Fibroadipogenic progenitor cells as drivers of angiogenesis during muscle regeneration

摘要 骨骼肌占身体质量的近一半，容易受到创伤性损伤，尤其是 四肢。受损的肌肉质量和功能必须迅速恢复，以最大限度地减少身体扭曲 防止长期残疾。此外，糟糕的结果会给人们带来沉重的情感和经济负担。 关于受影响的个人及其家人。NICHD的一个理想目标是提高再生能力 通过使用新兴技术来激活人体自身的生长途径和过程。在……下面 大多数情况下，受损的肌肉通过协调的多细胞反应有效地再生 涉及肌肉干细胞(卫星细胞，SCs)、内皮细胞(ECs)和成纤维细胞或成纤维脂肪细胞 前体细胞(FAP)以及其他常驻和浸润性细胞类型。然而，在组织丢失之后 临界阈值(体积肌肉损失，VML)，不会发生组织再生，质量或 功能已恢复。亚阈值和亚阈值之间区别的分子和细胞机制 再生创面与非再生VML之间的关系尚不清楚，这对 制定转化性干预措施。一种新的损伤和再生的穿孔活检模型 PI的实验室使用小鼠臀大肌突出了FAP，ECs和 干细胞在成功的肌肉再生中的作用。一个关键的观察是，如果局部FAP被移除，两个血管生成 而肌肉发生失败，使阈值下损伤改为类似于VML。FAP是否会影响这一点 通过直接作用于内皮细胞、肌源性细胞或两者的关系尚不清楚。因此，本研究项目 建议：1)确认FAP在允许亚临界VML损伤愈合方面的要求；2)测试 候选分子Periostin拯救缺乏创面的微血管和肌纤维再生的能力 FAP；3)确定Periostin信号是否直接传递给ECs、肌源性细胞或两者；以及4)执行无偏见的 蛋白质组筛选由FAP直接分泌或在ECs或 FAPs可能促进完整肌肉再生的肌源性细胞。这些实验将利用 该团队在微血管成像、肌肉再生、FAPs生物学和生物材料方面的集体专业知识 识别、表征和功能测试区分肌肉的关键细胞和分子因子 成功治愈的伤病和无法治愈的伤病。如果成功，这项研究项目将确定 有可能被转化为旨在改善临床的治疗方法的分子和方法 残疾人的结果，从而解决了基本肌肉和应用肌肉中未得到满足的关键需求 生物学。

ABSTRACT Skeletal muscle comprises nearly half of body mass and is subject to traumatic injuries, particularly of the extremities. Damaged muscle mass and function must be restored promptly to minimize physical distortion and prevent long-term disabilities. Furthermore, poor outcomes impose significant emotional and financial burdens on affected individuals and their families. An aspirational goal of the NICHD is to advance the ability to regenerate human limbs by using emerging technologies to activate the body’s own growth pathways and processes. Under most circumstances damaged muscle is efficiently regenerated through a coordinated multicellular response involving muscle stem cells (satellite cells, SCs), endothelial cells (ECs), and fibroblasts or fibroadipogenic precursor cells (FAPs) as well as other resident and infiltrating cell types. However, after the loss of tissue over a critical threshold (volumetric muscle loss, VML), tissue regeneration does not occur and neither mass nor function are regained. The molecular and cellular mechanisms underlying the distinction between subthreshold, regenerating wounds vs. nonregenerating VML are not yet sufficiently understood, posing a critical roadblock to development of translational interventions. A novel punch biopsy model of injury and regeneration developed in the PI’s laboratory using the mouse gluteus maximus muscle highlights the sequential activity of FAPs, ECs, and SCs in successful muscle regeneration. A key observation is that if local FAPs are removed, both angiogenesis and myogenesis fail to occur, making the subthreshold injury instead resemble VML. Whether FAPs effect this relationship by direct actions on ECs, myogenic cells, or both is unknown. Therefore, this research project proposes to: 1) confirm the requirement for FAPs in permitting healing of a subcritical VML injury; 2) test the ability of a candidate molecule, periostin, to rescue microvascular and myofiber regeneration in wounds lacking FAPs; 3) determine whether periostin signals directly to ECs, myogenic cells, or both; and 4) perform an unbiased proteomic screen for additional signaling molecules either secreted directly by FAPs or induced in ECs or myogenic cells by FAPs that may promote the regeneration of intact muscle. These experiments will leverage the team's collective expertise in microvascular imaging, muscle regeneration, FAPs biology, and biomaterials to identify, characterize, and functionally test key cellular and molecular factors differentiating between muscle injuries which heal successfully and those which cannot. If successful, this research project will identify molecules and methods which have the potential to be translated into therapies designed to improve clinical outcomes for disabled individuals, thereby addressing a key unmet need in both basic and applied muscle biology.