Stem Cell Surface Modification to Promote Nerve Regeneration

干细胞表面修饰促进神经再生

• 批准号: 10326864
• 负责人: Xiaofeng Jia
• 金额: $ 45.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326864
• 关键词: Address; Adhesions; Adipose tissue; Autologous; Autologous Transplantation; Cell Adhesion; Cell Differentiation process; Cell Survival; Cell Therapy; Cell Transplantation; Cell surface; Cell-Cell Adhesion; Cells; Chronic; Clinical; Clinical Research; Data; Development; Distal; Dose; Electric Stimulation; Electrophysiology (science); Environment; Extracellular Matrix; Foundations; Future; Glycoengineering; Gold; Growth Factor; Harvest; Human; Impairment; In Vitro; Injury; Intervention; Metabolic; Methodology; Methods; Modification; Morbidity - disease rate; Myopathy; Natural regeneration; Nature; Nerve; Nerve Regeneration; Neurons; Operative Surgical Procedures; Oral; Outcome; Pathway interactions; Patients; Peripheral Nerves; Peripheral nerve injury; Polysaccharides; Procedures; Property; Protocols documentation; Quality of life; Recovery of Function; Regenerative Medicine; Regulation; Safety; Series; Signal Pathway; Source; Stem cell transplant; Sulfhydryl Compounds; Surface; Surface Properties; Surgical incisions; Techniques; Technology; Testing; Time; Tissues; Transplantation; Trauma; Work; analog; base; cell type; clinical application; cost; efficacy evaluation; functional outcomes; improved; improved outcome; in vitro Assay; in vivo; in vivo evaluation; innovation; migration; nerve gap; nerve injury; nerve repair; nerve stem cell; novel; novel strategies; novel therapeutic intervention; peripheral nerve regeneration; peripheral nerve repair; repair model; repaired; sciatic nerve; stem cell therapy; stem cells; success; sugar; supportive environment; treatment optimization

Project Summary Peripheral nerve injury, especially critical-sized nerve gap injury, often results in poor recovery of function and impaired quality of life for the patient. Stem cell therapy holds significant promise; however, its clinical application has been largely hampered by limited stem cell adhesion and the lack of efficient differentiation. We have shown that our stem cell surface modification technique is able to profoundly influence specific cell-cell and cell-matrix interactions. Therefore, our specific aims are to develop and optimize novel candidate analogs to promote human adipose stem cell (hASC) adhesion and differentiation in vitro; to incorporate the cell surface modification technique into hASC-based therapies to improve peripheral nerve regeneration; and to investigate related mechanisms underlying improved nerve regeneration. Aim1: To develop and optimize novel analogs by metabolic glycoengineering (MGE) technology to promote hASC's cell adhesion and cell differentiation in vitro. We will optimize the cell surface modification with thiolated sugar analogs (ManNAc), evaluate the effects, and thoroughly characterize them to promote hASCs adhesion, proliferation, and differentiation. Aim2: To incorporate MGE into hASC-based therapies to improve peripheral nerve regeneration. With optimized ManNAc analogs, we will systemically evaluate the effect of glycoengineered hASCs on nerve regeneration after nerve repair and further optimize the therapy. Aim 3: To examine the mechanism by which thiol-derivatized ManNAc analogs contribute to nerve regeneration . With expected improvements in nerve regeneration, we will evaluate signaling pathways (e.g., Wnt / β after MGE'ed hASC transplantation. -catenin) modulated by MGE The innovation lies in our hypothesis to modify stem cell surface glycan properties with sugar analogs to improve cell survival and differentiation, our novel and effective technology, and the new application of these technologies in a fully translational nerve repair model to develop a novel treatment. The significance lies in the novel cell-based therapy with surface modification to address one of the most challenging aspects of nerve regeneration for critical-sized nerve gap repair, and the expected discovery of the mechanism underlying improved survival and differentiation by transplanted MGE'ed hASC. Our technology and protocols are highly translatable to the clinical environment. Success in this project will have direct translational implications for patients with peripheral nerve trauma requiring surgical repair. The clinical study of ManNAc has demonstrated the safety of single oral doses up to 6 g, and the FDA has approved the use of ManNAc to treat GNE Myopathy. Our study will lead to the development of novel therapeutic strategies for nerve repair that can contribute to future clinical interventions and maximize the benefits of stem cell therapy based on the new findings.

项目摘要 周围神经损伤，尤其是重大尺寸的神经间隙损伤，通常导致功能恢复不良和 患者的生活质量受损。干细胞疗法具有巨大的希望；但是，其临床应用 有限的干细胞粘合剂和缺乏有效的分化受到了很大的阻碍。我们已经显示了 我们的干细胞表面修饰技术能够深刻影响特定的细胞细胞和细胞 - 矩阵 互动。因此，我们的具体目的是开发和优化新颖的候选类似物以促进人类 脂肪干细胞（HASC）粘合剂和体外分化；结合细胞表面修饰 基于HASC的技术改善外周神经再生；并调查相关 基础的机制改善了神经再生。 AIM1：通过代谢糖工程（MGE）技术开发和优化新型类似物 在体外促进HASC的细胞粘合剂和细胞分化。我们将使用 硫醇化的糖类似物（MANNAC），评估效果并彻底表征它们以促进HASC 粘附，增殖和分化。 AIM2：将MGE纳入基于HASC的疗法中以改善周围神经再生。和 优化的MANNAC类似物，我们将系统地评估糖化性HASC对神经的影响 神经修复后再生并进一步优化治疗。 目标3： 考试 硫醇衍生化的甘露纳克类似物有助于神经的机制 再生 。 随着神经再生的预期改善， 我们将评估信号通路（例如，Wnt / MGE'ED HASC移植后的β。 -Catenin）由MGE调制 创新在于我们的假设，它用糖类似物对干细胞表面聚糖特性进行修饰 改善细胞的生存和差异化，我们的新颖有效的技术以及这些的新应用 完全翻译的神经修复模型中的技术以开发新的治疗方法。意义在于 基于细胞的新型疗法，具有表面修饰，以解决神经最挑战的方面之一 关键尺寸神经间隙修复的再生，以及对基础机制的预期发现 通过移植的MGE'ED HASC改善了生存和分化。我们的技术和协议很高 可以翻译成临床环境。该项目的成功将对 外周神经创伤患者需要手术修复。 MANNAC的临床研究已证明 单一口腔剂量的安全性高达6 g，FDA批准使用Mannac治疗片状肌病。 我们的研究将导致开发新的治疗策略以进行神经修复，这可能有助于 根据新发现，未来的临床干预措施并最大程度地提高了干细胞疗法的益处。