Novel Role of Estrogen Receptor-α on Regulating Chondrocyte Phenotype and Response to Mechanical Loading
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179716 | GEO | 2023/07/07
REPOSITORIES: GEO
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2017-12-02 | E-MTAB-5326 | biostudies-arrayexpress
Project description:Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD146low/negCD166low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (pre-chondrocytes) at 5-6 weeks of development; pellet assays confirmed these cells as functional, chondrocyte-restricted progenitors. Flow cytometry, qPCR and immunohistochemistry at 17 weeks revealed that the superficial layer of peri-articular chondrocytes was enriched in cells with this surface phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166negBMPR1B+ putative pre-chondrocytes. Functional characterization confirmed these cells as cartilage-committed, chondrocyte progenitors. The identification of a specific molecular signature for primary cartilagecommitted progenitors may provide essential knowledge for the generation of purified, clinically relevant cartilage cells from PSCs. A total of 15 samples were analyzed. In the first comparison, there were 6 biological replicates for both the chondrogenic condensations and total limb cells. In the second comparison, three biological replicates of chondrocytes from the articular region were compared to the 6 replicates of the condensations.
2013-12-16 | E-GEOD-51812 | biostudies-arrayexpress
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2013-01-31 | E-GEOD-43923 | biostudies-arrayexpress
Project description:Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD146low/negCD166low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (pre-chondrocytes) at 5-6 weeks of development; pellet assays confirmed these cells as functional, chondrocyte-restricted progenitors. Flow cytometry, qPCR and immunohistochemistry at 17 weeks revealed that the superficial layer of peri-articular chondrocytes was enriched in cells with this surface phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166negBMPR1B+ putative pre-chondrocytes. Functional characterization confirmed these cells as cartilage-committed, chondrocyte progenitors. The identification of a specific molecular signature for primary cartilagecommitted progenitors may provide essential knowledge for the generation of purified, clinically relevant cartilage cells from PSCs.
2013-12-16 | GSE51812 | GEO
Project description:The pathology of failure in currently used biological treatments (cell therapies and microfracture) for cartilage repair or early osteoarthritis (OA) is poorly understood. We aimed to identify a reliable panel of biological predictors, present in synovial fluid, which can be used in the preoperative setting to optimise patient selection and therapy efficacy. The-long term aim is to reduce the number of patients who progress to end-stage OA and require knee replacement by making earlier, less invasive treatments more effective. In this first stage, we have taken synovial fluid aspirates from patients undergoing autologous chondrocyte implantation (ACI) at our centre in Oswestry, UK. Synovial fluids (SFs) were obtained from 14 ACI responders (mean Lysholm improvement of 33 (17-54)) and 13 non-responders (mean Lysholm decrease of 14 (4-46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Dynamic range compression of synovial fluids coupled with label-free quantification mass spectrometry (MS), was used in an unbiased approach to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI.
2017-07-04 | PXD005220 | Pride
Project description:Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel highly expressed in chondrocytes that maintains cartilage homeostasis during development and throughout aging. Mutations in the channel cause a wide range of developmental disorders including skeletal dysplasias. The gain-of-function mutations V620I and T89I have been identified to lead to brachyolmia and metatropic dysplasia, respectively. Although it is known these mutations suppress hypertrophic differentiation, the mechanisms by which they alter chondrocyte response to mechanical loading remain to be elucidated. To determine the effect of these mutations on chondrocyte mechanotransduction, tissue-engineered cartilage was derived from differentiated CRISPR-edited human induced pluripotent stem cells harboring the moderate V620I or severe T89I TRPV4 mutations. Tissue-engineered hiPSC-derived cartilage was then subjected compressive mechanical loading at physiological levels, and RNA-sequencing was used to assess the transcriptomic signatures of wildtype and mutant tissue-engineered cartilage. Our results demonstrate that the V620I and T89I mutations lead to reduced mechanoresponsiveness, characterized by a lower number of differentially expressed genes and diminished activation of genes downstream of TRPV4 signaling and contributing towards the process of endochondral ossification. Changes in extracellular matrix production and organization were found to contribute towards the phenotype in V620I chondrocytes, whereas dysregulated retinoic acid signaling was linked to T89I, and disrupted proliferation was common to both. Our findings suggest that dysfunctional mechanotransduction arising due to the V620I and T89I mutations contribute to the developmental phenotypes observed in their respective skeletal dysplasias, introducing potential pharmacologic targets for these conditions.
2024-12-10 | GSE283659 | GEO
Project description:Objectives: Articular cartilage damage has become a universal health burden. Despite the recent progresses in cell-based cartilage regeneration, chondrocyte dedifferentiation has compromised the clinical outcomes, which is frequently seen in chondrocyte expansion and osteoarthritis, involving functional phenotype loss. However, its concept remains elusive with unknown intermediate process and mechanisms. Here we demonstrated a time-lapse atlas of chondrocyte dedifferentiation, to provide molecular details and informative biomarkers for clinical chondrocyte evaluation. Methods: Single-cell RNA sequencing (scRNA-seq) was employed to dissect the chondrocyte dedifferentiation and identify distinct cellular subpopulations. To validate the findings, live-cell metabolic assay, high-resolution imaging and ¡°assay for transposase-accessible chromatin with high throughput sequencing¡± (ATAC-seq) were conducted. Using a chemical inhibitor BTB06584 affecting on mitochondrial F1F0ATPase, we revealed the recovery potential of early and late dedifferentiated chondrocytes. Results:Our findings shape a biphasic model consist of early and late dedifferentiation stages. Early dedifferentiated chondrocytes uniquely obtained a transient glycolytic phenotype with an activation of metabolic and anti-oxidant genes; late dedifferentiated chondrocytes exhibited ultrastructural changes including mitochondrion damages and stress-associated chromatin remodeling. Using a chemical inhibitor BTB06584, we revealed that early and late dedifferentiated chondrocytes possessed distinguished recovery potential from functional phenotype loss. BTB06584 treatment ameliorated early phenotype loss through inhibiting MAPK pathway. Notably, this two-stage transition was validated in human chondrocyte culture. An image-based approach was established for clinical utilization, to efficiently predict chondrocytes plasticity with stage-specific biomarkers. Conclusion: Thus this study lays a foundation for future clinical chondrocyte quality regulation and provides insights for deeper understanding of chondrocyte dedifferentiation.
2022-01-20 | GSE193743 | GEO
Project description:Objectives: Articular cartilage damage has become a universal health burden. Despite the recent progresses in cell-based cartilage regeneration, chondrocyte dedifferentiation has compromised the clinical outcomes, which is frequently seen in chondrocyte expansion and osteoarthritis, involving functional phenotype loss. However, its concept remains elusive with unknown intermediate process and mechanisms. Here we demonstrated a time-lapse atlas of chondrocyte dedifferentiation, to provide molecular details and informative biomarkers for clinical chondrocyte evaluation. Methods: Single-cell RNA sequencing (scRNA-seq) was employed to dissect the chondrocyte dedifferentiation and identify distinct cellular subpopulations. To validate the findings, live-cell metabolic assay, high-resolution imaging and ¡°assay for transposase-accessible chromatin with high throughput sequencing¡± (ATAC-seq) were conducted. Using a chemical inhibitor BTB06584 affecting on mitochondrial F1F0ATPase, we revealed the recovery potential of early and late dedifferentiated chondrocytes. Results:Our findings shape a biphasic model consist of early and late dedifferentiation stages. Early dedifferentiated chondrocytes uniquely obtained a transient glycolytic phenotype with an activation of metabolic and anti-oxidant genes; late dedifferentiated chondrocytes exhibited ultrastructural changes including mitochondrion damages and stress-associated chromatin remodeling. Using a chemical inhibitor BTB06584, we revealed that early and late dedifferentiated chondrocytes possessed distinguished recovery potential from functional phenotype loss. BTB06584 treatment ameliorated early phenotype loss through inhibiting MAPK pathway. Notably, this two-stage transition was validated in human chondrocyte culture. An image-based approach was established for clinical utilization, to efficiently predict chondrocytes plasticity with stage-specific biomarkers. Conclusion: Thus this study lays a foundation for future clinical chondrocyte quality regulation and provides insights for deeper understanding of chondrocyte dedifferentiation.
2022-01-20 | GSE193742 | GEO
Project description:Novel Role of Estrogen Receptor-α on Regulating Chondrocyte Phenotype and Response to Mechanical Loading
| PRJNA744755 | ENA