Abstract
ABSTRACTNotochordal cells play a pivotal role in vertebral column patterning, contributing to the formation of the inner architecture of intervertebral discs (IVDs). Their disappearance during development has been associated with reduced repair capacity and IVD degeneration. Notochord cells can give rise to chordomas, a highly invasive bone cancer associated with late diagnosis. Understanding the impact of neoplastic cells during development and on the surrounding vertebral column could open avenues for earlier intervention and therapeutics. We investigated the impact of transformed notochord cells in the zebrafish skeleton using a line expressing RAS in the notochord under the control of the kita promoter, with the advantage of adulthood endurance. Transformed cells caused damage in the notochord and destabilised the sheath layer, triggering a wound repair mechanism, with enrolment of sheath cells (col9a2+) and expression of wt1b, similar to induced notochord wounds. Moreover, increased recruitment of neutrophils and macrophages, displaying abnormal behaviour in proximity to the notochord sheath and transformed cells, supported parallels between chordomas, wound and inflammation. Cancerous notochordal cells interfere with differentiation of sheath cells to form chordacentra domains, leading to fusions and vertebral clefts during development. Adults displayed IVD irregularities reminiscent of degeneration, including reduced bone mineral density and increased osteoclast activity, along with disorganised osteoblasts and collagen, indicating impaired bone homeostasis. By depleting inflammatory cells, we abrogated chordoma development and rescued the skeletal features of the vertebral column. Therefore, we showed that transformed notochord cells alter the skeleton during life, causing a wound-like phenotype and activating chronic wound response, suggesting parallels between chordoma, wound, IVD degeneration and inflammation, highlighting inflammation as a promising target for future therapeutics.This article has an associated First Person interview with the first author of the paper.
Highlights
The vertebral column is the central axis of the skeleton in all vertebrates
The architecture of the intervertebral discs (IVDs) is made by an annulus fibrosus (AF), a collagenous layer surrounding a hydrated and gelatinous nucleus pulposus (NP) core, which contains chondrocyte-like cells derived from embryonic notochord cells (Rodrigues-Pinto et al, 2014)
RESULTS kita-RAS induces wound-like destabilisation of the notochord Notochord-specific Gal4 lines crossed to UAS:EGFP-HRASV12 have been previously described as powerful models for inducing chordomas in zebrafish (Burger et al, 2014)
Summary
The vertebral column is the central axis of the skeleton in all vertebrates. It is composed of segments (vertebrae) connected by joint-like structures called intervertebral discs (IVDs). Control fish exhibited no expression of wt1b in the notochord, whereas kita-RAS showed strong wt1b expression by pre-neoplastic cells located at severe wounded regions in 100% of the cases analysed (20/20) (Fig. 2E).
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