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