An atlas of healthy and injured cell states and niches in the human kidney

Nature, Год журнала: 2023, Номер 619(7970), С. 585 - 594

Опубликована: Июль 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.

Язык: Английский

---

Multi-omics integration in the age of million single-cell data

Nature Reviews Nephrology, Год журнала: 2021, Номер 17(11), С. 710 - 724

Опубликована: Авг. 20, 2021

Язык: Английский

---

Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis

Cell Metabolism, Год журнала: 2022, Номер 34(12), С. 1977 - 1998.e9

Опубликована: Окт. 19, 2022

Язык: Английский

---

Single-cell analysis identifies the interaction of altered renal tubules with basophils orchestrating kidney fibrosis

Nature Immunology, Год журнала: 2022, Номер 23(6), С. 947 - 959

Опубликована: Май 12, 2022

Язык: Английский

---

Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury

Journal of the American Society of Nephrology, Год журнала: 2023, Номер 34(4), С. 554 - 571

Опубликована: Янв. 13, 2023

Significance Statement Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells single-nucleus multiomics (profiling transcriptome chromatin accessibility) AKI. They demonstrated that triggers a cell-cycle response in most epithelial nonepithelial cell types. also showed proinflammatory proximal tubule (PTCs) persist until 6 months post-AKI, although they decreased abundance over time, part, through death. Single-nucleus lineage-traced revealed regulatory features repair. These included activation state–specific transcription factors cis-regulatory elements, effects PTCs even repair, weeks injury event. Background proliferative as part an intrinsic cellular program, which can lead restoring structure function, or with persistence injured altered structure. However, molecular understanding these programs limited. Methods To examine transcriptional responses same upon ischemia-reperfusion (IRI), we combined genetic fate mapping ( Ki67 + ) labeled early IRI multiomics—profiling accessibility nucleus—and generated dataset 83,315 nuclei. Results triggered broad cycle preceded by type–specific global changes nephron, collecting vascular systems, stromal immune We observed heterogeneous population throughout segments marked loss from 4 months. Gene expression profiling nuclei highlighted differences between activity elements factors, accompanied corresponding target gene expression. Adaptive was associated reduced genes encoding transmembrane transport proteins essential function. Conclusions Analysis genome organization single-cell resolution using offers new insight into regulation Weeks mild-to-moderate IRI, aberrant epigenetic landscape, exhibit profile following

Язык: Английский

---

Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy

Cell Metabolism, Год журнала: 2024, Номер 36(5), С. 1105 - 1125.e10

Опубликована: Март 20, 2024

A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct anatomical regions. We generated transcriptomes of 446,267 cells chromatin accessibility profiles 401,875 developed a package analyze 408,218 metabolomes. find the same cell type, including thin limb, thick ascending limb loop Henle principal cells, display transcriptomic, accessibility, metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene revealed non-overlapping metabolic signatures between nephron segments dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating omics with clinical data identified PLEKHA1 as disease marker, its vitro knockdown increased expression PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying anatomy.

Язык: Английский

---

Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 12, 2024

Abstract Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured fails to undergo normal and assumes proinflammatory profibrotic phenotype that may promote fibrosis chronic kidney disease. The healthy failed change is marked by cell state-specific transcriptomic epigenomic changes. Single nucleus joint RNA- ATAC-seq sequencing offers an opportunity study the gene regulatory networks underpinning these changes in order identify key drivers. We develop regularized regression approach construct genome-wide parametric using multiomic datasets. generate single dataset from seven adult human samples apply our method drivers injury response associated with demonstrate highly effective tool for predicting cis- trans- elements transition use it NFAT5 as driver maladaptive state.

Язык: Английский

---

Cellular senescence of renal tubular epithelial cells in acute kidney injury

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 5, 2024

Abstract Cellular senescence represents an irreversible state of cell-cycle arrest during which cells secrete senescence-associated secretory phenotypes, including inflammatory factors and chemokines. Additionally, these exhibit apoptotic resistance phenotype. serves a pivotal role not only in embryonic development, tissue regeneration, tumor suppression but also the pathogenesis age-related degenerative diseases, malignancies, metabolic kidney diseases. The renal tubular epithelial (RTEC) constitutes critical cellular event progression acute injury (AKI). RTEC inhibits regeneration repair processes and, concurrently, promotes transition AKI to chronic disease via mechanisms underlying are multifaceted include telomere shortening or damage, DNA mitochondrial autophagy deficiency, disorders, endoplasmic reticulum stress, epigenetic regulation. Strategies aimed at inhibiting senescence, targeting clearance senescent RTEC, promoting apoptosis hold promise for enhancing prognosis AKI. This review primarily focuses on characteristics impact intervening AKI, aiming provide foundation understanding providing potentially effective approaches treatment.

Язык: Английский

---

An atlas of healthy and injured cell states and niches in the human kidney

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Июль 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.

Язык: Английский

---

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 30, 2022

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal characterized by progressive expansion cysts. To better understand cell types and states driving ADPKD progression, we analyze eight five healthy human samples, generating single multiomic atlas consisting ~100,000 nucleus transcriptomes ~50,000 epigenomes. Activation proinflammatory, profibrotic signaling pathways are driven proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts collecting duct cells. We identify GPRC5A as marker for cyst-lining that exhibits increased transcription factor binding motif availability NF-κB, TEAD, CREB retinoic acid receptors. validate distal enhancer regulating expression containing these motifs. This analysis reveals previously unrecognized cellular heterogeneity provides foundation to develop diagnostic therapeutic approaches.

Язык: Английский

---