Paris-Saclay University, CNRS, Neuroscience Paris-Saclay Institute, 91400 Saclay, France.
Paris-Saclay University, INSERM, Diseases and Hormones of the Nervous System-U1195, 94276 Le Kremlin-Bicêtre, France.
Cells. 2024 Nov 1;13(21):1808. doi: 10.3390/cells13211808.
Failure of myelin regeneration by oligodendrocytes contributes to progressive decline in many neurological diseases. Here, using in vitro and in vivo rodent models, functional blockade, and mouse brain demyelination, we demonstrate that Sonic hedgehog (Shh) expression in a subset of oligodendrocyte progenitor cells precedes the expression of myelin basic protein (MBP), a major myelin sheath protein. Primary cultures of rodent cortical oligodendrocytes show that Shh mRNA and protein are upregulated during oligodendrocyte maturation before the upregulation of MBP expression. Importantly, almost all MBP-positive cells are Shh positive during differentiation. During remyelination, we identify a rapid induction of Shh mRNA and peptide in oligodendroglial cells present in the demyelinated corpus callosum of mice, including a population of PDGFRα-expressing cells. Shh invalidation by an adeno-associated virus strategy demonstrates that the downregulation of Shh impairs the differentiation of oligodendrocytes in vitro and decreases MBP and myelin proteolipid protein expression in the demyelinated mouse brain at late stages of remyelination. We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies.
少突胶质细胞髓鞘再生的失败导致许多神经退行性疾病的进行性衰退。在这里，我们使用体外和体内啮齿动物模型、功能阻断和小鼠大脑脱髓鞘，证明了 Sonic hedgehog（Shh）在少突胶质细胞前体细胞中的表达先于髓鞘碱性蛋白（MBP）的表达，MBP 是主要的髓鞘蛋白。啮齿动物皮质少突胶质细胞的原代培养表明，Shh mRNA 和蛋白在髓鞘碱性蛋白表达上调之前在少突胶质细胞成熟过程中上调。重要的是，在分化过程中，几乎所有 MBP 阳性细胞都是 Shh 阳性的。在再髓鞘化过程中，我们在脱髓鞘的小鼠胼胝体中发现了少突胶质细胞中 Shh mRNA 和肽的快速诱导，包括一群表达 PDGFRα 的细胞。腺相关病毒策略的 Shh 无效性证明，Shh 的下调会损害体外少突胶质细胞的分化，并在再髓鞘化的晚期减少脱髓鞘小鼠大脑中的 MBP 和髓鞘蛋白脂蛋白表达。我们还报告了在小鼠大脑早期出生后髓鞘形成过程中 Shh 和 MBP 在少突胶质细胞中的平行表达。因此，我们确定了一种在少突胶质细胞分化和再髓鞘化中起关键作用的 Shh 信号，这对于设计更好靶向的再髓鞘化治疗策略具有潜在意义。
