Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney
Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney
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DOI：
10.2353/ajpath.2008.080433
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发表时间：
2008-12-01
影响因子：
6
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
--
作者：
Lin, Shuei-Liong;Kisseleva, Tatiana;Duffield, Jeremy S.
了解瘢痕形成肌成纤维细胞的来源对于了解炎症损伤引起纤维化的机制至关重要。利用表达增强型绿色荧光蛋白(GFP)的转基因小鼠模型，在I型胶原启动子和增强子的调控下，我们研究了肾脏中产生Col1a1的细胞的起源。在这里，我们发现在正常肾脏中，足细胞和周细胞都产生了增强型GFP检测到的Col1a1转录本，而在纤维化的肾脏中，Col1a1-GFP的表达准确地识别了肌成纤维细胞。为了确定循环免疫细胞对瘢痕形成的直接作用，野生型小鼠与Coll-GFP小鼠的骨髓嵌合，造成输尿管梗阻以诱导纤维化。对这些小鼠肾脏的组织学检查显示，少量纤维细胞重新聚集到纤维化的肾脏，但这些纤维细胞对间质纤维化没有显著贡献。相反，使用动力学建模和时间历程显微镜，我们发现表达Col1a1-GFP的周细胞是纤维化肾脏间质肌成纤维细胞的主要来源。我们的研究表明，血管损伤或血管因素是周细胞迁移和分化为肌成纤维细胞的最有可能的触发因素。因此，我们的结果有助于将纤维化研究的重点重新放在血管系统的损伤上，而不是上皮细胞的损伤上。(Am J Pathol2008173：16171627；DOI：10.2353/ajpath.2008.080433)
Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type 1, a I (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium. (Am J Pathol 2008, 173:1617-1627; DOI: 10.2353/ajpath.2008.080433)