Tissue engineered rostral migratory stream for directed neuronal replacement

用于定向神经元替换的组织工程嘴部迁移流

基本信息

批准号：
10527087
负责人：
Daniel Kacy Cullen
金额：
$ 8.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10527087
关键词：
Acute Address Adult Affect Aging Alzheimer&apos s Disease Anatomy Area Astrocytes Autologous Beds Behavioral Biomedical Engineering Brain Brain Injuries Cells Cerebral cortex Chronic Chronic Brain Injury Clinical Cognitive Corpus striatum structure Cues Dependence Development Engineering Exhibits Future Gingiva Harvest Human Implant In Vitro Injury Lateral Lesion Location Mesenchymal Stem Cells Methods Morphology Natural regeneration Nerve Degeneration Nerve Regeneration Nervous System Trauma Neurodegenerative Disorders Neurons Neurosphere Nude Rats Out-Migrations Parkinson Disease Pathway interactions Patients Persons Population Positioning Attribute Pre-Clinical Model Prosencephalon Proteins Publications Punch Biopsy Rattus Recovery Recovery of Function Regenerative Medicine Residual state Rodent Signal Transduction Site Source Specialist Stream Structure Target Populations Techniques Testing Tissue Engineering Tissues Traumatic Brain Injury Traumatic Brain Injury recovery Tube base biofabrication cell type clinical translation controlled cortical impact dentate gyrus design disability efficacy evaluation efficacy testing human stem cells improved in vitro testing in vivo injury recovery innovation insight migration minimally invasive motor deficit multidisciplinary nerve stem cell neural circuit neuroblast neurogenesis neuron loss neuronal replacement newborn neuron non-genetic novel olfactory bulb prevent protein expression repaired self assembly stem cell migration stem cells subventricular zone tissue stem cells translational approach

项目摘要

PROJECT SUMMARY Chronic disability due to traumatic brain injury (TBI) affects 2% of the total population, and neuronal loss is generally considered permanent, owing to limited capacity for neuroregeneration in the adult mammalian brain. There are currently no approved treatments for improving recovery after TBI, and innovative approaches to enhance neuroregeneration are desperately needed. Intriguingly, new neurons are generated in the subventricular zone (SVZ) and then guided to the olfactory bulb/tract (and possibly striatum) via the rostral migratory stream (RMS) for integration into existing circuitry. Recent publications have demonstrated that SVZ neuroblasts can be redirected into lesions, differentiate into region-specific neuronal cell types, integrate into circuitry, and improve functional recovery in adult rodents, but a translational strategy to direct and enhance neuroblast migration into lesions has yet to be established. To address this challenge, we have assembled a multi-disciplinary team of stem cell specialists, neurobiologists, clinicians, and tissue engineers to develop the first anatomically-inspired microtissue designed to structurally and functionally emulate the glial tube of the RMS. In an exciting breakthrough, our team developed novel microtissue engineering techniques that promote the self-assembly of astrocytes into longitudinally aligned bundles that recapitulate the organization of the glial tube of the RMS. To date, we have biofabricated this Tissue Engineered Rostral Migratory Stream (TE-RMS) using rodent derived astrocytes as well as human stem cell derived astrocytes and, importantly, we have shown that the TE-RMS directly facilitates the alignment and migration of immature neurons in vitro and in vivo. In the current proposal, we will first validate the TE-RMS as an in vitro test bed to elucidate mechanisms of neuronal progenitor migration and cell fate determination (Aim 1). We will then test the ability of the TE-RMS to divert endogenous neuronal progenitors in vivo and repair damaged cerebral cortex following experimental TBI in rats (Aim 2). In this Aim, the TE-RMS will be stereotaxically microinjected after the acute injury period to span from the SVZ into lesioned tissue, and the redirection of migrating neurons to repopulate cortical areas, functional integration with residual circuitry, and facilitation of behavioral recovery will be assessed. Finally, as a first step towards clinical translation, we will perform in vitro and in vivo studies to validate the TE-RMS built using astrocytes derived from stem cells harvested from adult human gingiva to develop methods for the eventual creation of autologous, patient-derived implants from an easily accessible cell source (Aim 3). The TE-RMS recapitulates the brain's own method for delivery and integration of new neurons. Thus, the execution of these Aims will significantly advance a translational bioengineering approach capable of providing targeted and sustained cell replacement following neurotrauma and/or degeneration. Our team is uniquely positioned to provide a feasible, yet highly innovative neuroregenerative approach that can have a significant impact on patients suffering from the otherwise intractable consequences of TBI.

项目概要创伤性脑损伤 (TBI) 导致的慢性残疾影响了总人口的 2%，神经元损失由于成年哺乳动物大脑的神经再生能力有限，通常被认为是永久性的。目前还没有批准的治疗方法可以改善 TBI 后的恢复，也没有创新的方法迫切需要增强神经再生。有趣的是，新的神经元在室下区（SVZ），然后通过吻端引导至嗅球/嗅束（可能还有纹状体）用于集成到现有电路中的迁移流（RMS）。最近的出版物表明 SVZ 神经母细胞可以被重定向到病灶，分化成区域特异性神经元细胞类型，整合到电路，并改善成年啮齿动物的功能恢复，但指导和增强的转化策略神经母细胞向病变的迁移尚未确定。为了应对这一挑战，我们组建了一个由干细胞专家、神经生物学家、临床医生和组织工程师组成的多学科团队开发第一个受解剖学启发的微组织，旨在在结构和功能上模拟神经胶质管均方根。我们的团队取得了令人兴奋的突破，开发了新颖的微组织工程技术，可促进星形胶质细胞自组装成纵向排列的束，概括了神经胶质的组织 RMS 管。迄今为止，我们已经生物制造了这种组织工程嘴部迁移流（TE-RMS）使用啮齿动物衍生的星形胶质细胞以及人类干细胞衍生的星形胶质细胞，重要的是，我们有研究表明 TE-RMS 直接促进体外和体内未成熟神经元的排列和迁移体内。在当前的提案中，我们将首先验证 TE-RMS 作为体外测试平台以阐明机制神经祖细胞迁移和细胞命运决定的研究（目标 1）。然后我们将测试 TE-RMS 的能力在实验后转移体内内源性神经元祖细胞并修复受损的大脑皮层大鼠 TBI（目标 2）。在这个目标中，TE-RMS 将在急性损伤期后进行立体定位显微注射，以从 SVZ 跨越到病变组织，以及迁移神经元的重定向以重新填充皮质区域，将评估与残余电路的功能整合以及行为恢复的促进作用。最后，作为作为临床转化的第一步，我们将进行体外和体内研究来验证所构建的 TE-RMS 使用从成人牙龈中采集的干细胞衍生的星形胶质细胞来开发方法最终从易于获取的细胞来源创建自体、患者来源的植入物（目标 3）。这 TE-RMS 概括了大脑自身传递和整合新神经元的方法。因此，执行这些目标将显着推进能够提供有针对性的转化生物工程方法以及神经损伤和/或变性后持续的细胞替代。我们的团队拥有独特的定位提供一种可行且高度创新的神经再生方法，可以对患有 TBI 的其他棘手后果的患者。