Nerve Repair through Muscle Progenitor Cell Transplantation

通过肌肉祖细胞移植修复神经

• 批准号: 8426241
• 负责人: Johnny Huard
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426241
• 关键词: Adult; Applications Grants; Area; Atrophic; Axon; Biological Assay; Blood Vessels; Bone Marrow Transplantation; Brain-Derived Neurotrophic Factor; Cardiac; Cell Differentiation process; Cell Therapy; Cells; Cues; Data; Defect; Endothelial Cells; Fluorescence-Activated Cell Sorting; Goals; Growth; Healed; Heart; Human; Immobilized Cells; Implant; In Vitro; Inflammatory; Injection of therapeutic agent; Injury; Light; Mediating; Mus; Muscle; Musculoskeletal; Musculoskeletal System; Myoblasts; Myocardium; Natural regeneration; Nerve; Nerve Fibers; Nerve Regeneration; Neuroglia; Neurons; Outcome; Pericytes; Peripheral Nerves; Play; Population; Process; Proliferating; Qualifying; Reporting; Research; Site; Skeletal Muscle; Stem cell transplant; Stem cells; Suspension substance; Suspensions; Techniques; Therapeutic; Time; Tissues; Transplantation; Vascular Endothelial Growth Factors; angiogenesis; articular cartilage; base; bone; functional restoration; healing; implantation; improved; in vivo; indexing; injured; loss of function; muscle transplantation; nerve injury; regenerative; repaired; research study; scaffold; sciatic nerve; stressor; tissue repair

DESCRIPTION (provided by applicant): Muscle Progenitor Cells (MPCs) isolated from skeletal muscle have been shown to be both multipotent and of significant therapeutic value for the repair of various tissues of the musculoskeletal system, including skeletal and cardiac muscles, bone and articular cartilage, yet their ability to undergo neurogenic differentiation has not been fully investigated. We have recently observed that mice and human MPCs are capable of undergoing in vitro and in vivo neurogenic and glial cell differentiation, and inducing functionl healing of sciatic nerve defects in mice. The repair process, determined by histological and immunohistochemical analyses, were also validated by a functional assay (sciatic functional index). Although we have reported that both murine MPCs (mMPCs) and human MPCs (hMPCs) promoted axonal in-growth through their differentiation into glial cells, it is likely that the use of a scaffold to immobilize the injected cells at the injury site could further promote nerve repair. Since we have recently shown that the use of cell sheets as a stem cell delivery vehicle, which immobilizes the cells at the site of injury, further improved the beneficial effect imparted by the stem cells on the injured cardiac and ligamentous tissues, we are proposing to characterize whether the nerve repair process could be enhanced, through the use of a cell sheet comprised of MPCs (Aim #1). Since we have observed that the regenerative potential of MPCs in various tissues correlates with the ability of the cells to induce angiogenesis, we posit that a similar mechanism may explain the beneficial effect imparted by the MPCs in nerve repair. Indeed, it has been observed that VEGF administration can support the growth of regenerating nerve fibers through the process of angiogenesis; moreover, the beneficial effect imparted by bone marrow transplantation on nerve repair appears to occur through the secretion of various trophic factors that promote axon angiogenesis. We are proposing to determine the influence that angiogenesis plays in the nerve healing process (Aim #2) through gain and loss of function experiments using VEGF and sFlt-1 expressing MPCs. Successful completion of these aims will not only provide exciting results for quantitative evidence of the efficacy of MPC transplantation to improve nerve healing, but could also shed light on the mechanism(s) of action by which progenitor cells interact with the microenvironment (especially via angiogenesis) at the site of nerve injury. PUBLIC HEALTH RELEVANCE: This grant application focuses on the use of muscle-derived progenitor cells to improve peripheral nerve repair through the use of cell sheets as a new delivery vehicle to immobilize progenitor cells at the site of injury to further promote nerve repar (Aim 1) and to determine the influence that angiogenesis (Aim 2) has on the repair process mediated by muscle progenitor cells during nerve regeneration.

描述（由申请人提供）：从骨骼肌中分离出来的肌肉祖细胞（MPC）既是多功能物质，又具有显着的治疗价值，可用于修复肌肉骨骼系统的各种组织，包括骨骼和心脏肌肉，骨骼和关节软骨的能力，尚未对神经根源进行了全面研究。我们最近观察到，小鼠和人类MPC能够在体外和体内神经源和神经胶质细胞分化，并诱导小鼠坐骨神经缺陷的功能愈合。通过组织学和免疫组织化学分析确定的修复过程也通过功能分析（坐骨神经功能指数）验证。尽管我们报告说，鼠MPC（MMPC）和人类MPC（HMPC）都通过分化为神经胶质细胞促进了轴突的增长，但很可能很可能 使用脚手架固定损伤部位的注射细胞可以进一步促进神经修复。由于最近我们已经表明，将细胞表作为干细胞递送工具（将损伤部位的细胞固定在干细胞递送工具中）进一步改善了干细胞对受伤的心脏和韧带组织所产生的有益效果，因此我们建议通过使用MPC组成MPC（aim aid aim aim x 1）来表征神经修复过程是否可以增强神经修复过程。 由于我们已经观察到各种组织中MPC的再生潜力与细胞诱导血管生成的能力相关，因此我们认为一种相似的机制可以解释MPC在神经修复中赋予的有益效果。确实，已经观察到，VEGF给药可以通过血管生成过程支持再生神经纤维的生长。此外，骨髓移植对神经修复的有益作用似乎是通过分泌各种营养因子来促进轴突血管生成的。我们提议通过使用VEGF和SFLT-1表达MPC的功能实验来确定血管生成在神经愈合过程中发挥作用（AIM＃2）的影响。这些目标的成功完成不仅将为MPC移植以改善神经愈合的功效的定量证据提供令人兴奋的结果，而且还可以阐明祖细胞在神经损伤部位与微环境（尤其是通过血管生成）相互作用的作用机制。 公共卫生相关性：该赠款的申请重点是使用肌肉衍生的祖细胞通过将细胞表作为一种新的递送工具来改善周围神经修复，以将祖细胞固定在受伤部位，以进一步促进神经repar（AIM 1）（AIM 1）并确定肌肉生成（AIM 2）对修复过程的影响（AIM 2）对肌肉培养细胞的介导了肌肉再生型的介导。