Development of a Cell-Based Therapy to Improve Recovery Following Immobilization

开发基于细胞的疗法以改善固定后的恢复

• 批准号: 10200674
• 负责人: Marni D. Boppart
• 金额: $ 33.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200674
• 关键词: Adult; Bed rest; Biophysics; Blood capillaries; Blood flow; CSPG4 gene; Caliber; Cell Proliferation; Cell Therapy; Cells; Cues; Data; Development; Disease; Elderly; Endothelial Cells; Ensure; Evaluation; Exercise; Goals; Growth; Growth Factor; Healthcare Systems; Hindlimb Suspension; Hydrogels; Image; Immobilization; In Vitro; Individual; Injury; Label; Laboratories; Longevity; MCAM gene; Mechanics; Messenger RNA; MicroRNAs; Modeling; Movement; Multipotent Stem Cells; Mus; Muscle; Muscle function; Muscular Atrophy; Outcome; Peptides; Perfusion; Pericytes; Peripheral; Permeability; Physical Rehabilitation; Physical therapy; Physiological; Procedures; Property; Proteins; Quality of life; Recovery; Regulation; Rehabilitation therapy; Research Personnel; Role; Skeletal Muscle; Source; Stimulus; Stromal Cells; Structure; System; Testing; Thinness; Time; Transfer RNA; Transplantation; Wild Type Mouse; Work; age related; aged; aging population; base; clinically relevant; conditional knockout; disability; exosome; improved; in vivo; innovation; mechanotransduction; muscle form; muscle strength; myogenesis; neurotrophic factor; novel; novel therapeutic intervention; paracrine; pre-clinical; preclinical study; prevent; programs; regenerative growth; regenerative therapy; rehabilitation strategy; release factor; repaired; response; severe injury; single photon emission computed tomography; skeletal muscle wasting; stem; stem cells

ABSTRACT Long-term immobilization or extended bed rest following severe injury or disease can initiate rapid and significant loss of skeletal muscle mass and function. Recovery may be slow and long-term disability is a potential outcome, particularly in older adults. Physical rehabilitation is commonly prescribed for individuals subjected to long-term bed rest, yet mobility may be severely compromised in older adults and intensity of movement may not be sufficient to facilitate full recovery. Thus, novel regenerative therapies are necessary to maximize positive outcomes associated with rehabilitation to prevent or treat long-term disability associated with immobilization in older adults. Pericytes are multipotent stem cells that reside around microvessels and capillaries and provide important structural and paracrine support necessary to regulate vessel permeability, vessel diameter and blood flow, endothelial cell proliferation, and stabilization of newly formed capillaries. Data from our laboratory demonstrate that perivascular stem and stromal cells are highly sensitive to biophysical cues in the niche, and that pericyte transplantation in combination with a physiological stimulus (exercise) can promote the release of regenerative growth and neurotrophic factors that positively influence skeletal muscle repair, growth, and strength. Thus, pericytes represent a clinically relevant cell source to expedite recovery of muscle mass and strength following a short or prolonged period of immobilization. The specific objective of this proposal is to exploit the mechanosensing properties of pericytes for the purpose of developing a new and exciting cell-based skeletal muscle rehabilitation strategy. Our central hypothesis is that there are pericyte subpopulations in skeletal muscle that are divergent in their response to a mechanical stimulus and uniquely assist with the recovery of muscle mass and strength following remobilization. Thus, this work seeks to: 1) determine the impact of mechanical strain on pericyte function, 2) determine the contribution of pericytes to skeletal muscle mass recovery following a period of immobilization in mice, and 3) develop a pericyte-derived exosome-based therapy for skeletal muscle recovery following a period of immobilization in mice. The work is highly innovative given the potential to identify a specific perivascular stem/stromal cell source with exceptional potential to recover skeletal muscle mass and function following a period of immobilization. The proposed work is significant because it is expected to create a superior pre-clinical strategy that can prevent and/or treat age-related disabilities, improving the quality of life for our growing aged population and reducing burden on the US healthcare system.

抽象的 严重受伤或疾病后的长期固定或延长的床休息可以迅速启动，并且 骨骼肌质量和功能的显着丧失。恢复可能很慢，长期残疾是 潜在的结果，特别是在老年人中。通常针对个人规定身体康复 经受长期床休息，但在老年人中可能会严重损害流动性和强度 运动可能不足以促进完全康复。因此，新颖的再生疗法对于 最大化与康复相关的积极结果，以预防或治疗长期残疾 老年人固定。周细胞是围绕微血管和 毛细血管并提供重要的结构和旁分泌支持，以调节血管渗透性， 血管直径和血流，内皮细胞增殖以及新形成的毛细血管的稳定。数据 从我们的实验室表明，血管周茎和基质细胞对生物物理高度敏感 利基市场中的提示，以及生理刺激（锻炼）结合的周细胞移植可以 促进释放再生生长和神经营养因素，从而积极影响骨骼肌肉 维修，生长和力量。因此，周细胞代表临床上相关的细胞来源，以加快恢复 固定时期短或长时间后，肌肉质量和力量。这个的具体目标 建议是利用周细胞的机械感应特性，以开发新的和 令人兴奋的基于细胞的骨骼肌肉康复策略。我们的中心假设是有周围 骨骼肌的亚群在对机械刺激和 独特的协助恢复肌肉质量和强度后的力量。因此，这项工作 寻求：1）确定机械应变对周细胞功能的影响，2）确定 一段时间固定在小鼠中后至骨骼肌质量恢复的周细胞，3） 一段时间固定在 老鼠。鉴于可能识别特定的周围茎/基质细胞的潜力，这项工作具有很高的创新性 恢复骨骼肌质量和功能的潜力极有潜力的来源 固定。拟议的工作很重要，因为它有望创建出色的前临床前 可以预防和/或治疗与年龄相关的残疾，改善我们衰老的生活质量的策略 人口和减轻美国医疗保健系统的负担。