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 严重损伤或疾病后长期不活动或长期卧床可能会导致快速和 骨骼肌质量和功能显着丧失。恢复可能会很缓慢并且会造成长期残疾 潜在的结果，特别是对于老年人。物理康复通常是针对个人进行的 长期卧床休息，但老年人的活动能力和活动强度可能会受到严重影响 运动可能不足以促进完全康复。因此，需要新的再生疗法 最大限度地提高与康复相关的积极成果，以预防或治疗相关的长期残疾 老年人需要固定。周细胞是驻留在微血管周围的多能干细胞 毛细血管并提供调节血管渗透性所需的重要结构和旁分泌支持， 血管直径和血流量、内皮细胞增殖以及新形成的毛细血管的稳定性。数据 我们实验室的研究表明，血管周围干细胞和基质细胞对生物物理高度敏感 生态位中的线索，周细胞移植与生理刺激（运动）相结合可以 促进再生生长和神经营养因子的释放，对骨骼肌产生积极影响 修复、生长和力量。因此，周细胞代表了临床相关的细胞来源，可加速细胞的恢复。 短期或长期固定后的肌肉质量和力量。此次活动的具体目标 建议是利用周细胞的机械传感特性来开发新的和 令人兴奋的基于细胞的骨骼肌康复策略。我们的中心假设是存在周细胞 骨骼肌中对机械刺激的反应不同的亚群 独特地协助复健后肌肉质量和力量的恢复。因此，这部作品 旨在：1) 确定机械应变对周细胞功能的影响，2) 确定 小鼠固定一段时间后周细胞到骨骼肌质量的恢复，以及 3) 开发 基于周细胞衍生的外泌体的疗法，用于一段时间的固定后骨骼肌的恢复 老鼠。鉴于有可能识别特定的血管周围干/基质细胞，这项工作具有高度创新性 经过一段时间的治疗后，具有恢复骨骼肌质量和功能的非凡潜力的来源 固定化。拟议的工作意义重大，因为它有望创建一个优越的临床前 可以预防和/或治疗与年龄相关的残疾、改善老年人生活质量的策略 人口并减轻美国医疗保健系统的负担。