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: 10445294
• 负责人: Marni D. Boppart
• 金额: $ 33.79万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445294
• 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; 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; mechanical stimulus; 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.

摘要 严重受伤或疾病后长期固定或延长卧床休息可引发快速和 骨骼肌质量和功能的显著丧失。康复可能是缓慢的，长期残疾是一种 潜在后果，特别是在老年人中。身体康复通常是为个人开的处方。 长期卧床休息，但老年人的行动能力可能会严重受损， 行动可能不足以促进完全恢复。因此，新的再生疗法是必要的 最大限度地提高与康复相关的积极结果，以预防或治疗与之相关的长期残疾 在老年人身上有固定功能。周细胞是一种多能干细胞，存在于微血管周围， 毛细血管，并提供调节血管通透性所必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，以及新生毛细血管的稳定。数据 来自我们实验室的实验证明血管周围干细胞和基质细胞对生物物理高度敏感。 提示在利基，周细胞移植结合生理刺激(运动)可以 促进对骨骼肌有积极影响的再生生长和神经营养因子的释放 修复、成长和力量。因此，周细胞代表了一种临床上相关的细胞来源，以加速其恢复。 肌肉在短时间或长时间固定后的肌肉质量和力量。这样做的具体目标是 建议利用周细胞的机械传感特性来开发一种新的和 激动型基于细胞的骨骼肌康复策略。我们的中心假设是有周细胞 骨骼肌中对机械刺激反应不同的亚群 独一无二的帮助恢复肌肉质量和力量后的再动员。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 在小鼠固定一段时间后，周细胞到骨骼肌群的恢复，以及3)发展成 周细胞来源的外切体为基础的治疗骨骼肌固定后的一段时间 老鼠。鉴于有可能识别特定的血管周围干细胞/基质细胞，这项工作具有很高的创新性 在经过一段时间后，具有恢复骨骼肌质量和功能的特殊潜力的来源 动弹不得。这项拟议的工作意义重大，因为它有望创造一个更好的临床前 能够预防和/或治疗与年龄相关的残疾的战略，改善我们日益增长的老年人的生活质量 人口和减轻美国医疗体系的负担。

项目成果

Optimization of a pericyte therapy to improve muscle recovery after limb immobilization.

优化周细胞疗法以改善肢体固定后的肌肉恢复。

• DOI: 10.1152/japplphysiol.00700.2021
• 发表时间: 2022
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Wu,Yu-Fu;Lapp,Samuel;Dvoretskiy,Svyatoslav;Garcia,Gabriela;Kim,Michael;Tannehill,Amanda;Daniels,Laureen;Boppart,MarniD
• 通讯作者: Boppart,MarniD

The Cholesterol Metabolite 27HC Increases Secretion of Extracellular Vesicles Which Promote Breast Cancer Progression.

胆固醇代谢物 27HC 增加细胞外囊泡的分泌，从而促进乳腺癌进展。

• DOI: 10.1210/endocr/bqab095
• 发表时间: 2021
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Baek,AmyE;Krawczynska,Natalia;DasGupta,Anasuya;Dvoretskiy,SvyatoslavVictorovich;You,Sixian;Park,Jaena;Deng,Yu-Heng;Sorrells,JanetE;Smith,BrandiPatrice;Ma,Liqian;Nelson,AdamT;McDowell,HannahB;Sprenger,Ashabari;Henn,Madelin
• 通讯作者: Henn,Madelin