Decoding myofibroblast origins in human kidney fibrosis

Christoph Kuppe, Mahmoud M Ibrahim, Jennifer Kranz, Xiaoting Zhang, Susanne Ziegler, Javier Perales-patón, Jitske Jansen, Katharina C. Reimer, James R. Smith, Ross Dobie, J R Wilson-Kanamori, Maurice Halder, Yaoxian Xu, Nazanin Kabgani, Nadine Kaesler, Martin Klaus, Lukas Gernhold, Victor G. Puelles, Tobias B. Huber, Peter BoorSylvia Menzel, Remco M. Hoogenboezem, Eric M. J. Bindels, Joachim Steffens, Jürgen Floege, Rebekka K. Schneider, Julio Saez-rodriguez, Neil C. Henderson, Rafael Kramann

Research output: Contribution to journalArticlepeer-review

Abstract

Kidney fibrosis is the hallmark of chronic kidney disease progression, however, currently no antifibrotic therapies exist. This is largely because the origin, functional heterogeneity and regulation of scar-forming cells during human kidney fibrosis remains poorly understood. Here, using single cell RNA-seq, we profiled the transcriptomes of proximal tubule and non-proximal tubule cells in healthy and fibrotic human kidneys to map the entire human kidney in an unbiased approach. This enabled mapping of all matrix-producing cells at high resolution, revealing distinct subpopulations of pericytes and fibroblasts as the major cellular sources of scar forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single cell RNA-seq and ATAC-seq experiments in mice, and spatial transcriptomics in human kidney fibrosis to functionally interrogate these findings, shedding new light on the origin, heterogeneity and differentiation of human kidney myofibroblasts and their fibroblast and pericyte precursors at unprecedented resolution. Finally, we used this strategy to facilitate target discovery, identifying Nkd2 as a myofibroblast-specific target in human kidney fibrosis.
Original languageEnglish
Pages (from-to)281–286
JournalNature
Volume589
Issue number7841
Early online date11 Nov 2020
DOIs
Publication statusPublished - 14 Jan 2021

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