Max Planck Institute for the Science of Light, 91058, Erlangen, Germany.
Max-Planck-Zentrum für Physik und Medizin, 91058, Erlangen, Germany.
Nat Commun. 2023 Oct 26;14(1):6814. doi: 10.1038/s41467-023-42339-7.
Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.
中枢神经系统 (CNS) 损伤后细胞外基质 (ECM) 的沉积会导致人类和其他哺乳动物形成抑制性瘢痕，而在斑马鱼中则有利于轴突再生。然而，这些不同命运的分子基础尚不清楚。在这里，我们将小富含亮氨酸的蛋白聚糖 (SLRPs) 确定为哺乳动物再生失败的一个促成因素。我们证明， SLRPs 软骨粘连蛋白、纤维调蛋白、亮氨酸丰富蛋白聚糖和脯氨酸丰富蛋白聚糖在啮齿动物和人类的中枢神经系统损伤中富集，但在斑马鱼中没有。将 SLRPs 靶向到斑马鱼损伤 ECM 中会抑制轴突再生和功能恢复。从机制上讲，我们发现 SLRPs 赋予损伤环境机械结构特性，不利于轴突生长。我们的研究揭示了 SLRPs 作为抑制性 ECM 因子，通过改变组织力学和结构来损害轴突再生，并确定其在人脑和脊髓损伤中的富集是其特征之一。这些发现表明，SLRPs 可能是促进中枢神经系统再生的治疗策略的靶点。
