Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nat Med. 2017 Jul;23(7):818-828. doi: 10.1038/nm.4354. Epub 2017 Jun 19.
Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis. We also found that type I collagen was highly expressed in the spinal cord during the scar-forming phase and induced astrocytic scar formation via the integrin-N-cadherin pathway. In a mouse model of spinal cord injury, pharmacological blockade of reactive astrocyte-type I collagen interaction prevented astrocytic scar formation, thereby leading to improved axonal regrowth and better functional outcomes. Our findings reveal environmental cues regulating astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury.
中枢神经系统（CNS）损伤将幼稚星形胶质细胞转化为反应性星形胶质细胞，这些反应性星形胶质细胞最终成为形成瘢痕的星形胶质细胞，可损害轴突再生和功能恢复。这种连续的表型变化，称为反应性星形胶质细胞增生，长期以来被认为是单向和不可逆的。然而，我们在这里报告，从损伤脊髓分离的反应性星形胶质细胞在逆行移植到幼稚脊髓时会恢复为幼稚星形胶质细胞，而在移植到损伤脊髓时会形成星形胶质瘢痕，表明反应性星形胶质细胞增生具有环境依赖性的可塑性。我们还发现，在形成瘢痕阶段，Ⅰ型胶原在脊髓中高度表达，并通过整合素-N-钙黏蛋白途径诱导星形胶质瘢痕形成。在脊髓损伤的小鼠模型中，通过药理学阻断反应性星形胶质细胞-Ⅰ型胶原相互作用，可防止星形胶质瘢痕形成，从而促进轴突再生和更好的功能恢复。我们的研究结果揭示了调节星形胶质细胞命运决定的环境线索，从而为 CNS 损伤提供了一个潜在的治疗靶点。
