Peripheral Nerve Surgery Unit, Department of Neurosurgery, Ulm University, District Hospital, 89312 Günzburg, Germany.
Institute of Neurobiochemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Exp Neurol. 2024 Dec;382:114981. doi: 10.1016/j.expneurol.2024.114981. Epub 2024 Oct 1.
Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1-13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes. In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages.
周围神经损伤（PNI）会在切断的神经残端处诱导神经瘤形成，导致患者的神经再生和功能恢复受损。到目前为止，对阻碍再生的神经瘤中的分子机制和细胞类型的研究还很少。在此，我们将切除的人类神经瘤组织与同一患者的完整供体神经进行比较。纳入了几个损伤后时间点（1-13 个月）的神经瘤，以便与分子和细胞过程进行时间相关性分析。我们观察到与完整神经相比，神经瘤中的轴突面积和产生髓磷脂的施万细胞（SCs）的比例减少。然而，SCs 的总 SOX10 阳性细胞数量相当。值得注意的是，包括 c-JUN、低亲和力神经营养因子受体（NTR）p75、SHH（sonic hedgehog）和 SC 增殖（磷酸化组蛋白 H3）在内的处于修复模式的 SC 标志物在神经瘤中上调，表明存在处于修复状态的 SC。一致地，在神经瘤中，促再生标志物如磷酸化即激活的 CREB（pCREB）、ATF3、GAP43 和 SCG10 上调。此外，神经瘤组织被多种类型的巨噬细胞浸润。最后，当在培养中取出时，神经瘤 SC 与对照 SC 相比，在增殖和形态方面没有区别。然而，培养的神经瘤 SC 保留了与对照 SC 不同的分子特征，包括炎症增加和髓鞘基因等分化标志物的基因表达减少。总之，人类神经瘤组织由具有修复状态的 SC 组成，并被多种类型的巨噬细胞强烈浸润。
