Frontiers in bioengineering and biotechnology · 2026
Multi-cell-component cartilage organoids simulate intercellular microstress, hypoxic microenvironment, and chondrocyte-endothelial crosstalk in vitro.
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Wang Zhengchao, Zhu Pengfei, Li Hongmei, Zhang Qingsong, Cheng Jiangxia, Cai Yu
Аннотация
INTRODUCTION: In cartilage-related studies, the existing in vitro cartilage models often fail to simulate the complex pathophysiology involving a hypoxic microenvironment, abnormal intercellular mechanical stress (microstress), and pathological crosstalk between chondrocytes and vascular endothelial cells. he aim of this study was to develop and validate a novel, simplified multi-cell-component cartilage organoid model capable of mimicking these three key OA-related features in vitro, using readily available cell lines.
METHODS: Organoids were constructed using SW1353 chondrocytes and HMEC-1 endothelial cell lines within low-adhesion grid microchambers. A monosodium iodoacetate (MIA)-induced OA model was developed. Histological and immunofluorescence analyses of the organoids were conducted to examine markers of matrix metabolism, cytoskeletal and intercellular microstress, hypoxic microenvironment, and chondrocyte -endothelial crosstalk. The organoid features were compared with those of standard 2D cell cultures and in vivo cartilages.
RESULTS: The multi-cell-component organoids successfully recapitulated critical in vivo features. They exhibited MIA-induced F-actin reorganization and PIEZO1 upregulation, developed a hypoxic core with elevated hypoxia-inducible factor 1-alpha (HIF-1α) levels, and formed an endothelial shell that invasively disrupted the chondrocyte core upon MIA treatment. This disruption was accompanied by the activation of vascular endothelial growth factor -NOTCH receptor 1 -delta-like ligand 4 (VEGF -NOTCH1 -DLL4) signaling, mirroring the pathological chondrocyte -endothelial crosstalk. Single-cell-component organoids simulated microstress-related changes but not hypoxia or chondrocyte -endothelial crosstalk.
DISCUSSION: The multi-cell-component cartilage organoids constructed from tumor-derived cell lines using low-adhesion grid microchambers partially simulated intercellular microstress, hypoxic microenvironment, and chondrocyte -endothelial crosstalk, which was similar to that observed in cartilages in vivo. These organoids provide a new strategy for conducting cartilage-related studies in vitro.
METHODS: Organoids were constructed using SW1353 chondrocytes and HMEC-1 endothelial cell lines within low-adhesion grid microchambers. A monosodium iodoacetate (MIA)-induced OA model was developed. Histological and immunofluorescence analyses of the organoids were conducted to examine markers of matrix metabolism, cytoskeletal and intercellular microstress, hypoxic microenvironment, and chondrocyte -endothelial crosstalk. The organoid features were compared with those of standard 2D cell cultures and in vivo cartilages.
RESULTS: The multi-cell-component organoids successfully recapitulated critical in vivo features. They exhibited MIA-induced F-actin reorganization and PIEZO1 upregulation, developed a hypoxic core with elevated hypoxia-inducible factor 1-alpha (HIF-1α) levels, and formed an endothelial shell that invasively disrupted the chondrocyte core upon MIA treatment. This disruption was accompanied by the activation of vascular endothelial growth factor -NOTCH receptor 1 -delta-like ligand 4 (VEGF -NOTCH1 -DLL4) signaling, mirroring the pathological chondrocyte -endothelial crosstalk. Single-cell-component organoids simulated microstress-related changes but not hypoxia or chondrocyte -endothelial crosstalk.
DISCUSSION: The multi-cell-component cartilage organoids constructed from tumor-derived cell lines using low-adhesion grid microchambers partially simulated intercellular microstress, hypoxic microenvironment, and chondrocyte -endothelial crosstalk, which was similar to that observed in cartilages in vivo. These organoids provide a new strategy for conducting cartilage-related studies in vitro.