Chen J Q Alida, McNamara Niamh B, Engelenburg Hendrik J, Jongejan Aldo, Wever Dennis D, Hopman Kaya, van Rixel Esmée, Nijhuis Paul J H, de Winter Fred, Moerland Perry D, Smolders Joost, Verhaagen Joost, Hamann Jörg, Huitinga Inge
Neuroimmunology Research Group, Netherlands Institute for Neuroscience, 1105BA, Amsterdam, The Netherlands.
Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam University Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Brain. 2024 Dec 24. doi: 10.1093/brain/awae414.
Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n=239) based on proportions of remyelinated lesions (RLs) into efficiently remyelinating donors (ERDs; n=21) and poorly remyelinating donors (PRDs; n=19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy), and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of epithelial-mesenchymal transition pathway, while in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signaling, TNF signaling and oxidative phosphorylation) were upregulated compared to ALs foamy of ERDs, suggesting that these latter pathways may counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG, and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF, and IGF1 were determined as key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We further identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10, and INHBB. Our study identified both known and novel genes associated with efficient remyelination that may facilitate the development of therapeutic strategies to promote tissue repair and clinical recovery in MS.
多发性硬化症（MS）是一种高度异质性疾病，个体之间以及病灶之间的髓鞘再生潜力各不相同。然而，髓鞘再生潜力背后的分子机制仍知之甚少。在本研究中，我们旨在利用MS供体和病灶之间髓鞘再生能力的内在异质性，来发现用于MS治疗的已知和新型促髓鞘再生分子。为了阐明髓鞘再生潜力背后不同的分子特征，我们根据荷兰脑库队列（n = 239）中髓鞘再生病灶（RLs）的比例，将MS供体分为高效髓鞘再生供体（ERDs；n = 21）和低效髓鞘再生供体（PRDs；n = 19）。我们对ERDs和PRDs的RLs、具有分支状和阿米巴样小胶质细胞/巨噬细胞形态的活跃病灶（非泡沫状活跃病灶，ALs non-foamy）、具有泡沫状小胶质细胞/巨噬细胞形态的活跃病灶（泡沫状活跃病灶，ALs foamy）以及外观正常的白质（NAWM）进行了批量RNA测序。我们发现非泡沫状活跃病灶与髓鞘再生呈正相关，而泡沫状活跃病灶则不然，这表明小胶质细胞/巨噬细胞状态在影响髓鞘再生潜力方面发挥作用。进行了生物信息学分析，以确定与髓鞘再生过程相关的关键途径和分子。我们发现在可比的MS病灶类型中，具有不同髓鞘再生潜力的供体之间存在明显差异。与PRDs相比，ERDs的RLs和非泡沫状活跃病灶显示上皮-间质转化途径上调，而在PRDs的泡沫状活跃病灶中，与炎症和损伤相关的途径（即MTORC1信号传导、TNF信号传导和氧化磷酸化）与ERDs的泡沫状活跃病灶相比上调，这表明后一种途径可能会阻碍髓鞘再生。我们发现一些基因在ERDs的RLs和/或非泡沫状活跃病灶中显著上调，这些基因先前已与髓鞘再生相关，包括CXCL12、EGF、HGF、IGF2、IL10、PDGFB、PPARG和TREM2，这说明了我们的供体和病灶分层的优势。TGFB1、TGFB2、EGF和IGF1被确定为在ERDs的RLs和非泡沫状活跃病灶中上调基因的关键上游调节因子。我们进一步鉴定了潜在的新型促髓鞘再生分子，如BTC、GDF10、GDF15、CCN1、CCN4、FGF5、FGF10和INHBB。我们的研究确定了与高效髓鞘再生相关的已知和新型基因，这可能有助于制定促进MS组织修复和临床恢复的治疗策略发展。
