Glial scar formation is a major obstacle to nerve regeneration following spinal cord injury (SCI). Pin1 and the PI3K/AKT/CDK2 signaling pathway play crucial roles in neuronal regulation, but research on their involvement in glial scarring remains limited. In this study, we have for the first time observed that Pin1, PI3K, AKT, and CDK2 are upregulated and interact with each other following SCI. Further experiments revealed that Pin1 contributes to the development of glial scars by promoting astrocyte proliferation, inhibiting apoptosis, and activating the PI3K/AKT/CDK2 pathway. Additionally, all‐trans retinoic acid (ATRA), a specific chemical inhibitor of Pin1, effectively suppresses Pin1 expression. However, its clinical application is limited by its short half‐life and susceptibility to inactivation. To address these issues, we have developed a thermosensitive sodium beta‐glycerophosphate (β‐GP)/chitosan (CS) hydrogel loaded with ATRA (β‐GP/CS@ATRA). This hydrogel exhibits favorable morphology and biocompatibility. Compared to free ATRA, the β‐GP/CS@ATRA hydrogel significantly enhances functional motor recovery after SCI and protects spinal cord tissue, thereby inhibiting glial scar formation. Mechanistically, ATRA administration blocks the development of glial scars and the activation of the PI3K/AKT/CDK2 pathway by inhibiting Pin1 expression. This study suggests that combining ATRA with a hydrogel to target Pin1 expression may be a promising strategy for treating glial scar formation following SCI.

中文翻译：

---

载有全反式视黄酸的温度敏感型 β-甘油磷酸钠/壳聚糖水凝胶调节 Pin1 以抑制脊髓损伤诱导的大鼠神经胶质瘢痕的形成


神经胶质瘢痕形成是脊髓损伤 （SCI） 后神经再生的主要障碍。Pin1 和 PI3K/AKT/CDK2 信号通路在神经元调节中起着至关重要的作用，但关于它们参与神经胶质瘢痕形成的研究仍然有限。在这项研究中，我们首次观察到 Pin1 、 PI3K 、 AKT 和 CDK2 在 SCI 后上调并相互相互作用。进一步的实验表明，Pin1 通过促进星形胶质细胞增殖、抑制细胞凋亡和激活 PI3K/AKT/CDK2 通路促进胶质瘢痕的发展。此外，全反式维甲酸 （ATRA） 是 Pin1 的特异性化学抑制剂，可有效抑制 Pin1 表达。然而，由于其半衰期短和易失活，其临床应用受到限制。为了解决这些问题，我们开发了一种负载有 ATRA （β-GP/CS@ATRA） 的热敏性 β-甘油磷酸钠 （β-GP）/壳聚糖 （CS） 水凝胶。这种水凝胶表现出良好的形态和生物相容性。与游离 ATRA 相比，β-GP/CS@ATRA 水凝胶可显着增强 SCI 后的功能运动恢复并保护脊髓组织，从而抑制神经胶质瘢痕形成。从机制上讲，ATRA 给药通过抑制 Pin1 表达来阻断神经胶质瘢痕的发展和 PI3K/AKT/CDK2 通路的激活。这项研究表明，将 ATRA 与水凝胶结合以靶向 Pin1 表达可能是治疗 SCI 后神经胶质瘢痕形成的一种有前途的策略。