PDF(Pubmed)
Abstract：
In human dystrophies, progressive muscle wasting is exacerbated by ectopic deposition of fat and fibrous tissue originating from fibro/adipogenic progenitors (FAPs). In degenerating muscles, the ability of these cells to promote successful healing is attenuated, and FAPs aberrantly expand and differentiate into adipocytes and fibroblasts. Thus, arresting the fibro/adipogenic fate of FAPs, without affecting their physiological role, represents a valuable therapeutic strategy for patients affected by muscle diseases. Here, using a panel of adipose progenitor cells, including human-derived FAPs, coupled with pharmacological perturbations and proteome profiling, we report that LY2090314 interferes with a genuine adipogenic program acting as WNT surrogate for the stabilization of a competent β-catenin transcriptional complex. To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined a poly-ethylene-glycol-fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound effectively represses adipogenesis at higher 3D scale, thus indicating the potential for LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles.
摘要：
在人类营养不良中，来自纤维/脂肪原细胞（FAP）的脂肪和纤维组织的异位沉积加剧了进行性肌肉萎缩。在退化的肌肉中，这些细胞辅助成功愈合的能力减弱，FAP异常扩增并分化为脂肪细胞和成纤维细胞。因此，阻止FAP的纤维脂肪源命运，在不影响其生理作用的情况下，对于受肌肉疾病影响的患者来说，这是一种有价值的治疗策略。这里,使用一组脂肪祖细胞，包括人类来源的FAP，以及药理学扰动和蛋白质组分析，我们报告说,LY2090314干扰了一个真正的成脂程序,该程序作为WNT替代来稳定合格的b-catenin转录复合物.为了预测LY2090314在限制人体肌肉脂肪异位沉积方面的有益影响，我们将聚-乙烯-乙二醇-纤维蛋白原仿生基质与这些祖细胞相结合，以创建脂肪生成的小型化3D模型。使用这个可扩展的系统，我们证明了两位数纳摩尔剂量的这种化合物在更高的3D尺度上有效抑制脂肪生成，从而为使用LY2090314限制营养不良肌肉中FAP衍生的脂肪浸润提供了具体证据。
