Hydrogels for delivery of muscle stem cells to diaphragm

用于将肌肉干细胞递送至隔膜的水凝胶

• 批准号: 10281444
• 负责人: Andres J Garcia
• 金额: $ 2.7万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281444
• 关键词: 3-Dimensional; Adhesions; Adhesives; Affect; Apoptosis; Biocompatible Materials; Biological Assay; Bone Regeneration; Bypass; C57BL/6 Mouse; Caring; Cell Survival; Cell Transplantation; Cell physiology; Cells; Cessation of life; Collagen; Defect; Differentiation Antigens; Dimensions; Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Electrodes; Encapsulated; Engineering; Engraftment; Euthanasia; Extracellular Matrix; Fiber; Formulation; Frequencies; Gel; Gene Expression; Genetic Diseases; Goals; Harvest; Heart failure; Histologic; Hydrogels; Image; Immunofluorescence Immunologic; In Situ Nick-End Labeling; In Vitro; Inferior; Injectable; Injections; Integrins; Isometric Exercise; Lead; Life Expectancy; Ligands; Limb structure; Location; Maleimides; Measures; Mechanical ventilation; Mechanics; Methods; Mus; Muscle; Muscle Weakness; Muscle satellite cell; Muscular Atrophy; Musculoskeletal; Natural regeneration; Neuromuscular Junction; Newborn Infant; Outcome; Output; Patients; Peptide Hydrolases; Peptides; Platinum; Proteins; Quality of life; Radial; Regenerative response; Respiratory Diaphragm; Respiratory Failure; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Role; Sarcolemma; Stains; Structure; Surface; Testing; Thinness; Tissues; Transducers; Transplantation; Vertebral column; Work; X-Linked Genetic Diseases; aged; base; bioimaging; cell behavior; crosslink; density; design; disability; improved; improved functioning; in vivo imaging system; male; palliative; parent grant; premature; receptor binding; respiratory; response; restoration; satellite cell; stem cell delivery; syndecan; synthetic peptide; targeted delivery; tissue fixing; ventilation

PROJECT ABSTRACT Duchenne muscular dystrophy (DMD) is an X-linked genetic disease that affects ~1 in 3,500 newborn males and is characterized by progressive muscle wasting and weakness. As a result, patients suffer from ambulatory disability, cardiac failure, and respiratory failure, the latter of which is a major contributor to premature death. Current treatments for respiratory care remain palliative, as there is no cure for DMD. The primary cause for DMD is the absence of functional dystrophin, a protein that provides structural support between the sarcolemma and extracellular matrix. A strategy for restoring dystrophin is to transplant satellite cells to a target muscle. Although this strategy would not be an efficient method to treat DMD throughout the body, the diaphragm muscle presents a viable and important target for the delivery of satellite cells due to its vital role in respiratory function. Upon successful engraftment of satellite cells to the diaphragm muscle, dystrophin, muscle excitability, and respiratory function can be restored, extending a DMD patient’s life expectancy, and improving the quality of life by potentially bypassing the need for mechanical ventilation. Delivery of satellite cells to the diaphragm muscle poses a challenge due to sub-optimal engraftment, survival, and function of transplanted cells, as well as the diaphragm’s thin dimensions and deep-seated location. This project seeks to overcome these hurdles by engineering a synthetic hydrogel-based bioactive cell injectable vehicle to deliver satellite cells to the dystrophic diaphragm and promote survival, expansion, differentiation, and engraftment of transplanted cells to improve diaphragm function. The goals of this proposal will be accomplished in a stepwise fashion. First, we will engineer synthetic hydrogels functionalized with adhesive peptides to maintain and direct muscle satellite cell function in 3D, including adhesion, survival, expansion, and differentiation. Second, we will evaluate the extent to which engineered hydrogels allow for delivery and engraftment of GFP+ muscle satellite cells in the diaphragm of mdx/mTR mice and the extent to which the diaphragm’s function improves. Successful outcomes in this work will have broad significance and impact by demonstrating the potential of this strategy as a treatment for respiratory failure in DMD patients. Rather than relying on mechanically assisted ventilation, a patient receiving this treatment can benefit from an extended and improved quality of life. Additionally, this work will build on a broader goal to demonstrate that designing biomaterials for stem cell delivery and engraftment to musculoskeletal tissue is a feasible strategy for encouraging regeneration of the targeted tissue.

项目摘要 杜兴氏肌营养不良症 (DMD) 是一种 X 连锁遗传病，约 3,500 名新生儿男性中就有 1 人受影响， 其特点是进行性肌肉萎缩和无力，因此患者会出现卧床不起的症状。 残疾、心力衰竭和呼吸衰竭，后者是过早死亡的主要原因。 目前的呼吸护理治疗仍然是姑息治疗，因为 DMD 是导致 DMD 的主要原因，无法治愈。 DMD 是指功能性肌营养不良蛋白的缺失，这是一种在肌膜之间提供结构支持的蛋白质 恢复肌营养不良蛋白的策略是将卫星细胞移植到目标肌肉。 虽然这种策略并不是治疗全身 DMD 的有效方法，但膈肌 由于卫星细胞在呼吸功能中发挥着至关重要的作用，因此它为卫星细胞的输送提供了一个可行且重要的目标。 卫星细胞成功植入膈肌后，肌营养不良蛋白、肌肉兴奋性和 呼吸功能可以恢复，延长DMD患者的预期寿命，提高生活质量 通过潜在地绕过机械通气的需要将卫星细胞输送到膈肌。 由于移植细胞的植入、存活和功能欠佳，以及 该项目试图通过隔膜的薄尺寸和深位置来克服这些障碍。 设计一种基于合成水凝胶的生物活性细胞注射载体，将卫星细胞递送至营养不良者 隔膜并促进移植细胞的存活、扩张、分化和植入，以改善 该提案的目标将逐步实现。首先，我们将进行设计。 用粘附肽功能化的合成水凝胶可维持和指导肌肉卫星细胞的功能 3D，包括粘附、存活、扩张和分化。 其次，我们将评估其程度。 工程水凝胶可以将 GFP+ 肌肉卫星细胞输送并植入到膈肌中 mdx/mTR 小鼠以及膈肌功能改善的程度。 通过展示该策略作为治疗方法的潜力，将具有广泛的意义和影响 DMD 患者呼吸衰竭，而不是依赖机械辅助通气。 此外，这项治疗将受益于延长和改善生活质量。 更广泛的目标是证明设计用于干细胞输送和植入的生物材料 肌肉骨骼组织是促进目标组织再生的可行策略。