Endogenous opioid signalling regulates spinal ependymal cell proliferation

• 成果类型: Article
• 署名作者: Yue, Wendy W. S.; Touhara, Kouki K.; Toma, Kenichi; Duan, Xin; Julius, David
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5659
• DOI: 10.1038/s41586-024-07889-w
• 发表日期: 2024-10-10
• 关键词: fluid-contacting neurons; dynorphin-a; neurogenic niche; cord-injury; receptors; stem; regeneration; mobilization; enhancement; nucleus

摘要

After injury, mammalian spinal cords develop scars to confine the lesion and prevent further damage. However, excessive scarring can hinder neural regeneration and functional recovery1,2. These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate scar progression. Previous research on scarring has primarily focused on astrocytes, but recent evidence has suggested that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain injuries, becoming a core scar component3-7. However, the mechanisms regulating ependymal proliferation in vivo remain unclear. Here we uncover an endogenous kappa-opioid signalling pathway that controls ependymal proliferation. Specifically, we detect expression of the kappa-opioid receptor, OPRK1, in a functionally under-characterized cell type known as cerebrospinal fluid-contacting neuron (CSF-cN). We also discover a neighbouring cell population that expresses the cognate ligand prodynorphin (PDYN). Whereas kappa-opioids are typically considered inhibitory, they excite CSF-cNs to inhibit ependymal proliferation. Systemic administration of a kappa-antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, a kappa-agonist impairs ependymal proliferation, scar formation and motor function following injury. Together, our data suggest a paracrine signalling pathway in which PDYN+ cells tonically release kappa-opioids to stimulate CSF-cNs and suppress ependymal proliferation, revealing an endogenous mechanism and potential pharmacological strategy for modulating scarring after spinal cord injury. Paracrine kappa-opioid signalling among cells surrounding the spinal cord central canal modulates scar formation after injury.