Creating endogenous Stem Cell Niches to Promote Functional Brain Repair Post-TBI

项目摘要 创伤性脑损伤（TBI）导致一系列复杂的神经生理和功能缺陷，严重的长期 残疾和受影响个体的预后不良。TBI后出现的显著脑组织损失是一个主要的 造成这些不良后果的原因。目前针对TBI相关创伤的单一成分的干预措施在很大程度上 未能防止广泛的脑组织损失并促进修复和功能恢复。移植和宿主神经 干细胞（NSC）具有多方面的治疗潜力，因为它们能够产生有效量的 神经保护因子，除了促进复杂的大规模修复和重建受损的脑组织。 然而，目前的策略未能增加内源性NSC和营养因子的活性，以促进持久的 在中度至重度TBI后的修复和恢复。我们假设同种异体外源性神经干细胞移植 在能够吸引和保留内源性NSC和保护因子的选择性工程化糖质基质中， 会促进脑外伤后脑组织的功能修复这里提出的异位NSC生态位的创建可以维持 神经干细胞在其未分化状态，并有助于赋予神经保护和功能的保存慢性TBI后。 为了实现这一目标，我们将利用硫酸软骨素糖胺聚糖独特的结构和功能属性 （CS-GAG）硫酸化以设计能够富集营养因子的新型工程化CS-GAG（eCS-GAG）基质， 以及维持移植的和宿主NSC处于其未分化状态。我们将单独植入eCS-GAG基质， 或与NSC组合用于中度至重度TBI的啮齿动物模型。我们将评估增强的潜力， 营养因子富集eCS-GAG基质，以促进NSC自我更新并促进神经保护和功能 与其他硫酸化和未硫酸化GAG基质对照相比，TBI后长期恢复。我们的方法很新颖 因为它利用了CS-GAG硫酸化的组成和功能多样性，以促进内源性 神经干细胞，并提出内源性保护因子内的工程化学基质，以显着 改善中重度TBI后NSC功效。

PROJECT SUMMARY Traumatic Brain Injuries (TBIs) result in a range of complex neurophysiological and functional deficits, severe long-term disability, and poor prognosis for the affected individuals. The significant brain tissue loss encountered post-TBI is a major contributor to these poor outcomes. Current interventions that target single components of TBI related trauma have largely failed to prevent widespread brain tissue loss and promote repair and functional recovery. Transplanted and host Neural Stem Cells (NSCs) possess multifaceted therapeutic potential, owing to their ability to produce efficacious amounts of neuroprotective factors in addition to facilitating complex large-scale repair and reconstruction of damaged brain tissue. However, current strategies fail to augment endogenous NSC and trophic factor activity necessary to promote long-lasting repair and recovery after a moderate-to-severe TBI. We hypothesize that the transplantation of allogeneic exogenous NSCs in a selectively engineered glycomaterial matrix capable of attracting and retaining endogenous NSCs and protective factors will facilitate functional repair of brain tissue post TBI. The creation of an ectopic NSC niche as proposed here can maintain NSCs in their undifferentiated state, and help confer neuroprotection and preservation of function chronically post-TBI. Toward this goal, we will exploit the unique structural and functional attributes of Chondroitin Sulfate Glycosaminoglycan (CS-GAG) sulfation to design novel engineered CS-GAG (eCS-GAG) matrices that are capable of enriching trophic factors, and maintaining transplanted and host NSCs in their undifferentiated state. We will implant eCS-GAG matrices either alone or in combination with NSCs in a rodent model of moderate-to-severe TBI. We will evaluate the enhanced potential of trophic factor enriching eCS-GAG matrices to promote NSC self-renewal and facilitate neuroprotection and functional recovery chronically post-TBI when compared to other sulfated and unsulfated GAG matrix controls. Our approach is novel in that it exploits the compositional and functional diversity of CS-GAG sulfation to facilitate the haptotaxis of endogenous NSCs, and presentation of endogenous protective factors within the engineered chemistry of the matrix to significantly improve NSC efficacy after moderate-to-severe TBI.