A Conductive Polymer-Stem Cell System to Augment Endogenous Stroke Repair Mechanisms and Improve Functional Stroke Recovery

摘要 促进中枢神经系统再生的能力仍然难以捉摸。中风是导致中风的主要原因 死亡和残疾，给中风幸存者、他们的照顾者和社会带来了巨大的负担。虽然 在过去的几十年里，急性中风的护理进展很快，只有一小部分患者符合条件 用于这些治疗。这使得大多数中风患者得不到有效的药物治疗来增强他们的 中风恢复了。生物材料提供了一种与神经系统互动的独特途径。干细胞治疗 是另一种新兴的中风疗法，在基础和临床试验中都显示出希望。然而，最优的 干细胞输送的方法和环境仍不清楚。我们已经开发出一种新的干细胞输送方式 利用导电聚合物支架将神经干细胞移植到中风患者体内的系统(ElectricStem) 大脑。由于聚合物具有导电性，电刺激可以与移植的神经相结合。 干细胞。我们已经证明了移植的神经干细胞的电调制显著 与传统的干细胞移植相比，可改善中风的康复。在我们的初步研究中，电气 神经干细胞移植的调节也增加了内源性干细胞在大脑中的产生 -表明这种改善的复苏可能存在一种机制。关于这些角色的进一步调查 内源性干细胞在卒中康复中的作用将确定卒中康复的重要机制。通过评估 在接受电调制的移植神经干细胞中，哪些蛋白质上调，我们有 发现锡钙素-2(STC2)是促进恢复的重要途径。STC2是一种糖蛋白，具有 旁分泌效应，对细胞的周转和存活起作用。如果在移植过程中增加STC2产量 神经干细胞，动物的功能结果得到了改善，我们看到了更多的内源性 干细胞的产生。如果干细胞中STC2水平降低，功能和功能的改善 内源性干细胞的生产就会丧失。我们提议的研究调查了ElectricStem招募员工的能力 内源性干细胞并改变其在中风后受损的啮齿动物脑组织中的活性。其影响 对移植的神经干细胞和宿主脑的电调制的评估将与 STC2通路。该项目还将评估STC2是否为中风康复的潜在疗法。最后，我们的 ElectricStem系统将用于翻译衰老啮齿动物模型，以确定有前途的功能 在年轻成年动物身上看到的改善在老年动物身上也观察到了。使用这些新技术，我们的目标是 验证通过生物工程系统增强重要的内源性恢复途径的假设 将改善中风后的神经修复。

Abstract The ability to promote regeneration of the central nervous system remains elusive. Stroke is a leading cause of death and disability and creates immense burdens on stroke survivors, their caregivers, and society. Although acute stroke care has rapidly progressed over the past decades, only a small proportion of the patients qualify for these treatments. This leaves a majority of stroke patients without effective medical therapy to augment their stroke recovery. Biomaterials offer a unique avenue to interact with the nervous system. Stem cell treatments are another emerging stroke therapy that shows promise in both basic and clinical trials. However, the optimal method and environment for stem cell delivery remains unknown. We have developed a new stem cell delivery system (ElectricStem) that utilizes conductive polymer scaffolds to transplant neural stem cells into the stroked- brain. Because the polymers are conductive, electrical stimulation can be combined with the transplanted neural stem cells. We have demonstrated that electrical modulation of transplanted neural stem cells dramatically improves stroke recovery over traditional stem cell transplantation alone. In our preliminary studies, electrical modulation of neural stem cell transplants also increases the production of endogenous stem cells in the brain – suggesting a possible mechanism for this improved recovery. Further investigation about the role these endogenous stem cells play in stroke recovery will identify important stroke recovery mechanisms. By evaluating what proteins are upregulated in the transplanted neural stem cells that receive electrical modulation, we have identified stanniocalcin-2 (STC2) as an important pathway for improved recovery. STC2 is a glycoprotein with paracrine effects that plays a role in cell turnover and survival. If STC2 production is increased in transplanted neural stem cells, the animals have improved functional outcomes, and we see greater numbers of endogenous stem cells produced. If STC2 levels are decreased in the stem cells, the improvement in function and endogenous stem cell production is lost. Our proposed research investigates the ability of ElectricStem to recruit endogenous stem cells and alter their activity within the injured rodent brain tissue following stroke. The effects of electrical modulation on the transplanted neural stem cells and host brain will be evaluated in relation to the STC2 pathway. The project will also evaluate if STC2 is a potential therapy for stroke recovery. Finally, our ElectricStem system will be used in a translational aged rodent model to determine if the promising functional improvements seen in young adult animals are observed in older animals. Using these new techniques, we aim to test the hypothesis that augmentation of important endogenous recovery pathways via bioengineered systems will improve neural repair following stroke.