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 死亡和残疾，并对中风幸存者、他们的照顾者和社会造成巨大负担。虽然 在过去的几十年里，急性卒中护理进展迅速，但只有一小部分患者符合条件 对于这些治疗。这使得大多数中风患者没有有效的药物治疗来增加他们的 中风恢复生物材料提供了与神经系统相互作用的独特途径。干细胞治疗 是另一种新兴的中风治疗方法，在基础和临床试验中都显示出了希望。然而，最佳 干细胞递送的方法和环境仍然未知。我们开发了一种新的干细胞输送方法 系统（ElectricStem），该系统利用导电聚合物支架将神经干细胞移植到中风患者体内， 个脑袋因为聚合物是导电的，电刺激可以与移植的神经细胞相结合。 干细胞我们已经证明，移植的神经干细胞的电调制显着 与传统的单独干细胞移植相比，改善了中风恢复。在我们的初步研究中， 神经干细胞移植的调节也增加了脑中内源性干细胞的产生 - 提出了这种改进的恢复的可能机制。进一步研究这些作用 内源性干细胞在中风恢复中的作用将确定重要的中风恢复机制。通过评估 在接受电调节的移植神经干细胞中，哪些蛋白质被上调， 将斯钙素-2（STC 2）鉴定为改善恢复的重要途径。STC 2是一种糖蛋白， 旁分泌效应在细胞更新和存活中起作用。如果STC 2的产量增加， 神经干细胞，动物有改善的功能结果，我们看到更多的内源性 干细胞生产。如果STC 2水平在干细胞中降低，则功能和免疫功能的改善可能会降低。 内源性干细胞产生丧失。我们提议的研究调查了ElectricStem的招募能力， 内源性干细胞，并改变其在中风后受损的啮齿动物脑组织内的活性。的影响 电调制对移植的神经干细胞和宿主脑的影响将根据神经干细胞的功能进行评估。 STC 2途径。该项目还将评估STC 2是否是中风恢复的潜在疗法。最后我们 ElectricStem系统将用于平移老化啮齿动物模型中，以确定有希望的功能 在年轻的成年动物中观察到的改善在年长的动物中观察到。利用这些新技术，我们的目标是 为了验证这一假设，通过生物工程系统增强重要的内源性恢复途径， 会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.