Injectable Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

可注射混合 SMART 球体增强干细胞治疗中枢神经系统损伤

• 批准号: 10752890
• 负责人: Kibum Lee
• 金额: $ 39.1万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752890
• 关键词: 3-Dimensional; Address; Animal Model; Axon; Biocompatible Materials; Biological Process; Cell Differentiation process; Cell Therapy; Cells; Central Nervous System; Characteristics; Cicatrix; Clinic; Clinical; Complex; Cues; Data; Development; Differentiation and Growth; Disease; Drug Delivery Systems; Environment; Extracellular Matrix; Functional disorder; Generations; Gliosis; Goals; Growth; Human; Hybrids; Impairment; Implant; In Vitro; Inflammation; Inflammatory; Injectable; Injury; Investigation; Laminin; Medicine; Methods; Microglia; Mission; Modeling; Nanotechnology; Natural regeneration; Nerve Regeneration; Neurites; Neurologic Deficit; Neuronal Differentiation; Neuronal Plasticity; Neurons; Neurosciences; Neurosphere; Organoids; Patients; Population; Proliferating; Property; Public Health; Recovery of Function; Research; Signal Transduction; Site; Spinal cord injury; Stem cell transplant; Survival Rate; System; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Translating; Treatment outcome; United States National Institutes of Health; axon growth; axon regeneration; axonal sprouting; biodegradable scaffold; biomaterial compatibility; cell assembly; central nervous system injury; clinical application; controlled release; disability; effective therapy; implantation; improved; in vivo; inflammatory modulation; inhibitor; innovation; innovative technologies; multidisciplinary; nano; nanomaterials; nerve stem cell; nervous system disorder; neural; neural circuit; neurogenesis; neuronal growth; neuronal survival; new technology; next generation; notch protein; novel; permissiveness; regeneration potential; repaired; scaffold; spatiotemporal; stem cell biology; stem cell differentiation; stem cell fate; stem cell growth; stem cell survival; stem cell therapy; stem cells; success; synergism; technology platform; three dimensional cell culture; tool; tumor-immune system interactions

PROJECT SUMMARY Current stem cell-based treatments for central nervous system (CNS) injuries such as spinal cord injury (SCI), are severely hampered by poor stem cell survival rates, inefficient integration, loss of neural plasticity, and uncontrollable differentiation of implanted cells, all of which are caused by the highly inhibitory and inflammatory microenvironment at disease or injury sites. Specifically, gliosis at the injury site causes the secretion of inhibitory factors leading to poor axon regeneration and sprouting of surviving neuronal populations, resulting in the intrinsic limitations of the CNS to regenerate after the initial injury. Therefore, there is an urgent need for effective strategies to generate a robust population of functional neurons derived from patient-derived stem cells and re- establish the damaged neural circuitry. To this end, we propose to integrate several fields of research, including nanotechnology, biomaterials, neuroscience, and stem cell biology, to develop a novel nanoscaffold-based stem cell assembly platform that allows for the generation of favorable microenvironments during stem cell implantation and the control of stem cell fate in vivo for potential clinical applications. To address the fundamental impediment of regeneration associated with CNS injuries and diseases, we propose to develop injectable 3D-Hybrid SMART neuro-spheroids for enhanced stem cell therapy and effective treatment of SCI in vivo. The 3D-Hybrid SMART neuro-spheroids are assembled from biodegradable scaffold nanomaterials enriched with natural neural ECM to promote neural stem cell (NSC) survival and differentiation. The SMART neuro-spheroids also permit the loading of a bioactive molecule (i.e., Notch inhibitor), resulting in the synergy between suppressing neuroinhibitory signaling and promoting neural stem cell (NSC) survival and differentiation. This novel technology platform will be further integrated into two clinically advanced models: i) an inflammatory CNS organoid model incorporated with microglia, and ii) a spinal cord injury animal model. This multidisciplinary study will provide a next-generation platform for research and cell therapy in neuro-regenerative medicine from the perspective of developing a new 3D spheroid assembly method for enhanced stem cell survival and suppression of inhibitory environment after CNS injuries. We propose to verify our central hypothesis and achieve our objectives by addressing the following specific aims: AIM #1 – Develop bioactive and biodegradable-nanoscaffold-based injectable 3D-Hybrid SMART spheroids; AIM #2 – Investigate deep drug (Notch-i) delivery in SMART spheroids and study neuronal differentiation of stem cells and axonal growth under neuroinhibitory and immune microenvironments in vitro; AIM #3 – Determine the therapeutic effects of 3D-Hybrid SMART spheroids on the modulation of neuroinhibitory microenvironments and the enhancement of SCI functional recovery in vivo. Collectively, we anticipate that our proposed studies will provide an innovative, highly effective, and robust method for developing therapeutic interventions for neurological disorders.

项目摘要 当前针对中枢神经系统（CNS）损伤的干细胞治疗，例如脊髓损伤（SCI）， 干细胞存活率较差，效率低下，神经元可塑性的丧失和 植入细胞的无法控制的分化，所有这些细胞都是由高度抑制和炎症引起的 疾病或受伤部位的微环境。具体而言，损伤部位的神经病会导致抑制作用 导致轴突再生不良和生存神经元种群发芽的因素，导致 最初受伤后，中枢神经系统对再生的固有局限性。因此，迫切需要有效 产生源自患者衍生的干细胞并重新衍生的功能性神经元种群的策略 建立受损的神经回路。为此，我们建议整合几个研究领域，包括 纳米技术，生物材料，神经科学和干细胞生物学，以开发一种新型的基于纳米的茎 细胞组装平台，可以在干细胞期间生成有利的微环境 植入和控制干细胞命运在体内用于潜在临床应用。 为了解决与中枢神经系统损伤和疾病有关的再生的基本障碍，我们 提出开发可注射的3D杂交智能神经丝状类的建议，以增强干细胞疗法和有效 体内SCI的治疗。 3D杂交智能神经 - 球形素是由可生物降解的脚手架组装的 富含天然神经ECM的纳米材料可促进神经元干细胞（NSC）生存和分化。 智能神经 - 球状素还允许加载生物活性分子（即缺口抑制剂），从而导致 抑制神经抑制信号传导和促进神经元干细胞（NSC）存活与 分化。这个新颖的技术平台将进一步整合到两个临床高级模型中：i） 与小胶质细胞合并的炎性CNS类器官模型，ii）脊髓损伤动物模型。这 多学科研究将为神经再生的研究和细胞疗法提供下一代平台 从开发一种新的3D球体组装方法来增强干细胞的角度来看 中枢神经系统损伤后的抑制环境的生存和抑制。 我们建议通过解决以下特定的特定来验证我们的中心假设并实现我们的目标 目的：目标＃1 - 开发基于生物活性和可生物降解的基于纳米的可注射3D-HYBRID SMART 球体； AIM＃2 - 研究智能球体中的深度药物（Notch-i）和研究神经元 在神经抑制和免疫环境下的干细胞和轴突生长的分化 体外; AIM＃3 - 确定3D杂交智能球体对调节的治疗作用 神经抑制性微环境和体内SCI功能恢复的增强。共同 我们预计我们的拟议研究将为一种创新，高效且健壮的方法提供 为神经系统疾病开发治疗性干预措施。