Dual‐Lineage Chondrocyte‐Like Cells in the Nucleus Pulposus of Aging Intervertebral Discs Are Accelerated by Hedgehog Signaling Inactivation

Intervertebral disc (IVD) degeneration, a major contributor to chronic low back pain, is characterized by the age‐related replacement of notochord‐derived nucleus pulposus cells (NPCs) with chondrocyte‐like or fibrotic cells (CLCs). However, the cellular origins of CLCs and mechanisms driving their emergence remain contentious. Using genetic lineage tracing with Shh‐Cre and Gli1‐CreER T2 to track notochordal and non‐notochordal cells, respectively, we demonstrate that CLCs arise from dual lineages: notochordal NPCs and non‐notochordal Gli1 + progenitors. We identified three CLC subtypes, including nested (N‐CLCs), clustered (C‐CLCs), and disordered (D‐CLCs), with distinct morphological and/or molecular profiles. N‐CLCs and C‐CLCs originate from NPCs, whereas D‐CLCs derive from Gli1 + cells infiltrating the NP. Furthermore, conditional ablation of Smo , an essential transducer of Hh signaling, in adult discs accelerated degeneration and promoted both NP‐derived (Krt19 + N‐CLCs) and non‐NPC‐derived (Krt19 − D‐CLCs) populations. These results establish that Hh signaling suppresses dual‐lineage CLC expansion during aging. Our findings resolve controversies surrounding CLC origins, delineate their dynamic progression during degeneration, and highlight Hh signaling as a promising therapeutic target to counteract pathological cell fate shifts in aging discs.