Advances in Kidney Disease and Health, Journal Year: 2023, Volume and Issue: 30(2), P. 148 - 163
Published: March 1, 2023
Language: Английский
Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 585 - 594
Published: July 19, 2023
Abstract Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell single-nucleus assays (>400,000 nuclei or cells) spatial imaging technologies to a broad spectrum healthy reference kidneys (45 donors) diseased (48 patients). This has provided high-resolution cellular atlas 51 main types, which include rare previously undescribed populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors localizations spanning entire kidney. We also define 28 states across nephron segments interstitium that were altered in injury, encompassing cycling, adaptive (successful maladaptive repair), transitioning degenerative states. Molecular signatures permitted localization these injury using transcriptomics, while large-scale 3D analysis (around 1.2 million neighbourhoods) corresponding linkages active immune responses. These analyses defined biological pathways are relevant time-course niches, including underlying epithelial repair predicted with decline function. integrated multimodal human represents comprehensive benchmark neighbourhoods, outcome-associated publicly available interactive visualizations.
Language: Английский
Citations
363
Journal of the American Society of Nephrology, Journal Year: 2021, Volume and Issue: 32(4), P. 897 - 912
Published: March 4, 2021
The repertoire of protein expression along the renal tubule depends both on regulation transcription and alternative splicing that can generate multiple proteins from a single gene.A full-length, small-sample RNA-seq protocol profiled transcriptomes for all 14 segments microdissected mouse kidneys.This study identified >34,000 transcripts, including 3709 were expressed in segment-specific manner. All data are provided as an online resource (https://esbl.nhlbi.nih.gov/MRECA/Nephron/). Many genes unique patterns solute carriers, factors, or G protein-coupled receptors account function. Mapping distribution transcripts associated with Wnk-SPAK-PKA signaling, renin-angiotensin-aldosterone cystic diseases kidney illustrated applications resource. method allowed full-length mapping reads, which facilitated comprehensive, unbiased characterization exon usage tubule, known isoforms Cldn10, Kcnj1 (ROMK), Slc12a1 (NKCC2), Wnk1, Stk39 (SPAK), Slc14a2 (UT-A urea transporter). It also many novel distribution. These included variants altered structure (Slc9a8, Khk, Tsc22d1, Scoc), may affect untranslated, regulatory regions (Pth1r, Pkar1a, Dab2).Full-length, sequencing gene-expression tubule. data, resource, include quantitative qualitative differences transcripts. Identification prove critical to understanding physiology pathophysiology.
Language: Английский
Citations
151
Annual Review of Physiology, Journal Year: 2021, Volume and Issue: 84(1), P. 507 - 531
Published: Nov. 29, 2021
The kidney maintains electrolyte, water, and acid-base balance, eliminates foreign waste compounds, regulates blood pressure, secretes hormones. There are at least 16 different highly specialized epithelial cell types in the mammalian kidney. number of endothelial cells, immune interstitial might even be larger. concerted interplay between is critical for function. Traditionally, cells were defined by their function or microscopical morphological appearance. With advent new single-cell modalities such as transcriptomics, epigenetics, metabolomics, proteomics we entering into a era type definition. This technological revolution provides opportunities to classify understand functions.
Language: Английский
Citations
137
Science Advances, Journal Year: 2022, Volume and Issue: 8(23)
Published: June 8, 2022
Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map cells, pathways, genes using unaffected regions nephrectomy tissues undiseased biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics proteomics, near-single-cell 3D CODEX imaging, spatial metabolomics to hierarchically identify genes, cells. Integrated data these different technologies coherently cell types/subtypes within nephron segments interstitium. These profiles cell-level functional organization following its physiological functions link subtypes proteins, metabolites, pathways. They further show that messenger RNA levels along are congruent activity. This provides framework for classification when multiple molecular mechanisms underlie convergent clinical phenotypes.
Language: Английский
Citations
123
Nature Immunology, Journal Year: 2022, Volume and Issue: 23(6), P. 947 - 959
Published: May 12, 2022
Language: Английский
Citations
86
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown
Published: July 29, 2021
Abstract Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, interactions within tissue neighborhoods. We have applied multiple single-cell or -nucleus assays (>400,000 nuclei/cells) spatial imaging technologies to a broad spectrum healthy reference (n = 42) kidneys. This has provided high resolution cellular atlas 100 that include rare novel populations. The multi-omic approach provides detailed transcriptomic epigenomic regulatory factors, localizations for major spanning entire kidney. further identify define states altered in injury, encompassing cycling, adaptive maladaptive repair, transitioning degenerative affecting several segments. Molecular signatures these permitted localization injury neighborhoods using transcriptomics, large-scale 3D analysis ∼1.2 million linkages active immune responses. These analyses defined biological pathways relevant niches, including underlying transition from predicted were with decline function during chronic disease. human atlas, neighborhoods, will be valuable resource future studies.
Language: Английский
Citations
76
Kidney International, Journal Year: 2022, Volume and Issue: 102(6), P. 1291 - 1304
Published: Sept. 13, 2022
Language: Английский
Citations
71
iScience, Journal Year: 2022, Volume and Issue: 25(4), P. 104097 - 104097
Published: March 16, 2022
High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse human kidneys, in healthy distinct paradigms. First, we established feasibility nine which revealed a cell neighborhood centered around population
Language: Английский
Citations
62
Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(6), P. 347 - 360
Published: March 17, 2022
Language: Английский
Citations
58
Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(10), P. 628 - 642
Published: July 22, 2022
Language: Английский
Citations
42