Endogenous stem cells promote regeneration of muscle in rotator cuff repair

内源干细胞促进肩袖修复中的肌肉再生

• 批准号: 10362392
• 负责人: Brian Feeley
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362392
• 关键词: Achievement; Activities of Daily Living; Address; Adipose tissue; Affect; Age; Aging; Agonist; American; Anterior; Atrophic; Cells; Chronic; Clinical; Clinical Research; Disease; Economic Burden; Fatty acid glycerol esters; Fibrosis; Future; Gene Expression; Gene Expression Profile; Health; Health Care Costs; Human; Impairment; In Vitro; Infiltration; Injury; Lead; Magnetic Resonance Imaging; Modeling; Mus; Muscle; Muscle Development; Muscle satellite cell; Muscular Atrophy; Natural regeneration; Operative Surgical Procedures; Pathologic; Patient-Focused Outcomes; Patients; Phenotype; Population; Process; Productivity; Property; Quality of life; Recovery; Role; Rotator Cuff; Source; Tendon structure; Time; Tissue Differentiation; Tissues; Translating; Upper Extremity; Wages; age related; aging population; arm; cell motility; clinically relevant; effective therapy; human data; improved; in vitro regeneration; in vivo; in vivo Model; limb injury; medical attention; military veteran; muscle degeneration; muscle regeneration; novel therapeutic intervention; older patient; patient population; physically handicapped; progenitor; regeneration potential; regenerative; repaired; response; rotator cuff tear; stem cell proliferation; stem cells; supraspinatus muscle; surgery outcome; targeted treatment; tissue regeneration; treatment strategy

Rotator cuff (RC) tears are the most common upper extremity injury, with over two million Americans seeking medical attention annually. With the increased age of our veterans' population, RC tears are becoming a vital health issue for the VA patients. Secondary muscle degradation following tears, including atrophy and fatty infiltration (FI) are critical factors that directly determine the clinical outcome of patients with this injury. Muscle residential fibro/adipogenic progenitor (FAP) cells have been found to be the major cellular source of fat in RC muscle after massive tendon tears. We recently discovered that these cells represent a heterogeneous cell population capable of both regenerative and pathologic responses to muscle injury. Importantly, FAPs can differentiate into a beige adipose tissue (BAT) phenotype that may have a role in promoting muscle recovery and regeneration in chronic injury states. However, at this time, no studies have evaluated factors that influence the fate of FAPs in human cuff tears, nor what FAP regenerative capabilities could be in clinical scenarios such as rotator cuff repair. Clinically, both patient age and size of the rotator cuff tear have been found to be independent factors that associate with poorer muscle quality and worse patient outcomes. However, the interplay between patient and rotator cuff tear size and their influence on muscle stem cell proliferation, differentiation, and regenerative capabilities is not known at this time. To address this problem, we will perform the first large-scale clinical study evaluating FAP phenotypic properties in patients with rotator cuff tears. Expanding on our promising mouse studies that show FAPs are capable of stimulating muscle regeneration, we will perform a rigorous set of studies that will determine the regenerative capabilities of human FAPs in this clinically relevant scenario to confirm our hypothesis that the ability of FAPs to promote healthy muscle regeneration is dependent on the size of the tear and age of the patient due to changes in FAP gene expression. By the end of this study, we will understand how clinically important factors (age, tear size) affect the degeneration and regeneration potential of human FAPs, which should provide critical information on how these endogenous stem cells can be leveraged to improve precision guided patient outcomes with targeted therapeutic strategies in the near future.

肩袖（RC）撕裂是最常见的上肢损伤，超过200万美国人 每年都去看医生。随着我们的退伍军人的人口年龄的增加，钢筋混凝土眼泪是 成为退伍军人事务部病人的重要健康问题撕裂后继发性肌肉退化， 包括萎缩和脂肪浸润（FI）是直接决定临床 这种损伤的患者。肌肉驻留细胞/脂肪形成祖细胞（FAP）具有 被发现是大规模肌腱撕裂后RC肌肉中脂肪的主要细胞来源。我们最近 发现这些细胞代表了一种异质细胞群，能够再生和再生， 肌肉损伤的病理反应。重要的是，FAP可以分化成米色脂肪组织， (BAT)表型可能在促进慢性损伤中的肌肉恢复和再生中起作用 states.然而，在这个时候，没有研究评估影响FAPs命运的因素， 人类袖带撕裂，也没有什么FAP再生能力可以在临床情况下，如旋转肌 袖带修复。临床上，患者年龄和肩袖撕裂的大小都被发现是 与较差的肌肉质量和较差的患者结果相关的独立因素。然而，在这方面， 患者与肩袖撕裂大小相互作用及其对肌干细胞的影响 增殖、分化和再生能力目前尚不清楚。为了解决这个 问题，我们将进行第一个大规模的临床研究，评估FAP的表型特性， 肩袖撕裂患者。扩大我们有前途的小鼠研究，表明FAP能够 刺激肌肉再生，我们将进行一系列严格的研究， 在这种临床相关的情况下，人类FAP的再生能力证实了我们的假设 FAP促进健康肌肉再生的能力取决于撕裂的大小， 由于FAP基因表达的变化，患者的年龄。到本研究结束时，我们就会明白 临床上重要的因素（年龄、泪液大小）如何影响 人类FAP，这应该提供关于这些内源性干细胞如何被 利用近距离有针对性的治疗策略， 未来