The innate immune response influences neural repair after spinal cord injury (SCI). Here, we combined myeloid-specific transcriptomics and single-cell RNA sequencing to uncover not only a common core but also temporally distinct gene programs in injury-activated microglia and macrophages (IAM). Intriguingly, we detected a wide range of microglial cell states even in healthy spinal cord. Upon injury, IAM progressively acquired overall reparative, yet diversified transcriptional profiles, each comprising four transcriptional subtypes with specialized tasks. Notably, IAM have both distinct and common gene signatures as compared to neurodegeneration-associated microglia, both engaging phagocytosis, autophagy, and TyroBP pathways. We also identified an immediate response microglia subtype serving as a source population for microglial transformation and a proliferative subtype controlled by the epigenetic regulator histone deacetylase 3 (HDAC3). Together, our data unveil diversification of myeloid and glial subtypes in SCI and an extensive influence of HDAC3, which may be exploited to enhance functional recovery.

先天免疫反应影响脊髓损伤（SCI）后的神经修复。在这里，我们结合了骨髓特异性转录组学和单细胞 RNA 测序，不仅揭示了损伤激活的小胶质细胞和巨噬细胞 (IAM) 中的共同核心，而且揭示了时间上不同的基因程序。有趣的是，即使在健康的脊髓中，我们也检测到了多种小胶质细胞状态。受伤后，IAM 逐渐获得全面的修复性但多样化的转录谱，每个转录谱包含四种具有专门任务的转录亚型。值得注意的是，与神经退行性变相关的小胶质细胞相比，IAM 具有不同和共同的基因特征，两者都参与吞噬作用、自噬和 TyroBP 途径。我们还鉴定了一种立即反应小胶质细胞亚型，作为小胶质细胞转化的源群体，以及由表观遗传调节剂组蛋白脱乙酰酶 3 (HDAC3) 控制的增殖亚型。总之，我们的数据揭示了 SCI 中骨髓和神经胶质亚型的多样化以及 HDAC3 的广泛影响，这些影响可用于增强功能恢复。