Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn^−/− mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI.

创伤性脑损伤 （TBI） 是全球因受伤而导致死亡和残疾的主要原因。已知细胞外基质 （ECM） 重塑对 TBI 病理生理学有显着贡献。糖胺聚糖是 ECM 中丰富的长链、可变硫酸化多糖，以前已被证明在 TBI 后发生了重大变化。在这项研究中，我们试图描述 TBI 后糖胺聚糖改变的动力学，并发现负责损伤后观察到的糖胺聚糖变化的精确生物学过程。我们对 TBI 或单独开颅手术后从小鼠中分离的脑组织进行了最先进的质谱分析。我们在 TBI 后第 1 天和第 7 天观察到糖胺聚糖的动态变化，与单独的开颅手术组织相比，硫酸乙酰肝素、硫酸软骨素和透明质酸在一周后仍显着增加。与单独开颅手术相比，我们没有观察到实验性 TBI 后小鼠循环糖胺聚糖的明显变化，也没有观察到 TBI 和严重多发性创伤患者与轻度损伤对照患者相比的明显变化，这表明损伤部位糖胺聚糖的增加是由局部合成驱动的。随后，我们在 TBI 后 7 天对小鼠脑组织进行了无偏倚的全基因组转录组学分析，发现透明质酸合酶 2 、 glypican-3 和核心蛋白聚糖的显着诱导。通过比较野生型和 Dcn^-/-小鼠的多模式行为测试，进一步检查了损伤后核心蛋白聚糖的功能作用。我们发现 Dcn 的遗传消融导致 TBI 对功能的整体负面影响，加剧 TBI 后的运动障碍。 总的来说，我们的结果提供了 TBI 后大脑 ECM 中糖胺聚糖改变的时空特征，并支持 TBI 后核心蛋白聚糖上调的重要适应性作用。