单细胞 RNA 测序分析揭示了人类骨关节炎的进展。

OBJECTIVES: Understanding the molecular mechanisms underlying human cartilage degeneration and regeneration is helpful for improving therapeutic strategies for treating osteoarthritis (OA). Here, we report the molecular programmes and lineage progression patterns controlling human OA pathogenesis using single-cell RNA sequencing (scRNA-seq). METHODS: We performed unbiased transcriptome-wide scRNA-seq analysis, computational analysis and histological assays on 1464 chondrocytes from 10 patients with OA undergoing knee arthroplasty surgery. We investigated the relationship between transcriptional programmes of the OA landscape and clinical outcome using severity index and correspondence analysis. RESULTS: We identified seven molecularly defined populations of chondrocytes in the human OA cartilage, including three novel phenotypes with distinct functions. We presented gene expression profiles at different OA stages at single-cell resolution. We found a potential transition among proliferative chondrocytes, prehypertrophic chondrocytes and hypertrophic chondrocytes (HTCs) and defined a new subdivision within HTCs. We revealed novel markers for cartilage progenitor cells (CPCs) and demonstrated a relationship between CPCs and fibrocartilage chondrocytes using computational analysis. Notably, we derived predictive targets with respect to clinical outcomes and clarified the role of different cell types for the early diagnosis and treatment of OA. CONCLUSIONS: Our results provide new insights into chondrocyte taxonomy and present potential clues for effective and functional manipulation of human OA cartilage regeneration that could lead to improved health.

目的：了解人类软骨退化和再生的分子机制有助于改善治疗骨关节炎（OA）的治疗策略。在这里，我们使用单细胞 RNA 测序（scRNA-seq）报告控制人类 OA 发病机制的分子程序和谱系进展模式。

方法：我们对 10 名接受膝关节置换手术的 OA 患者的 1464 个软骨细胞进行了无偏转录组范围的 scRNA-seq 分析、计算分析和组织学检测。我们使用严重程度指数和对应分析研究了 OA 景观的转录程序与临床结果之间的关系。

结果：我们在人类 OA 软骨中鉴定出了七个分子定义的软骨细胞群体，包括具有不同功能的三种新型表型。我们以单细胞分辨率呈现了不同 OA 阶段的基因表达谱。我们发现增殖性软骨细胞、预肥大软骨细胞和肥大软骨细胞（HTCs）之间存在潜在的转变，并在 HTCs 中定义了一个新的细分。我们揭示了软骨祖细胞（CPCs）的新标志物，并通过计算分析证明了 CPCs 与纤维软骨细胞之间的关系。值得注意的是，我们针对临床结果得出了预测性靶标，并阐明了不同细胞类型在 OA 的早期诊断和治疗中的作用。

结论：我们的研究结果为软骨细胞分类学提供了新的见解，并为有效和功能性地操纵人类 OA 软骨再生提供了潜在的线索，从而改善健康状况。