Immunomodulatory Hydrogels for Stem Cell Therapy after TBI

描述(申请人提供)：疾病控制中心报告称，有170万美国人遭受创伤性脑损伤，其中50万是儿童。由于创伤性脑损伤(TBI)的复杂性以及缺乏有效的治疗选择，临床治疗具有挑战性。由于损伤的复杂性，包括炎症、细胞丢失和水肿，小分子抗炎或神经保护策略不太成功，可能需要细胞治疗。具体地说，干细胞治疗有可能显着改善创伤性脑损伤后的预后。然而，神经干细胞(NSC)治疗成功的一个主要障碍是由于宿主T细胞和自然杀伤细胞(NK细胞)介导的移植NSC的凋亡，导致移植后NSC存活率较低。在这里，我们建议设计和设计用于神经干细胞的原位凝胶水凝胶载体，使其在体内具有几天到几周的免疫豁免期。我们建议利用Fas配体介导的T细胞和NK细胞的细胞死亡来为NSCs产生免疫豁免区。我们认为，提高NSC的存活率是评估NSC疗法治疗脑外伤潜力的关键和必要条件。我们的目标是为神经干细胞设计合适的水凝胶载体，在脑外伤的实验模型中测试它们在体内促进神经干细胞存活的能力，并最终调查相对于未治疗的队列，神经干细胞存活增强是否确实能改善脑外伤啮齿动物模型的运动和认知能力。成功完成拟议的研究将对改善脑外伤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.