Traumatic spinal cord injury (SCI) elicits a cascade of secondary injury mechanisms that induce profound changes in glia and neurons resulting in their activation, injury or cell death. The resultant imbalanced microenvironment of acute SCI also negatively impacts regenerative processes in the injured spinal cord. Thus, it is imperative to uncover endogenous mechanisms that drive these acute injury events. Here, we demonstrate that the active form of bone morphogenetic protein-4 (BMP4) is robustly and transiently upregulated in acute SCI in rats. BMP4 is a key morphogen in neurodevelopment; however, its role in SCI is not fully defined. Thus, we elucidated the ramification of BMP4 upregulation in a preclinical model of compressive/contusive SCI in the rat by employing noggin, an endogenous antagonist of BMP ligands, and LDN193189, an intracellular inhibitor of BMP signaling. In parallel, we studied cell-specific effects of BMP4 on neural precursor cells (NPCs), oligodendrocyte precursor cells (OPCs), neurons and astrocytes in vitro. We demonstrate that activation of BMP4 inhibits differentiation of spinal cord NPCs and OPCs into mature myelin-expressing oligodendrocytes, and acute blockade of BMPs promotes oligodendrogenesis, oligodendrocyte preservation and remyelination after SCI. Importantly, we report for the first time that BMP4 directly induces caspase-3 mediated apoptosis in neurons and oligodendrocytes in vitro, and noggin and LDN193189 remarkably attenuate caspase-3 activation and lipid peroxidation in acute SCI. BMP4 also enhances the production of inhibitory chondroitin sulfate proteoglycans (CSPGs) in activated astrocytes in vitro and after SCI. Interestingly, our work reveals that despite the beneficial effects of BMP inhibition in acute SCI, neither noggin nor LDN193189 treatment resulted in long-term functional recovery. Collectively, our findings suggest a role for BMP4 in regulating acute secondary injury mechanisms following SCI, and a potential target for combinatorial approaches to improve endogenous cell response and remyelination.

中文翻译：

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骨形态发生蛋白4的急性上调调节内源性细胞反应并促进脊髓损伤中的细胞死亡。

创伤性脊髓损伤（SCI）引发了一系列继发性损伤机制，这些机制可诱导神经胶质和神经元发生深刻变化，从而导致其激活，损伤或细胞死亡。急性SCI导致的微环境失衡也对受伤脊髓的再生过程产生负面影响。因此，必须找到驱动这些急性损伤事件的内源性机制。在这里，我们证明了骨形态发生蛋白4（BMP4）的活性形式在大鼠急性SCI中被强烈和短暂地上调。BMP4是神经发育中的关键形态发生素。但是，它在SCI中的作用尚未完全定义。因此，我们通过使用头蛋白（BMP配体的内源性拮抗剂）和LDN193189，阐明了在大鼠压缩/挫伤性SCI的临床前模型中BMP4上调的后果。BMP信号的细胞内抑制剂。同时，我们研究了BMP4对神经前体细胞（NPC），少突胶质细胞前体细胞（OPC），神经元和星形胶质细胞的细胞特异性作用。我们证明激活BMP4抑制脊髓NPC和OPC分化成成熟的表达髓鞘的少突胶质细胞，而对BMP的急性阻滞促进SCI后少突胶质生成，少突胶质细胞保存和髓鞘再生。重要的是，我们首次报道BMP4在体外直接诱导神经元和少突胶质细胞中caspase-3介导的凋亡，并且头蛋白和LDN193189显着减弱急性SCI中caspase-3的激活和脂质过氧化作用。在体外和脊髓损伤后，BMP4还可增强星形胶质细胞中抑制性硫酸软骨素蛋白聚糖（CSPG）的产生。有趣的是，我们的工作表明，尽管BMP抑制在急性SCI中具有有益作用，但noggin或LDN193189治疗均未导致长期功能恢复。总的来说，我们的发现表明BMP4在调节SCI后的急性继发性损伤机制中具有作用，并且是改善内源性细胞反应和髓鞘再生的组合方法的潜在靶标。