Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis
Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis
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DOI：
10.2353/ajpath.2010.090517
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发表时间：
2010-01-01
影响因子：
6
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
--
作者：
Humphreys, Benjamin D.;Lin, Shuei-Liong;Duffield, Jeremy S.
了解肾脏肌成纤维细胞的起源具有重要意义，因为这些细胞在纤维化肾病中负责瘢痕的形成。最近的研究表明，上皮细胞是肌成纤维细胞的重要来源，其过程被描述为上皮细胞到间质细胞的转化；然而，缺乏体内确证性研究。为了定量评估肾上皮细胞对肌成纤维细胞的贡献，我们使用Cre/Lox技术对肾纤维化模型中的肾上皮进行基因标记和命运图。在转化生长因子β(1)处理后，这些小鼠体外培养的遗传标记的原代近端上皮细胞很容易诱导肌成纤维细胞的标记物。然而，使用红色荧光蛋白或β -半乳糖苷酶作为命运标记，我们没有发现上皮细胞在体内迁移到小管基底膜外并分化为间质肌成纤维细胞的证据。因此，尽管肾上皮细胞在体外可以获得间充质标记物，但它们在体内并不直接促进间质肌成纤维细胞的形成。谱系分析表明，在肾形成过程中，foxd1阳性（(+)）间充质细胞产生成体CD73（+）、血小板衍生生长因子受体β(+)、平滑肌肌动蛋白阴性间质周细胞，这些foxd1衍生间质细胞在纤维化过程中扩增分化为平滑肌肌动蛋白（+）肌成纤维细胞，占肌成纤维细胞的绝大多数。这些数据表明，直接针对体内周细胞分化的治疗策略可能有效地影响纤维化肾脏疾病。（美国病理学杂志，2010,176:85-97;DOI: 10.2353/ajpath.2010.090517）
Understanding the origin of myofibroblasts in kidney is of great interest because these cells are responsible for scar formation in fibrotic kidney disease. Recent studies suggest epithelial cells are an important source of myofibroblasts through a process described as the epithelial-to-mesenchymal transition; however, confirmatory studies in vivo are lacking. To quantitatively assess the contribution of renal epithelial cells to myofibroblasts, we used Cre/Lox techniques to genetically label and fate map renal epithelia in models of kidney fibrosis. Genetically labeled primary proximal epithelial cells cultured in vitro from these mice readily induce markers of myofibroblasts after transforming growth factor beta(1) treatment. However, using either red fluorescent protein or beta-galactosidase as fate markers, we found no evidence that epithelial cells migrate outside of the tubular basement membrane and differentiate into interstitial myofibroblasts in vivo. Thus, although renal epithelial cells can acquire mesenchymal markers in vitro, they do not directly contribute to interstitial myofibroblast cells in vivo. Lineage analysis shows that during nephrogenesis, FoxD1-positive((+)) mesenchymal cells give rise to adult CD73(+), platelet derived growth factor receptor beta(+), smooth muscle actin-negative interstitial pericytes, and these FoxD1-derivative interstitial cells expand and differentiate into smooth muscle actin(+) myofibroblasts during fibrosis, accounting for a large majority of myofibroblasts. These data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease. (Am J Pathol 2010, 176:85-97; DOI: 10.2353/ajpath.2010.090517)