Work

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

Year: 2025

Type: article

Abstract: ABSTRACT 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.

Source: Aging Cell

DOI: 10.1111/acel.70248

Authors: Lei Zhang, Chunmei Xiu, Hongji You, Jianquan Chen

Institutions: Soochow University, Hangzhou City University

Language: English

Topic: Spine and Intervertebral Disc Pathology

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,790