PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity.
PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity.
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DOI：
10.1101/gad.260554.115
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发表时间：
2015-06-01
影响因子：
10.5
通讯作者：
Olson LE
中科院分区：
文献类型：
--
作者：
Iwayama T;Steele C;Yao L;Dozmorov MG;Karamichos D;Wren JD;Olson LE
脂肪组织纤维化发生在肥胖期间，并与代谢功能障碍有关。Iwayama等人发现白色脂肪组织中的血管周围细胞是纤维/脂肪形成的祖细胞，并表明PDGFRα靶向祖细胞的可塑性是一种纤维化机制。纤维化是一种常见的疾病过程，纤维化细胞通过分泌紊乱的细胞外基质（ECM）扰乱器官功能。脂肪组织纤维化发生在肥胖期间，并与代谢功能障碍有关，但纤维化细胞的起源仍不清楚。在这里，我们使用一个发育模型来研究白色脂肪组织（WAT）的血管周围细胞及其引起器官纤维化的潜力。我们发现nesting - cre转基因靶向WAT的血管周围细胞（外表皮细胞和周细胞样细胞），nesting - gfp特异性标记周细胞样细胞。血管周围细胞中PDGFRα信号的激活导致它们转化为ecm合成的纤维化细胞。在这种转变发生之前，PDGFRα信号上调mTOR信号和核糖体生物发生途径，并扰乱与细胞生长和组织稳态有关的表观遗传印迹基因网络的表达。巢蛋白- gfp +细胞在体外分化为脂肪细胞，移植到受体小鼠体内形成WAT。然而，PDGFRα信号传导抑制脂肪形成，转而产生原纤维化细胞，导致移植实验中纤维化WAT。这些结果确定了血管周围细胞是WAT的纤维/脂肪生成祖细胞，并表明PDGFRα靶向祖细胞的可塑性是促纤维化的机制。
Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction. Iwayama et al. identify perivascular cells as fibro/adipogenic progenitors in white adipose tissue and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism. Fibrosis is a common disease process in which profibrotic cells disturb organ function by secreting disorganized extracellular matrix (ECM). Adipose tissue fibrosis occurs during obesity and is associated with metabolic dysfunction, but how profibrotic cells originate is still being elucidated. Here, we use a developmental model to investigate perivascular cells in white adipose tissue (WAT) and their potential to cause organ fibrosis. We show that a Nestin-Cre transgene targets perivascular cells (adventitial cells and pericyte-like cells) in WAT, and Nestin-GFP specifically labels pericyte-like cells. Activation of PDGFRα signaling in perivascular cells causes them to transition into ECM-synthesizing profibrotic cells. Before this transition occurs, PDGFRα signaling up-regulates mTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis. Isolated Nestin-GFP+ cells differentiate into adipocytes ex vivo and form WAT when transplanted into recipient mice. However, PDGFRα signaling opposes adipogenesis and generates profibrotic cells instead, which leads to fibrotic WAT in transplant experiments. These results identify perivascular cells as fibro/adipogenic progenitors in WAT and show that PDGFRα targets progenitor cell plasticity as a profibrotic mechanism.
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影响因子：
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作者：
Berry R;Jeffery E;Rodeheffer MS
通讯作者：
Rodeheffer MS
影响因子：
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作者：
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作者：
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作者：
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