotic cell death in vitro as well as in vivo. Taken together, these studies identify Mmp14 as a requisite cell survival factor that maintains dermal fibroblast viability in postnatal dermal tissues.
2024-05-24 | GSE266914 | GEO
Project description:Collagen type VI regulates TGFβ bioavailability in skeletal muscle
| PRJNA948852 | ENA
Project description:In this study, an α2(VI) deficient mouse (Col6α2-KO) model was used to examine the role of Type VI collagen in oral tissues. To examine bone properties, µCT was employed, and bone volume and bone mineral density (BMD) was measured in oral tissues. To further investigate its molecular basis, proteome analysis was performed using protein extracted from alveolar bone. In addition, alveolar bone loss progression was evaluated with a periodontitis induced model. µCT analysis showed the Col6α2- KO mice had less volume of alveolar bone, dentin and dental pulp, while the width of periodontal ligament (PDL) was greater than WT. The BMD in alveolar bone and dentin were elevated in Col6α2-KO mice compared with WT. Our proteome analysis showed significant changes in proteins related to ECM organization and elevation of proteins associated with biomineralization in the Col6α2-KO mice. In induced periodontitis, Col6α2-KO mice had greater alveolar bone loss compared to WT. In conclusion, Type VI collagen has role in controlling biomineralization in alveolar bone and that changes in the ECM of alveolar bone could be associated with greater bone loss from periodontitis.
2022-11-21 | PXD037422 | Pride