­­­Kidney organoids recapitulate human basement membrane assembly in health and disease

Mychel Rpt Morais, Pinyuan Tian, Craig Lawless, Syed Murtuza-baker, Louise Hopkinson, Steven Woods, Aleksandr Mironov, David A Long, Daniel P Gale, Telma Mt Zorn, Susan J Kimber, Roy Zent, Rachel Lennon

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournaleLife
Volume11
Early online date25 Jan 2022
DOIs
Publication statusPublished - 25 Jan 2022

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