Morais, Mychel Rpt;
Tian, Pinyuan;
Lawless, Craig;
Murtuza-Baker, Syed;
Hopkinson, Louise;
Woods, Steven;
Mironov, Aleksandr;
... Lennon, Rachel; + view all
(2022)
Kidney organoids recapitulate human basement membrane assembly in health and disease.
eLife
, 11
, Article e73486. 10.7554/eLife.73486.
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Abstract
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 BM assembly and provide a platform for understanding its wider relevance in human development and disease.
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