Diversity Supplement for: Engineered Asymmetric Hydrogel for Muscle Stem Cell Polarity and Fate Specification

多样性补充：用于肌肉干细胞极性和命运规范的工程不对称水凝胶

• 批准号: 10807823
• 负责人: Woojin Han
• 金额: $ 4.23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807823
• 关键词: Adipocytes; Apoptosis; Biology; Biomechanics; Biophysics; Cell Polarity; Cell division; Cell physiology; Cells; Chronic; Communication; Disease; Engineering; Extracellular Matrix; Fibrosis; Functional disorder; Goals; Hydrogels; Infiltration; Inflammation; Injury; Ion Channel; Knowledge; Muscle; Muscle satellite cell; Myofibroblast; Natural regeneration; Outcomes Research; Parents; Piezo 1 ion channel; Proliferating; Research; Role; Signal Transduction; Skeletal muscle injury; Specific qualifier value; Supporting Cell; design; druggable target; interstitial; manufacture; mechanical signal; mechanotransduction; mesenchymal stromal cell; muscle regeneration; paracrine; progenitor

PROJECT ABSTRACT Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal stromal cells that support muscle satellite cell (MuSC) function, including activation, proliferation, and differentiation. Unlike MuSCs, these cells reside within the muscle interstitial space and thus communicate with MuSCs through paracrine factors. In normal muscle regeneration, activated FAPs undergo apoptosis as the inflammation resolves and regeneration proceeds. However, in chronic muscle injuries and diseases, activated FAPs persist and differentiate into either myofibroblasts or adipocytes that drive fibrosis and fatty infiltration, respectively. However, to date, there is a limited understanding of how the FAPs interact with their microenvironment to regulate their activation, proliferation, and fate determination. In this Diversity Supplement application, we will determine the mechanistic role by which FAPs respond to passive and active mechanical signals via mechanosensitive PIEZO1 ion channel. This research strengthens and expands the scope of the parent R01 project by revealing how FAPs integrate biophysical signals derived from their synthetic niche and provide additional means to control MuSC polarity and cell divisions in the engineered asymmetric niche. Towards this goal, Aim 1 will determine how PIEZO1 regulates FAPs activation, proliferation, and differentiation. Aim 2 will determine how PIEZO1 in FAPs regulates extracellular matrix stiffness mechanosensing. Aim 3 will determine how PIEZO1 in FAPs regulates responsivity to tensile loading and unloading. The outcomes of this research will advance the current knowledge of FAPs biology, identify druggable targets to mitigate fibrosis and fatty infiltration in skeletal muscle injuries and diseases, and inform the design of ex vivo FAPs manufacturing platform for expanding MuSCs and/or producing FAPs secretome for acellular therapies.

项目摘要 纤维 - 辅助祖细胞（FAP）是支持肌肉的间质基质细胞 卫星细胞（MUSC）功能，包括激活，增殖和分化。与MUSC不同，这些细胞 驻留在肌肉间质空间内，从而通过旁分泌因素与MUSC沟通。在 正常的肌肉再生，激活的FAP会随着炎症的消退和再生而经历凋亡 收益。但是，在慢性肌肉损伤和疾病中，激活的FAP持续并分化为 分别驱动纤维化和脂肪浸润的肌纤维细胞或脂肪细胞。但是，迄今为止，有一个 对FAP如何与微环境相互作用以调节其激活的有限了解， 增殖和命运决定。在这种多样性补充应用中，我们将确定机械 FAP通过机械敏感的压电通道对被动和主动机械信号做出反应的角色。 这项研究通过揭示FAP的整合方式来增强和扩大父r01项目的范围 源自其合成生态位的生物物理信号，并提供了控制MUSC极性和 工程非对称利基市场中的细胞分裂。达到这个目标，AIM 1将决定Piezo1如何调节 FAP激活，增殖和分化。 AIM 2将确定FAP中的Piezo1如何调节 细胞外基质刚度机械感应。 AIM 3将确定FAP中的Piezo1如何调节响应性 进行拉伸加载和卸载。这项研究的结果将提高当前FAP的知识 生物学，确定可药物靶标可减轻骨骼肌损伤和疾病中的纤维化和脂肪浸润， 并告知用于扩展MUSC和/或生产FAPS的离体FAPS制造平台的设计 细胞疗法的分泌组。