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.

项目概要 目前基于干细胞的治疗中枢神经系统（CNS）损伤，如脊髓损伤（SCI）， 干细胞存活率低、整合效率低、神经可塑性丧失以及 植入细胞无法控制的分化，所有这些都是由高度抑制和炎症引起的 具体来说，损伤部位的神经胶质增生会导致抑制性物质的分泌。 导致轴突再生不良和存活神经群体发芽的因素，导致 中枢神经系统在初次损伤后再生的内在局限性因此，迫切需要有效性。 产生源自患者干细胞的强大功能神经元群体的策略，并重新 为此，我们建议整合多个研究领域，包括 纳米技术、生物材料、神经科学和干细胞生物学，开发一种新型的基于纳米支架的干细胞 细胞组装平台，允许在干细胞过程中产生有利的微环境 体内干细胞命运的植入和控制，用于潜在的临床应用。 为了解决与中枢神经系统损伤和疾病相关的再生的根本障碍，我们 建议开发可注射的 3D-Hybrid SMART 神经球体，以增强干细胞治疗和有效 3D-Hybrid SMART 神经球由可生物降解的支架组装而成。 富含天然神经 ECM 的纳米材料可促进神经干细胞 (NSC) 存活和分化。 SMART 神经球体还允许加载生物活性分子（即 Notch 抑制剂），从而产生 抑制神经抑制信号传导和促进神经干细胞（NSC）存活之间的协同作用 这种新颖的技术平台将进一步集成到两个临床先进模型中：i） 结合小胶质细胞的炎性中枢神经系统类器官模型，以及 ii) 脊髓损伤动物模型。 多学科研究将为神经再生研究和细胞治疗提供下一代平台 从医学的角度开发增强干细胞的新3D球体组装方法 中枢神经系统损伤后抑制环境的生存和抑制。 我们建议通过解决以下具体问题来验证我们的中心假设并实现我们的目标 目标：AIM #1 – 开发基于生物活性和可生物降解纳米支架的可注射 3D-Hybrid SMART 球体；AIM #2 – 研究 SMART 球体中的深部药物 (Notch-i) 递送并研究神经元 神经抑制和免疫微环境下干细胞的分化和轴突生长 体外；AIM #3 – 确定 3D-Hybrid SMART 球体对调节的治疗效果 神经抑制微环境和 SCI 体内功能恢复的增强。 我们预计我们提出的研究将为以下方面提供一种创新、高效且稳健的方法： 制定针对神经系统疾病的治疗干预措施。