Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
Commun Biol. 2024 Jul 4;7(1):813. doi: 10.1038/s42003-024-06513-x.
Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.
治疗进展性多发性硬化症 (MS) 的策略仍然有限。在这里，我们发现 miR-145-5p 在继发进展性 MS 患者的慢性病变组织中独特地过度表达。我们在 miR-145 敲除小鼠中诱导急性和慢性脱髓鞘，以确定其对髓鞘修复失败的贡献。在急性脱髓鞘后，无法检测到 miR-145 缺失的优势。然而，在慢性脱髓鞘后，miR-145 缺失的动物表现出增强的髓鞘修复和功能恢复，与野生型动物相比，胼胝体中的星形胶质细胞和小胶质细胞的存在发生改变。miR-145 敲除动物的这种改善反应与慢性杯状藻暴露后野生型动物中 miR-145-5p 的病理性上调相吻合，与人类慢性病变相平行。此外，miR-145 在少突胶质细胞（OLs）中的特异性过表达严重阻碍了分化，并对存活产生负面影响。RNAseq 分析显示这些细胞中的转录组发生改变，涉及髓鞘形成的主要途径下调。我们的数据表明，miR-145-5p 的病理性积累是慢性脱髓鞘的一个独特特征，并强烈暗示髓鞘修复失败，可能是由于 OL 分化的抑制以及其他神经胶质细胞的改变。这在慢性 MS 病变中得到了反映，因此 miR-145-5p 可作为进展性 MS 中一种潜在的相关治疗靶点。
