Nilsson Gisela, Mottahedin Amin, Zelco Aura, Lauschke Volker M, Ek C Joakim, Song Juan, Ardalan Maryam, Hua Sha, Zhang Xiaoli, Mallard Carina, Hagberg Henrik, Leavenworth Jianmei W, Wang Xiaoyang
Centre of Perinatal Medicine & Health, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy University of Gothenburg Gothenburg Sweden.
Department of Physiology and Pharmacology Karolinska Institute Stockholm Sweden.
FASEB Bioadv. 2023 Jun 17;5(8):336-353. doi: 10.1096/fba.2023-00030. eCollection 2023 Aug.
Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform-specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN-KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs-iOPN-KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN-KO mice compared to control mice. Accordingly, adult OPN-KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin-related proteins. In contrast, neonatal oligodendrocytes from OLs-iOPN-KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs-iOPN-KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform-specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
异常髓鞘形成是早产脑白质损伤和多发性硬化等白质疾病病理机制的基础。骨桥蛋白（OPN）被认为在髓鞘形成中发挥作用。小鼠OPN mRNA可翻译为分泌型异构体（sOPN）或细胞内异构体（iOPN）。OPN是否以异构体特异性方式参与髓鞘形成尚不清楚。在此，我们构建了在所有细胞中均缺乏两种OPN异构体的小鼠模型（OPN-KO），以及全身缺乏sOPN但在少突胶质细胞中特异性表达iOPN的小鼠模型（OLs-iOPN-KI）。对新生小鼠脑部分离出的少突胶质细胞进行转录组分析表明，与对照组小鼠相比，OPN-KO小鼠在缺乏两种OPN异构体的情况下，与髓鞘形成增加和细胞周期调控改变相关的基因及信号通路显著富集。相应地，透射电子显微镜成像显示，成年OPN-KO小鼠轴突髓鞘形成增加，髓鞘相关蛋白表达上调。相比之下，与对照组小鼠相比，OLs-iOPN-KI小鼠新生少突胶质细胞中与细胞黏附、运动和血管发育增加以及轴突/神经元发育减少相关的基因及信号通路存在差异调节。OLs-iOPN-KI小鼠在幼年小鼠髓鞘形成早期出现髓鞘形成异常，成年后出现轴突变性迹象。这些结果表明，OPN以异构体特异性方式参与髓鞘形成，并可能在异构体之间存在相互作用，影响轴突完整性。因此，在针对白质损伤和疾病中OPN的治疗策略中，需要分别考虑OPN的两种异构体。
