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Single-Cell RNA Sequencing Reveals Cellular Heterogeneity and Reparative Mechanisms in Cystic Change of Osteonecrosis of the Femoral Head

ABSTRACT: Aims: Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating condition often accompanied by cystic change in the affected bone. Previous studies and our clinical observation have suggested the potential for tissue repair within the cystic change, but the underlying cellular mechanisms remain unclear. This study aims to investigate the heterogeneity of cells in the cystic change region, focusing on chondrocytes and endothelial cells, using single-cell RNA sequencing (scRNA-seq) and subsequent histological validation. Method: Cystic change tissues were obtained from patients undergoing total hip arthroplasty. Single-cell RNA sequencing was performed to identify distinct cell populations, particularly chondrocytes and endothelial cells. Alcian blue staining was employed to detect chondrocytes, while immunohistochemistry (IHC) was used to verify the presence of repair-associated chondrocytes. Additionally, HE staining was performed to further analyze tissue architecture like blood vessels. Results: ScRNA-seq analysis identified two major cell types in the cystic change region: endothelial cells involved in angiogenesis and chondrocytes, which included subpopulations associated with cartilage repair. Alcian blue staining showed strong cartilage matrix staining within the cystic change. Immunohistochemistry further validated the expression of repair-associated markers in the chondrocyte population, suggesting active cartilage repair. Cellular communication analysis revealed intercellular interactions between reparative chondrocyte via matrix proteins (FN1, COL1A1) and integrin receptors on angiogenic endothelial cell, suggesting their potential collaboration in the repair process. Conclusion: This study highlights the positive effects of cystic change region of SIONFH in the process of repair based on clinical observations and single-cell RNA sequencing technology. The presence of functionally distinct cell populations, including angiogenic endothelial cells and repair-associated chondrocytes, within cystic change region of SIONFH. The findings suggest a biological basis for repair in the cystic change tissue, providing insights that may inform future therapeutic strategies targeting bone and cartilage regeneration in osteonecrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290411 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Previous studies have demonstrated relative deficiencies of repair tissue within articular lesions when compared to articular cartilage. While cells occupying the lesions might be of mesenchymal origin, they do not recapitulate differentiation to the chondrogenic phenotype of normal articular chondrocytes. Nevertheless, attributes of repair tissue appear similar to chondrocytes and their precursors at various other different states. We hypothesized that analyses of gene expression profiles for these other cell phenotypes would elucidate the identity of repair tissue cells. Total RNA was isolated from repair tissue samples, neonatal articular cartilage, primary articular chondrocytes maintained in monolayer culture and passaged weekly over 28 days, and bone marrow stromal cells expanded to 80% confluence in monolayer culture. Total RNA was linearly amplified and applied to a 9413-probe set equine-specific cDNA microarray. Four repair tissue samples were compared with a dye-swap experimental design to four samples from each of the three other cell populations for a total of twelve comparisons, or twenty-four slides. Differential expression of genes of interest was validated by real-time quantitative polymerase chain reaction. Statistical analysis revealed that a total of 934 (9.9%), 1839 (19.5%), and 940 (10.0%) probe sets were differentially expressed for the bone marrow stromal cells versus repair tissue, de-differentiated chondrocytes versus repair tissue, and neonatal articular chondrocytes versus repair tissue comparisons, respectively. Transcriptional and translational machinery gene ontological categories were over-represented in transcripts demonstrating stable expression amongst the three comparisons. Biomarkers typically associated with normal articular cartilage and fibrocartilage repair tissue comprised much of the genes with the greatest levels of differential expression amongst the three comparisons. Overall, the profiles indicated that repair cells were more chondrogenic than bone marrow stromal cells and de-differentiated chondrocytes. However, transcript levels of key biomarkers and growth factors for repair tissue cells four months post-operatively fell far short of those of neonatal articular chondrocytes destined to undergo normal cartilage maturation.

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Single-Cell RNA Sequencing Reveals Cellular Heterogeneity and Reparative Mechanisms in Cystic Change of Osteonecrosis of the Femoral Head

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