Replicative Potential of Muscle Stem Cells

肌肉干细胞的复制潜力

• 批准号: 10685322
• 负责人: Bradley B Olwin
• 金额: $ 50.73万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685322
• 关键词: Address; Affect; Aging; Automobile Driving; Basal lamina; Cell Count; Cell Cycle; Cell Maintenance; Cell physiology; Cells; Complex; Coupled; Data; Daughter; Dependence; Elements; Epidermal Growth Factor Receptor; FGFR1 gene; Goals; Health; Health Care Costs; Healthcare; Hospitalization; Injury; Knowledge; Life; MAP Kinase Gene; Mediating; Messenger RNA; Minor; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle function; Muscle satellite cell; Mutate; Myoblasts; Myopathy; Neuromuscular Diseases; Nuclear; Pathway interactions; Performance; Phenotype; Physiological; Population; Proliferating; Quality of life; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Source; Testing; age related; aged; daughter cell; experimental study; improved; muscle aging; mutant; p38 Mitogen Activated Protein Kinase; patient home care; polarized cell; postmitotic; receptor; satellite cell; self-renewal; single cell sequencing; skeletal muscle wasting; stem cell population; stem cells; therapeutic development

Project Summary Skeletal muscle tissue is maintained and can be dynamically modeled to fit ongoing needs by changes in muscular activity. Myofibers, the primary cells that comprise the contractile elements of skeletal muscle, are post-mitotic and maintained by a pool of stem cells, termed satellite cells, which are localized to a niche be- tween the myofiber and overlying basal lamina. Loss of mobility arising from loss of skeletal muscle function occurs following an injury, is an inevitable consequence of aging and a consequence of many neuromuscular diseases, the latter two resulting in reduced quality of life and increased morbidity, requiring hospitalization or home care, significantly raising health care costs. These complex physiological changes are well documented but the mechanisms responsible for these changes are not understood. SCs (satellite cells) maintain muscle throughout life, providing a constant source of new myonuclei that appears to occur primarily by asymmetric division. Loss of SC asymmetric division contributes to age-related losses of SC function during aging and to the dystrophic muscle phenotype. Enhancing the ability of SCs to di- vide asymmetrically improves strength in aged muscle and improves dystrophic muscle function. The depend- ence of skeletal muscle health on SC maintenance, which in turn requires SCs divide asymmetrically empha- sizes an essential role for SC asymmetric division that has not been adequately addressed. EGFR (epidermal growth factor receptor) and FGFR1 signaling promote SCs to divide asymmetrically, identifying these as two critical signaling pathways involved in maintaining SCs. Activation of EGFR signaling improves dystrophic muscle phenotypes and activation of FGFR1 signaling in SCs from aged muscle rescues asymmetric division restoring SC numbers to youthful levels and increases strength in aged mice, suggesting that SC asymmetric division is essential to maintain skeletal muscle health. The primary premise for the proposed experiments in this application is that driving SCs to divide asymmetrically improves muscle health. However, SCs comprise a minor population of cells within skeletal muscle (1-3%) and thus, how can improvement of SC health affect an entire muscle? To fulfill this knowledge gap, we plan to identify the pathways driving SCs to divide asymmetri- cally and elucidate the mechanisms by which stimulation of SC asymmetric division enhances skeletal muscle function.

项目摘要 骨骼肌组织得以维持，并且可以动态地建模，以适应通过改变骨骼肌组织来进行的持续需求。 肌肉活动。肌纤维是构成骨骼肌收缩成分的初级细胞， 有丝分裂后，由一池干细胞维持，称为卫星细胞，定位于一个小生境， 在肌纤维和上覆的基底层之间。骨骼肌功能丧失导致活动能力丧失 在受伤后发生，是衰老的必然结果，也是许多神经肌肉疾病的结果。 疾病，后两者导致生活质量下降和发病率增加，需要住院治疗，或 家庭护理，大大提高了医疗保健费用。这些复杂的生理变化有据可查 但造成这些变化的机制尚不清楚。 SC（卫星细胞）在整个生命过程中维持肌肉，提供新肌核的恒定来源， 似乎主要通过不对称分裂发生。SC不对称分裂的丧失有助于年龄相关的 衰老过程中SC功能的丧失以及营养不良性肌肉表型。提高供应链的能力， VIDE不对称地提高了老年肌肉的力量，并改善了营养不良的肌肉功能。依赖- 骨骼肌健康对SC维持的影响，这反过来又要求SC不对称地分裂， 规模的一个重要作用，SC不对称分工，尚未得到充分解决。EGFR（表皮 生长因子受体）和FGFR 1信号促进SC不对称分裂，将其鉴定为两种 参与维持SC的关键信号通路。EGFR信号传导的活化改善营养不良性 肌肉表型和FGFR 1信号在来自老年肌肉的SC中的激活拯救了不对称分裂 使SC数量恢复到年轻水平，并增加老年小鼠的力量，这表明SC不对称 分裂是维持骨骼肌健康的关键。所提议的实验的主要前提是， 这种应用是驱动SC不对称地分裂改善了肌肉健康。然而，SC包括 骨骼肌内的细胞数量很少（1-3%），因此，SC健康的改善如何影响骨骼肌内的细胞数量？ 整个肌肉？为了填补这一知识空白，我们计划确定驱动SC分裂不对称的途径， 阐明刺激SC不对称分裂增强骨骼肌的机制 功能

项目成果

Post-Transcriptional Regulation in Skeletal Muscle Development, Repair, and Disease.

• DOI: 10.1016/j.molmed.2020.12.002
• 发表时间: 2020-12
• 期刊: Trends in molecular medicine
• 影响因子: 13.6
• 作者: K. Weskamp;B. Olwin;R. Parker

Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome.

肌肉干细胞功能障碍会损害唐氏综合症小鼠模型的肌肉再生。

• DOI: 10.1038/s41598-018-22342-5
• 发表时间: 2018
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pawlikowski,Bradley;Betta,NicoleDalla;Elston,Tiffany;Williams,DarianA;Olwin,BradleyB
• 通讯作者: Olwin,BradleyB

The regenerating skeletal muscle niche drives satellite cell return to quiescence.

• DOI: 10.1016/j.isci.2022.104444
• 发表时间: 2022-06-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Cutler, Alicia A.;Pawlikowski, Bradley;Wheeler, Joshua R.;Dalla Betta, Nicole;Elston, Tiffany;O'Rourke, Rebecca;Jones, Kenneth;Olwin, Bradley B.
• 通讯作者: Olwin, Bradley B.