移植 A2 型星形胶质细胞可促进脊髓损伤后的神经修复和髓鞘再生。

Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury.

机构信息

Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.

Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.

出版信息

Cell Commun Signal. 2023 Feb 16;21(1):37. doi: 10.1186/s12964-022-01036-6.

DOI:10.1186/s12964-022-01036-6

PMID:36797790

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9936716/

Abstract

BACKGROUND

Limited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors.

METHODS

We used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery.

RESULTS

Astrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes.

CONCLUSIONS

A2 astrocyte transplantation could be a promising potential therapy for SCI. Video abstract.

摘要

背景

脊髓损伤 (SCI) 的有效治疗方面进展有限，这强调了对新型治疗方法的迫切需求。作为重要的中枢神经系统组成部分，固有星形胶质细胞在调节 SCI 后恢复方面发挥着关键作用。在这项研究中，比较了移植 A1 或 A2 星形胶质细胞后 SCI 的恢复情况。A1 星形胶质细胞是有害的，因为它们上调神经毒性经典补体级联基因。相反，A2 星形胶质细胞的特点是神经保护，因为它们上调许多神经营养因子的产生。

方法

我们使用脂多糖或白细胞介素-4 刺激的小胶质细胞产生的不同上清液来生成 A1 和 A2 星形胶质细胞。我们通过将 A1 和 A2 星形胶质细胞与神经元共培养来检测星形胶质细胞对神经元的影响。我们将星形胶质细胞移植到脊髓损伤部位，并评估损伤进展、神经恢复、胶质形成和运动功能恢复。

结果

星形胶质细胞在脂多糖或白细胞介素-4 刺激的小胶质细胞上清液中培养后分别极化成 A1 和 A2 表型。此外，将 A2 星形胶质细胞与神经元共培养可显著抑制谷氨酸诱导的神经元凋亡，并促进神经元树突分支程度。与移植 A1 星形胶质细胞相比，将这些 A2 星形胶质细胞移植到小鼠脊髓损伤部位可显著改善运动功能恢复，保留未受损的上位通路，减少胶质瘢痕沉积，并增加损伤部位的神经丝形成。此外，在 A2 组中还检测到具有潜在有益 A2 样基因的增强型 A2 星形胶质细胞。此外，卢索快速蓝染色和电子显微镜检查表明，与移植 A1 星形胶质细胞相比，移植 A2 星形胶质细胞后，髓鞘的保存更完整，结构更有序。