Designing cancer-inspired scaffolds for neural repair

创伤性神经损伤导致衰弱和永久性瘫痪，部分原因是慢性炎症 会阻碍伤口愈合我们的首要目标是设计神经修复的生物材料策略 神经胶质细胞是重要的神经细胞，能够调节炎症和组织， 再生神经胶质细胞在损伤后变得反应性，增殖并维持促炎性细胞因子。 环境导致慢性炎症。最近的研究表明，这些神经胶质细胞，即 星形胶质细胞和小胶质细胞，可以适应表型神经保护和修复给予正确的刺激。在我们 在自己的工作中，使用患者设计的脑癌模型，我们发现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蛋白。 聚糖，训练局部细胞，包括神经胶质细胞，采用抗炎表型。我们假设 癌细胞产生的因子可能会影响新材料的设计，以重新训练反应性胶质细胞， 炎症和促进损伤后修复。为了解决这些假设，我们将在本提案中提出1） 表征几种患者来源的细胞外基质蛋白和细胞表面聚糖的表达 脑癌细胞，2）从该表征中鉴定出调节神经胶质细胞的潜在候选分子 表型，和3）筛选在正常条件下诱导抗炎神经胶质表型的配体组合 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， 通量生物材料平台，以及用于“点击”化学的可编程配体， 利用癌症为组织再生提供信息的潜力。最终，了解大脑 癌症决定了神经细胞的行为，使它们偏向抗炎表型， 开发材料来指导损伤环境的重塑并促进修复， 广泛应用于多种组织和病理学。

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.