Designing cancer-inspired scaffolds for neural repair

创伤性神经损伤会导致虚弱和永久性瘫痪，部分原因是慢性炎症 防止伤口愈合。我们的总体目标是设计神经修复的生物材料策略。 神经胶质细胞是一种重要的神经细胞，能够调节炎症和组织 再生。神经胶质细胞在损伤后变得活跃，增殖并维持促炎性反应 导致慢性炎症的环境。最近的研究表明，这些胶质细胞，即 星形胶质细胞和小胶质细胞可以在适当的刺激下适应神经保护和修复的表型。在我们的 通过使用病人设计的脑癌模型，我们发现将神经胶质细胞引入癌细胞 显著改变神经胶质细胞的反应性。已知癌细胞表达基质蛋白和细胞表面 培养局部细胞，包括神经胶质细胞，使其具有抗炎表型的多糖。我们假设 癌细胞产生的因子可能会为新材料的设计提供信息，以重新训练反应性胶质细胞以抑制 发炎和促进损伤后的修复。为了解决这些假设，我们将在本提案中1) 几种患者来源的细胞外基质蛋白和细胞表面多糖的表达特征 脑癌细胞，2)从这个特征识别潜在的候选分子调节神经胶质细胞 表型，以及3)正常条件下诱导抗炎神经胶质表型的配体组合的筛选 和发炎的情况。这种方法将利用患者来源的胶质母细胞瘤癌细胞，两个高 吞吐量生物材料平台和可编程配体，用于单击化学以建立治疗性 利用癌症为组织再生策略提供信息的可能性。最终，了解大脑是如何 癌症决定神经细胞的行为，使其偏向抗炎表型，将使 开发材料以指导损伤环境的重塑并促进修复，可能的 在许多组织和病理学中广泛应用。

Traumatic neural injury causes debilitating and permanent paralysis, in part because chronic inflammation prevents the wound from healing. Our over-arching goal is to design biomaterial strategies for neural repair that instruct remodeling of glial cells – important neural cells capable of regulating inflammation and tissue regeneration. Glial cells become reactive after injury, propagating and maintaining the pro-inflammatory environment leading to chronic inflammation. Recent studies have shown that these glial cells, namely astrocytes and microglia, can adapt phenotypes for neuroprotection and repair given the right stimuli. In our own work using a patient-designed model of brain cancer, we found introduction of glial cells to cancer cells significantly alters glial cell reactivity. Cancer cells are known to express matrix proteins and cell-surface glycans that train local cells, including glial cells, to adopt anti-inflammatory phenotypes. We hypothesize that factors produced by cancer cells may inform design of new materials to retrain reactive glial cells to suppress inflammation and promote repair after injury. To addressing these hypotheses, we will in this proposal 1) characterize expression of extracellular matrix proteins and cell-surface glycans from several patient-derived brain cancer cells, 2) from this characterization identify potential candidate molecules regulating glial cell phenotype, and 3) screen for ligand combinations inducing anti-inflammatory glial phenotypes under normal and inflamed conditions. This approach will leverage patient-derived glioblastoma cancer cells, two high throughput biomaterial platforms, and programmable ligands for ‘click’ chemistry to establish the therapeutic potential of using cancer to inform strategies for tissue regeneration. Ultimately, understanding how brain cancer dictates behavior of neural cells, biasing them toward anti-inflammatory phenotypes, will enable development of materials to instruct remodeling of the injury environment and promote repair, with possibly widespread applications in a number of tissues and pathologies.