首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease
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Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease

机译:骨髓干细胞修复基底膜胶原蛋白缺陷并逆转遗传性肾脏疾病

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摘要

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter ≈70–90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3−/− mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen α3 chain with concomitant emergence of α4 and α5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3−/− mice or irradiated COL4A3−/− mice with BM from adult COL4A3−/− mice. The α3(IV) collagen produced by BM-derived podocytes integrates into the GBM and associates with other α-chains to form type IV collagen triple helical networks. This study demonstrates that BM-derived stem cells can offer a viable strategy for repairing basement membrane defects and conferring therapeutic benefit for patients with Alport syndrome.
机译:IV型胶原蛋白是基底膜的主要成分,并且每天通过专门的肾小球基底膜(GBM)过滤约70-90升血浆的肾小球的肾小球。在Alport综合征中,一种主要影响肾脏的进行性疾病,与GBM相关的IV型胶原蛋白基因(COL4A3,COL4A4或COL4A5)的突变导致基底膜结构缺陷,蛋白尿,肾衰竭以及所有三个GBM胶原蛋白三螺旋体缺失链由于强制性的翻译后组装要求。在这里,我们证明了将野生型骨髓(BM)移植到受辐照的COL4A3 -/-小鼠中可能导致BM来源的祖细胞作为上皮细胞(足细胞)和肾小球系膜细胞的募集与未经治疗的COL4A3相比,受损的肾小球导致IV型胶原蛋白α3链表达的部分恢复,并伴有α4和α5链表达的出现;肾小球结构的改善与蛋白尿的显着减少;肾脏整体组织学的改善sup>-/-小鼠或用成年COL4A3 -/-小鼠的BM辐照的COL4A3 -/-小鼠。由BM衍生的足细胞产生的α3(IV)胶原蛋白整合到GBM中,并与其他α链结合形成IV型胶原蛋白三螺旋网络。这项研究表明,BM源性干细胞可以为Alport综合征患者提供修复基底膜缺损并赋予治疗益处的可行策略。

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