Implantable biofunctional hydrogel for muscle stem cell transplantation

用于肌肉干细胞移植的可植入生物功能水凝胶

• 批准号: 9375058
• 负责人: Young Charles Jang
• 金额: $ 20.6万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375058
• 关键词: Address; Adhesions; Adhesives; Basic Science; Biochemical; Biocompatible Materials; Biomimetics; Bolus Infusion; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Cellular biology; Characteristics; Clinic; Collagen; Data; Defect; Duchenne muscular dystrophy; Dystroglycan; Elasticity; Engineering; Engraftment; Exhibits; Extracellular Matrix; Fibronectins; Foundations; Future; Gel; Goals; Growth Factor; Histologic; Homeostasis; Human; Hydrogels; Imaging technology; Inflammation; Injectable; Injury; Intervention; Laminin; Ligands; Luciferases; Maleimides; Measures; Metabolic; Monitor; Motor Neurons; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Myopathy; Natural regeneration; Neuromuscular Junction; Outcome; Patients; Peptide Hydrolases; Peptides; Peripheral; Polyethylene Glycols; Population; Proliferating; Property; Regenerative Medicine; Research; Skeletal Muscle; Stem cells; System; Technology; Testing; Time; Transgenic Mice; Translating; Transplantation; Traumatic injury; Urine; Vascular Endothelial Growth Factors; Vascularization; Work; bioluminescence imaging; clinical efficacy; controlled release; experimental study; functional improvement; improved; in vivo; in vivo imaging; innovation; male; mouse model; muscle physiology; muscle regeneration; muscle transplantation; myogenesis; neuromuscular; neurotrophic factor; novel; receptor binding; reconstitution; regenerative; release factor; repaired; scaffold; self-renewal; stem cell niche; synaptogenesis; synthetic peptide; systemic toxicity

PROJECT SUMMARY To maintain skeletal muscle homeostasis and to repair damaged muscle, a functional pool of muscle stem cell (MuSC) undergoes asymmetric division in which committed progenies proliferate, differentiate, and fuse with existing myofibers or form de novo myofibers, while other populations of MuSC progeny self-renew to replenish the quiescent stem cell pool for future rounds of regeneration. Due to these unique properties, MuSC has been an attractive target for interventions, and cell-based therapy has been extensively studied to treat a variety of muscle wasting conditions. While direct transplantation of MuSC contributes to muscle regeneration to some degree, the clinical efficacy of direct cell transplantation is severely limited by sub-optimal engraftment, survival, and lack of functional benefits. To overcome these challenges, we engineered polyethylene glycol (PEG)- Maleimide hydrogels functionalized with adhesion ligands found in the native MuSC niche. Excitingly, our preliminary data show that MuSC delivered via biomimetic vehicle exhibit a significant improvement in transplantation efficiency compared to cells only control. To build upon our exciting preliminary findings, this proposal will test the working hypothesis that MuSC delivered within PEG-mal hydrogel functionalized to mimic native niche will synergistically augment long-term stem cell engraftment, restore regenerative, metabolic, and contractile function of dystrophic recipient muscle. As such, following specific aims will be investigated: Aim1 is to evaluate engineered PEG-mal hydrogel for optimal delivery, survival, engraftment, and MuSC function in vivo. Aim 2 examines whether co-delivery of MuSC and selected stem cell niche factors, VEGF and GDNF delivered within the biofunctional hydrogel, synergistically boost transplant efficiency and muscle function. The outcomes of this work serve as a vehicle for translating the basic sciences to the clinics, where the engineered biomaterial will contribute to accelerating the repair for the muscle traumatic injury, as well as other degenerative muscle diseases in human patients.

项目摘要 为了维持骨骼肌稳态并修复受损的肌肉，肌肉干细胞的功能池 （MUSC）经历不对称的分裂，其中承诺的后代扩散，分化和融合 现有的肌纤维或从头肌纤维形成，而其他MUSC后代自我更新的种群可以补充 静止的干细胞池，用于将来的再生一轮。由于这些独特的特性，MUSC一直是 对干预措施的有吸引力的目标，基于细胞的治疗已被广泛研究以治疗各种 肌肉浪费条件。 MUSC直接移植有助于肌肉再生 程度，直接细胞移植的临床疗效受到亚最佳植入，生存， 缺乏功能福利。为了克服这些挑战，我们设计了聚乙烯乙二醇（PEG） - 马来酰亚胺水凝胶用在天然MUSC生态裂中发现的粘附配体功能化。令人兴奋的是，我们的 初步数据表明，通过仿生型交付的MUSC在 与仅细胞对照相比，移植效率。为了建立我们令人兴奋的初步发现， 提案将检验以下假设，即在PEG-MAL水凝胶中递送至模拟的MUSC 本地利基市场将协同增强长期干细胞植入，恢复再生，代谢和 营养不良的受体肌肉的收缩功能。因此，将研究以下特定目标：AIM1是 评估工程化的PEG-MAL水凝胶以在体内最佳输送，生存，植入和MUSC功能。 AIM 2检查了MUSC和选定的干细胞生态位因子，VEGF和GDNF的共同传递是否已交付 在生物功能性水凝胶中，协同提高移植效率和肌肉功能。结果 这项工作是将基本科学转化为诊所的工具，该诊所是工程生物材料的 将有助于加速修复肌肉创伤性损伤以及其他退化性肌肉 人类患者的疾病。