Lumbar discs are cartilaginous tissues between vertebrae, composed of the nucleus pulposus, annulus fibrosus, and cartilage endplates. These structures act as shock absorbers and provide spinal flexibility. The nucleus pulposus tissue, containing nucleus pulposus progenitor cells (NPPCs) and their derivatives, plays a vital role in maintaining spinal structure and function. This study employed histological staining and single-nucleus sequencing for young, young herniated, and aged human nucleus pulposus tissues to characterize and compare lumbar disc herniation and aging-related changes. Histological analysis revealed strong similarities between aged and herniated lumbar disc tissues, including extracellular matrix reduction and disruption, senescent cell accumulation, and increased inflammation. Single-nucleus transcriptome analysis revealed that NPPCs and their derivatives showed significant differential gene expression, and identified NFATC2 as a common upstream regulator in both aging and herniated lumbar discs through transcription factor analysis. Further investigation using primary NPPCs demonstrated that NFATC2 knockdown delayed cellular senescence and enhanced chondrogenic differentiation, while its activation accelerated NPPC aging. This research establishes NFATC2 as a core driving factor in lumbar disc aging and herniation, presenting a potential therapeutic target.
Key findings from the study include:

1. Cellular Senescence and Progenitor Cell Decline: The research identified that aging in the nucleus pulposus (NP) is characterized by increased cellular senescence and a reduction in nucleus pulposus progenitor cells (NPPCs). Aging NP exhibits 67% decline in CD24⁺CD44⁻ NPPCs, linked to ECM loss (COL2A1↓, ACAN↓) and SASP-driven proteoglycan degradation. This decline in NPPCs contributes to the deterioration of disc function and structure.
2. NFAT1 Upregulation Promotes Senescence: An age-related increase in NFAT1 expression was observed, which promotes the senescence of NPPCs. This upregulation is implicated in both the aging process and the herniation of lumbar discs, suggesting NFAT1 as a potential therapeutic target.
3. Molecular Alterations in Aging Discs: Single-nucleus RNA sequencing revealed significant molecular changes in aged NP tissues, including alterations in gene expression profiles associated with senescence and extracellular matrix degradation. These changes underscore the complex molecular landscape contributing to disc aging and herniation.
4. Potential for Therapeutic Interventions: The study's findings offer insights into the mechanisms of disc aging and herniation, highlighting potential avenues for developing therapies aimed at mitigating NPPC senescence and preserving disc integrity.

These findings mirror the therapeutic targeting strategies employed in NET-driven pathologies, highlighting potential for repurposing TLR/IL-17 inhibitors in disc disorders. The work entitled “Single-nucleus transcriptomics decodes the link between aging and lumbar disc herniation” was published on Protein & Cell (published on May. 22, 2025).
DOI: 10.1093/procel/pwae030