Immunomodulatory Hydrogels for Stem Cell Therapy after TBI

描述（由申请人提供）：疾病控制中心报告说，170万美国人遭受创伤性脑损伤，其中50万是儿童。创伤性脑损伤（TBI）的临床管理是具有挑战性的，由于损伤的复杂性以及由于缺乏有效的治疗方案。由于涉及炎症、细胞损失和水肿的损伤的复杂性质，细胞疗法可能是必要的，因为小分子抗炎或神经保护策略还不是很成功。特别是干细胞治疗有可能显着改善TBI后的结果。然而，成功的神经干细胞（NSC）治疗的一个主要障碍是移植后由于宿主T细胞和自然杀伤（NK）细胞介导的移植的NSC的凋亡，它们的存活率差。在这里，我们建议设计和工程师在原位凝胶化水凝胶载体的神经干细胞，使他们赋予免疫豁免的一段时间内几天到几个星期在体内。我们建议利用Fas配体介导的T细胞和NK细胞的细胞死亡来产生神经干细胞的免疫豁免区。我们认为，提高NSC存活率是评估NSC治疗TBI潜力的关键和必要条件。我们的目的是设计合适的水凝胶载体NSC，测试他们的能力，以促进NSC在TBI的实验模型在体内的生存，并最终调查是否确实增强NSC的生存结果在运动和认知改善的啮齿动物模型TBI相对于未经处理的队列。成功完成拟议的研究将对改善TBI患者的生活质量产生重大影响，并对其他器官系统的干细胞治疗产生影响。

DESCRIPTION (provided by applicant): The center for disease control reports that 1.7 million Americans suffer traumatic brain injuries, half a million of whom are children. Clinical management of traumatic brain injury (TBI) is challenging due to the complexity of the injury as well as due to the paucity of effective treatment options. Due to the complex nature of the injury involving inflammation, cell loss and edema, cell therapies may be necessary as small molecular anti-inflammatory or neuroprotective strategies have not been very successful. Specifically stem cell therapy has the potential to significantly improve outcomes after TBI. However, one major impediment to successful neural stem cell (NSC) therapy is their poor survival after transplantation due to host T cells and Natural Killer (NK) cell mediated apoptosis of transplanted NSCs. Here, we propose to design and engineer in situ gelling hydrogel carriers for NSCs such that they confer immune-privilege for a period of days to weeks in vivo. We propose to exploit the Fas-ligand mediated cell death of T cells and NK cells to generate an immune privilege zone for NSCs. We posit that enhancing NSC survival is a critical and necessary condition to evaluating NSC therapy's potential for treating TBI. Our aims are designed to design the appropriate hydrogel carriers for NSC, test their ability to promote NSC survival in vivo in an experimental model of TBI, and finally investigate whether indeed enhanced NSC survival results in motor and cognitive improvement in a rodent model of TBI relative to untreated cohorts. Successful completion of the proposed studies would have significant impact on improvement of the quality of life of individuals with TBI, and have implications for stem cell therapies in other organ systems.