Programmable Hydrogels for Optimized Human Oligodendrocyte Transplantation in Demyelinating Disease

摘要 一些最具破坏性的神经退行性疾病，如多发性硬化症，其特征在于： 慢性脱髓鞘和阻止有效髓鞘修复和髓鞘再生的组织环境。而 细胞疗法有可能促进髓鞘再生和恢复失去的神经功能， 这阻碍了它们成功地转化为临床治疗。其中，供体存活率 少突胶质细胞（OPC）的制备和OPC命运的维持是关键障碍。值得注意的是， 移植到脊髓损伤模型中的95%的神经祖细胞（NPC）在注射后死亡1，2， 而当移植到缺血组织中时，只有1-3%的NPC存活3，4。这种过度细胞的结果 死亡是细胞内同种异体抗原的释放，这可能会加剧局部炎症， 移植物的最终排斥反应事实上，在人类先天性神经胶质细胞替代疗法的初步试验后， 在髓鞘形成不足的情况下，即使在长期的情况下， 免疫抑制5.在本提案中，我们力求应对这些重大挑战。在目标1中，我们将设计， 合成和表征一系列新型剪切稀化和生物活性水凝胶以促进存活， 当人（h）OPC在注射期间经受剪切应力时，使细胞死亡最小化。在aim 2中，我们将使用 最佳的剪切稀化水凝胶（STH）配方将细胞输送到Shiverer/Rag 2胼胝体中， /-小鼠，一种先天性髓鞘生成不足疾病的模型，已被广泛接受为研究的金标准。 髓鞘形成细胞制剂的评估。在目标3中，我们将采用一个大型动物模型（兔）， 我们最近在实验室开发的脱髓鞘， 比如多发性硬化症我们还将设计可编程（p）STH，以将hOPC保留在损伤部位， 控制细胞命运以最大化移植细胞到损伤的兔脑中的骨髓生成潜力。总的来说， 这是一个非常创新的MPI建议，结合了最先进的生物材料，神经科学和独特的 动物模型由两名PI（生物工程师和神经科学家）的互补专业知识驱动。成功 我们的目标的实现将可能导致新的水凝胶的设计和动物模型的发展， 提高细胞疗法治疗破坏性脊髓病的潜力。

ABSTRACT Some of the most devastating neurodegenerative diseases such as multiple sclerosis, are characterized by chronic demyelination and a tissue environment that prevents efficient myelin repair and remyelination. While cell therapies have the potential to promote remyelination and restore lost neurological function, major barriers remain that hamper their successful translation to clinical treatment. Among these, survival of donor oligodendrocytes cell (OPC) preparations and maintenance of OPC fate are key obstacles. Notably, more than 95% of neural progenitor cells (NPCs) transplanted into models of spinal cord injury die following injection 1,2, while only 1-3% of NPCs survive when transplanted into ischemic tissue 3,4. The result of such excessive cell death is the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft for eventual rejection. Indeed, following initial trials of glial cell replacement therapy in human congenital hypomyelination, half of the subjects developed alloantibodies even in the context of prolonged immunosuppression 5. In this proposal, we seek to address these major challenges. In aim 1, we will design, synthesize and characterize a series of novel shear-thinning and bioactive hydrogels to promote survival and minimize cell death when human (h)OPCs are subjected to shear stress during injection. In aim 2 we will use the optimal shear-thinning hydrogel (STH) formulation to deliver cells into the corpus callosum of Shiverer/Rag2- /- mice, a model of congenital hypomyelinating disease that has been widely accepted as the gold standard for the assessment of myelinating cell preparations. In aim 3, we will employ a large animal model (rabbit) of demyelination that we recently developed in our laboratories and better mimics the state of demyelinating disease like multiple sclerosis. We will also design programmable (p)STH to retain hOPC at the site of injury and control cell fate to maximize the myelogenic potential of transplanted cells into the injured rabbit brain. Overall, this is a very innovative MPI proposal that combines state-of-the-art biomaterials, neuroscience and unique animal models driven by the complementary expertise of two PIs, a bioengineer and a neuroscientist. Successful attainment of our goals will likely lead to design of novel hydrogels and development of animal models that may improve the potential of cell therapies for the treatment of devastating myelopathies.