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

导电聚合物干细胞系统可增强内源性中风修复机制并改善功能性中风恢复

• 批准号: 10585376
• 负责人: Paul George
• 金额: $ 38.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585376
• 关键词: Ablation; Acute; Adult; Affect; Aftercare; Age; Animals; Antibodies; Array tomography; Biocompatible Materials; Biomedical Engineering; Brain; Caregivers; Caring; Cause of Death; Cells; Central Nervous System; Clinical Trials; Data; Differentiation Antigens; Elderly; Electric Stimulation; Electrophysiology (science); Eligibility Determination; Embolectomy; Environment; Equilibrium; Glycoproteins; Imaging Techniques; Immune response; Infarction; Investigation; Label; Mediating; Medical; Methods; Natural regeneration; Nervous System; Neuronal Differentiation; Pathway interactions; Patients; Play; Polymers; Production; Property; Proteins; Publishing; Qualifying; Rattus; Recombinants; Recovery; Recovery of Function; Research; Resolution; Rodent; Rodent Model; Role; Signal Transduction; Societies; Stains; Statistical Methods; Stem Cell Factor; Stem cell transplant; Stroke; Survivors; Synapses; System; Techniques; Testing; Therapeutic Studies; Tissues; Transplantation; United States; Use of New Techniques; Work; acute stroke; aged; brain tissue; disability; early phase clinical trial; functional improvement; high dimensionality; improved; injured; innovation; mature animal; microscopic imaging; multidisciplinary; nerve stem cell; neural repair; novel strategies; paracrine; pharmacologic; post stroke; pre-clinical; progenitor; recruit; release factor; repaired; scaffold; stanniocalcin 2; stem cell biology; stem cell delivery; stem cell therapy; stem cells; stroke model; stroke patient; stroke recovery; stroke survivor; stroke therapy; transcriptome; translational model; young adult

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.

抽象的 促进中枢神经系统再生的能力仍然难以捉摸。中风是主要原因 死亡和残疾，并在中风生存，他们的照顾者和社会上创造了巨大的伯恩斯。虽然 在过去的几十年中，急性中风护理迅速发展，只有一小部分患者有资格 对于这些治疗。这使大多数中风患者没有有效的医疗疗法来增加他们的 中风恢复。生物材料为与神经系统互动提供了独特的途径。干细胞处理 是另一种新兴的中风疗法，在基本和临床试验中都表现出希望。但是，最佳 干细胞输送的方法和环境仍然未知。我们已经开发了一个新的干细胞输送 使用导电聚合物支架来移植神经干细胞中的系统（电系统） 脑。由于聚合物是导电的，因此可以将电刺激与移植神经结合 干细胞。我们已经证明了移植神经干细胞的电气调节 仅比传统的干细胞移植改善中风恢复。在我们的初步研究中 神经元干细胞移植的调节还增加了大脑内源性干细胞的产生 - 提出可能改善恢复的可能机制。进一步调查这些角色 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 哪种蛋白质在接收电气调制的移植神经干细胞中上调，我们有 确定stanniocalcin-2（STC2）是改善恢复的重要途径。 STC2是一种糖蛋白 旁分泌作用在细胞更新和存活中起作用。如果在移植中增加了STC2的产生 神经干细胞，动物有改善的功能结果，我们看到了更多的内源性 产生的干细胞。如果干细胞中的STC2水平降低，则功能的改善和 内源性干细胞产生丢失。我们提出的研究调查了电力系统招募的能力 中源性干细胞并改变其在中风后受伤的啮齿动物脑组织中的活性。效果 将评估移植神经元干细胞和宿主脑的电气调节 STC2途径。该项目还将评估STC2是否是中风恢复的潜在疗法。最后，我们的 电力系统系统将在翻译的啮齿动物模型中使用，以确定是否有承诺的功能 在老年动物中观察到年轻动物的改善。使用这些新技术，我们的目标 测试通过生物工程系统增强重要内源恢复途径的假设 中风后会改善神经修复。