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.

项目总结 目前以干细胞为基础的中枢神经系统(CNS)损伤治疗，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 移植细胞的不可控分化，所有这些都是由高度抑制和炎症引起的 疾病或损伤部位的微环境。具体地说，损伤部位的胶质细胞增生症会导致抑制因子的分泌。 导致存活神经元群体轴突再生和萌发不良的因素，导致 中枢神经系统在最初损伤后再生的内在局限性。因此，迫切需要有效的 从患者来源的干细胞中产生强大的功能神经元群体的策略，并重新 建立受损的神经回路。为此，我们建议整合几个领域的研究，包括 纳米技术、生物材料、神经科学和干细胞生物学，以开发一种新型的纳米支架干细胞 允许在干细胞过程中产生有利微环境的细胞组装平台 干细胞在体内的植入和命运的控制具有潜在的临床应用价值。 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3D-混合智能神经球体以增强干细胞治疗 脊髓损伤的体内治疗。由可生物降解支架组装的3D-混合智能神经球体 富含天然神经ECM的纳米材料可促进神经干细胞(NSC)的存活和分化。 智能神经球体还允许加载生物活性分子(即Notch抑制剂)，导致 抑制神经抑制信号和促进神经干细胞(NSC)存活和 差异化。这一新的技术平台将进一步集成到两种临床先进模型中：i)和 炎性中枢神经系统器质性小胶质细胞复合模型，以及脊髓损伤动物模型。这 多学科研究将为神经再生的研究和细胞治疗提供下一代平台 从医学角度开发一种用于增强干细胞的新的三维球体组装方法 中枢神经系统损伤后抑制性环境的存活和抑制。 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：目标1-开发生物活性和可生物降解-纳米支架基可注射3D-混合智能 球体；目的2-研究智能球体中的深层药物释放(Notch-I)，并研究神经元 神经抑制和免疫微环境下干细胞分化与轴突生长 在体外；目的#3-确定3D-混合智能球体的治疗效果 神经抑制微环境与促进在体脊髓损伤功能恢复。总而言之， 我们期待我们提出的研究将提供一种创新的、高效的和可靠的方法 开发神经疾病的治疗干预措施。