Morita Yoshinori, Shiraki Yukihiro, Kato Akira, Nagatani Yasuhiro, Ando Ryota, Nakashima Hiroaki, Imagama Shiro, Enomoto Atsushi
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nagoya J Med Sci. 2025 May;87(2):305-319. doi: 10.18999/nagjms.87.2.305.
Scar formation after spinal cord injury (SCI) hampers axonal regeneration and functional recovery. Previous studies have shown that scar formation is attributable to both gliosis and fibrosis, the latter requiring fibroblast proliferation and extracellular matrix deposition. In this setting, there are essentially two cell types generating new fibroblasts: pericytes and tissue-resident fibroblasts. Here, we showed that Meflin, a glycosylphosphatidylinositol-anchored protein (a specific marker of fibroblasts across multiple organs) is expressed by fibroblasts in the normal mouse spinal cord. An in situ hybridization analysis showed that Meflin cells arose from the meninges and perivascular region of the spinal parenchyma after spinal cord compression injury. That finding was corroborated by single-cell transcriptomic data from normal and injured mouse spinal cords. Interestingly, Meflin cells are positive for the fibroblast markers collagen type I and platelet-derived growth factor receptor (PDGFR) α but not for pericyte markers such as PDGFRβ and chondroitin sulfate proteoglycan 4 in the normal spinal cord. Those findings are consistent with the recent view that tissue-resident fibroblasts play a central role in many other types of fibrotic disease. A lineage-tracing experiment using a knock-in mouse line that expressed inducible Cre recombinase under the control of the Meflin promoter showed that Meflin cells yield PDGFRβ myofibroblasts but not glial cells positive for glial fibrillary acidic protein. These findings suggest that the Meflin population contains the cells of origin of myofibroblasts that are involved in scar formation after SCI.
脊髓损伤（SCI）后的瘢痕形成会阻碍轴突再生和功能恢复。先前的研究表明，瘢痕形成归因于胶质化和纤维化，后者需要成纤维细胞增殖和细胞外基质沉积。在这种情况下，基本上有两种细胞类型可产生新的成纤维细胞：周细胞和组织驻留成纤维细胞。在此，我们表明，Meflin是一种糖基磷脂酰肌醇锚定蛋白（多个器官中成纤维细胞的特异性标志物），在正常小鼠脊髓中由成纤维细胞表达。原位杂交分析表明，脊髓压迫损伤后，Meflin细胞起源于脊髓实质的脑膜和血管周围区域。来自正常和受伤小鼠脊髓的单细胞转录组数据证实了这一发现。有趣的是，在正常脊髓中，Meflin细胞对成纤维细胞标志物I型胶原蛋白和血小板衍生生长因子受体（PDGFR）α呈阳性，但对周细胞标志物如PDGFRβ和硫酸软骨素蛋白聚糖4呈阴性。这些发现与最近的观点一致，即组织驻留成纤维细胞在许多其他类型的纤维化疾病中起核心作用。使用在Meflin启动子控制下表达诱导型Cre重组酶的敲入小鼠品系进行的谱系追踪实验表明，Meflin细胞产生PDGFRβ肌成纤维细胞，但不产生对胶质纤维酸性蛋白呈阳性的神经胶质细胞。这些发现表明，Meflin群体包含参与SCI后瘢痕形成的肌成纤维细胞的起源细胞。
