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 为了维持骨骼肌的稳态和修复受损的肌肉，肌肉干细胞的功能库 （MuSC）经历不对称分裂，其中定向后代增殖，分化，并与 现有的肌纤维或从头形成肌纤维，而其他MuSC后代群体自我更新以补充 静止的干细胞库用于未来的再生。由于这些独特的特性，MuSC已被 一个有吸引力的干预目标，和细胞为基础的治疗已被广泛研究，以治疗各种 肌肉萎缩症虽然MuSC的直接移植有助于肌肉再生，但在某些情况下， 在一定程度上，直接细胞移植的临床疗效受到次优植入，存活， 缺乏功能性的好处。为了克服这些挑战，我们设计了聚乙二醇（PEG）- 马来酰亚胺水凝胶用在天然MuSC生态位中发现的粘附配体官能化。令人兴奋的是，我们 初步数据显示，通过仿生载体递送的MuSC在以下方面表现出显著的改善： 与仅细胞对照相比的移植效率。在我们令人兴奋的初步发现的基础上， 该提案将测试MuSC在PEG-mal水凝胶内递送的工作假设， 天然生态位将协同增强长期干细胞植入，恢复再生，代谢， 营养不良受体肌肉的收缩功能。因此，将研究以下具体目标： 评估工程化PEG-mal水凝胶的最佳递送、存活、植入和体内MuSC功能。 目的2检查MuSC和选择的干细胞龛因子、VEGF和GDNF的共递送是否递送了肿瘤细胞。 在生物功能性水凝胶内，协同提高移植效率和肌肉功能。成果 这项工作的一部分作为将基础科学转化为临床的工具， 将有助于加速肌肉创伤性损伤以及其他退行性肌肉的修复 人类患者的疾病。