Abstract
Intervertebral disc degeneration (IDD) is a prevalent cause of low back pain, significantly impacting health worldwide. While IDD is associated with aging, its precise molecular mechanisms remain inadequately understood, limiting the development of targeted therapies. Nucleus pulposus cells (NPCs) are crucial to maintaining disc integrity and are central to understanding IDD progression. This study used single-cell and bulk RNA sequencing to dissect the cellular landscape and gene expression profiles in IDD. By analyzing these data, we identified distinct NPC subtypes and their roles in the degenerative disc microenvironment. Pseudotime and cellular communication network analyses further elucidated the temporal progression and signaling interactions of NPCs during disc degeneration. Four critical genes-TCF19, GDF15, RNMT, and C12orf45-were identified as significantly upregulated in IDD. TCF19 emerged as a key gene in the transitional states of NPCs, suggesting its pivotal role in IDD progression. In vivo experiments using a rat model indicated that Tcf19 knockdown significantly mitigated disc degeneration, reducing both abnormal collagen deposition and inflammation markers. This study unveils the complex molecular dynamics within IDD, providing new insights into distinct NPC subtypes and key genetic players. TCF19, in particular, holds promise as a therapeutic target for IDD. Our findings lay the groundwork for developing targeted treatment strategies, potentially improving the management and outcomes for individuals suffering from disc degeneration.