Kidney organoids recapitulate human basement membrane assembly in health and disease.
Kidney organoids recapitulate human basement membrane assembly in health and disease.
复制标题
DOI：
10.7554/elife.73486
复制
发表时间：
2022-01-25
期刊：
影响因子：
7.7
通讯作者：
Lennon R
中科院分区：
文献类型：
--
作者：
Morais MRPT;Tian P;Lawless C;Murtuza-Baker S;Hopkinson L;Woods S;Mironov A;Long DA;Gale DP;Zorn TMT;Kimber SJ;Zent R;Lennon R
基底膜(BMS)是覆盖所有连续细胞层的复杂的大分子网络。基本成分包括IV型胶原和层粘连蛋白，它们受到人类遗传变异的影响，导致一系列虚弱的疾病，包括肾脏、肌肉和脑血管表型。我们研究了人多能干细胞来源的肾脏器官体内BM组装的动力学。我们解析了它们的全球BM组成，并在BM组装中发现了一个保守的时间序列，与哺乳动物的胚胎肾脏平行。我们发现了关键的BM亚型的出现，这些亚型被Col4A5中的一个致病变异所改变。结合器官、胎儿和成人肾脏蛋白质组，我们发现了从发育到成年的BM组成的动态调节，并通过单细胞转录分析绘制了BM成分的细胞来源。总体而言，我们定义了肾脏有机体BM组装的复杂和动态性质，并为了解其在人类发育和疾病中的更广泛相关性提供了一个平台。
Basement membranes (BMs) are complex macromolecular networks underlying all continuous layers of cells. Essential components include collagen IV and laminins, which are affected by human genetic variants leading to a range of debilitating conditions including kidney, muscle, and cerebrovascular phenotypes. We investigated the dynamics of BM assembly in human pluripotent stem cell-derived kidney organoids. We resolved their global BM composition and discovered a conserved temporal sequence in BM assembly that paralleled mammalian fetal kidneys. We identified the emergence of key BM isoforms, which were altered by a pathogenic variant in COL4A5. Integrating organoid, fetal, and adult kidney proteomes, we found dynamic regulation of BM composition through development to adulthood, and with single-cell transcriptomic analysis we mapped the cellular origins of BM components. Overall, we define the complex and dynamic nature of kidney organoid BM assembly and provide a platform for understanding its wider relevance in human development and disease.