Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia

Fibroblast activation protein-alpha (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP(+) cells, we find that they reside in most tissues of the adult mouse. FAP(+) cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP(+) cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP(+) stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia. FAP+ cells were sorted from two mesenchymal tissues, visceral adipose and skeletal muscle, and from an epithelial organ, the pancreas. These were compared to MEFs. Cells were isolated in duplicate experiments and these were analysed separately. These were compared to previously published publicly available CD4+ T-cell subset data.成纤维细胞活化蛋白-α（Fibroblast activation protein-alpha, FAP）可特异性标记人类癌症与慢性炎症病灶中的间充质来源基质细胞。在癌症小鼠模型中，这类细胞已被证实具有免疫抑制活性，但针对其在正常组织中的分布与功能的研究仍相对有限。 借助一种可实现FAP阳性（FAP(+)）细胞生物发光成像的转基因小鼠品系，我们发现这类细胞广泛存在于成年小鼠的绝大多数组织中。 从骨骼肌、脂肪组织与胰腺三个部位分离得到的FAP(+)细胞具有高度相似的转录组特征，提示它们拥有共同的细胞谱系来源。 骨骼肌中的FAP(+)细胞是局部卵泡抑素（follistatin）的主要产生来源，而骨髓中的FAP(+)细胞则表达Cxcl12与KitL基因。 对这类细胞进行实验性清除会导致肌肉量丢失，并分别削弱B细胞生成与红细胞生成过程，揭示了它们在维持正常肌肉量与造血功能中的关键作用。 值得注意的是，在可移植与自发癌症小鼠模型中，当出现癌症诱导的恶病质与贫血时，上述组织中的这类细胞均发生了显著改变。 据此推测，FAP(+)基质细胞可能在癌症的两类不良结局中发挥作用：肿瘤对这类细胞的招募可导致免疫监视失效，而正常组织中这类细胞的异常改变则会促成恶病质与贫血这类副肿瘤综合征。 研究人员从两种间充质组织——内脏脂肪与骨骼肌，以及上皮器官胰腺中分离得到FAP(+)细胞，并将其与小鼠胚胎成纤维细胞（Mouse Embryo Fibroblasts, MEFs）进行对比。实验以重复操作开展，各重复样本单独进行分析，并与已公开发表的CD4+ T细胞亚群数据集进行比较。