Department of Neonatology, Children's Hospital of Fudan University, Shanghai 201102, China; Key Laboratory of Neonatal Diseases, National Health Commission, China.
Department of Neonatology, Children's Hospital of Fudan University, Shanghai 201102, China; Key Laboratory of Neonatal Diseases, National Health Commission, China.
Brain Res. 2021 Sep 1;1766:147522. doi: 10.1016/j.brainres.2021.147522. Epub 2021 May 16.
Hyaluronan is one of the major components of the neural extracellular matrix (ECM) and provides structural support in physiological conditions. Altered hyaluronan regulation is implicated in the pathogenesis of white matter injury (WMI), such as perinatal WMI, multiple sclerosis (MS), traumatic brain injury (TBI). Early research reported diverse central nervous system (CNS) insults led to accumulated high-molecular-weight (HMW) hyaluronan in hypomyelinating/demyelinating lesions. Furthermore, recent findings have shown an elevated production of hyaluronan fragments in WMI, possibly resulting from HMW hyaluronan degradation. Subsequent in vitro studies identified bioactive hyaluronan fragments with a specific molecular weight (around 2x10 Da) regulating oligodendrocyte precursor cells (OPCs) maturation and myelination/remyelination in WMI. However, it is unclear about the effective hyaluronidases in generating bioactive hyaluronan fragments. Several hyaluronidases are proposed recently. Although PH20 is shown to block OPCs maturation by generating bioactive hyaluronan fragments in vitro, it seems unlikely to play a primary role in WMI with negligible expression levels in vivo. The role of other hyaluronidases on OPCs maturation and myelination/remyelination is still unknown. Other than hyaluronidases, CD44 and Toll-like receptors 2 (TLR2) are also implicated in HMW hyaluronan degradation in WMI. Moreover, recent studies elucidated bioactive hyaluronan fragments interact with TLR4, initiating signaling cascades to mediate myelin basic protein (MBP) transcription. Identifying key factors in hyaluronan actions may provide novel therapeutic targets to promote OPCs maturation and myelination/remyelination in WMI.
透明质酸是神经细胞外基质（ECM）的主要成分之一，在生理条件下提供结构支持。透明质酸调节异常与脑白质损伤（WMI）的发病机制有关，如围产期 WMI、多发性硬化症（MS）、创伤性脑损伤（TBI）。早期研究报道，多种中枢神经系统（CNS）损伤导致低髓鞘化/脱髓鞘病变中高分子量（HMW）透明质酸的积累。此外，最近的研究结果表明，WMI 中透明质酸片段的产生增加，可能是由于 HMW 透明质酸的降解。随后的体外研究发现，具有特定分子量（约 2x10 Da）的生物活性透明质酸片段可调节 WMI 中少突胶质前体细胞（OPC）的成熟和髓鞘形成/再髓鞘化。然而，产生生物活性透明质酸片段的有效透明质酸酶尚不清楚。最近提出了几种透明质酸酶。虽然 PH20 被证明通过在体外产生生物活性透明质酸片段来阻止 OPC 成熟，但由于其在体内表达水平极低，似乎不太可能在 WMI 中发挥主要作用。其他透明质酸酶对 OPC 成熟和髓鞘形成/再髓鞘化的作用仍不清楚。除了透明质酸酶，CD44 和 Toll 样受体 2（TLR2）也参与 WMI 中 HMW 透明质酸的降解。此外，最近的研究阐明了生物活性透明质酸片段与 TLR4 相互作用，启动信号级联反应，介导髓鞘碱性蛋白（MBP）转录。确定透明质酸作用中的关键因素可能为促进 WMI 中 OPC 成熟和髓鞘形成/再髓鞘化提供新的治疗靶点。
