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Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development [human snRNA-seq]

ABSTRACT: Mammalian kidneys maintain fluid homeostasis through the cellular activity of nephrons and the conjoined collecting system. Each epithelial network originates from distinct progenitor cell populations that reciprocally interact during development. To extend our understanding of human and mouse kidney development, we profiled chromatin organization (ATAC-seq) and gene expression (RNA-seq) in developing human and mouse kidneys. Data were analyzed at a species level and then integrated into a common, cross-species multimodal data set. Comparative analysis of cell types and developmental trajectories identified conserved and divergent features of chromatin organization and linked gene activity, revealing species- and cell-type specific regulatory programs. Identification of human-specific enhancer regions linked through GWAS studies to kidney disease highlights the potential of developmental modeling to provide clinical insight.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232479 | GEO | 2024/06/21

REPOSITORIES: GEO

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Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development [mouse snATAC-seq]

Project description:Mammalian kidneys maintain fluid homeostasis through the cellular activity of nephrons and the conjoined collecting system. Each epithelial network originates from distinct progenitor cell populations that reciprocally interact during development. To extend our understanding of human and mouse kidney development, we profiled chromatin organization (ATAC-seq) and gene expression (RNA-seq) in developing human and mouse kidneys. Data were analyzed at a species level and then integrated into a common, cross-species multimodal data set. Comparative analysis of cell types and developmental trajectories identified conserved and divergent features of chromatin organization and linked gene activity, revealing species- and cell-type specific regulatory programs. Identification of human-specific enhancer regions linked through GWAS studies to kidney disease highlights the potential of developmental modeling to provide clinical insight.

2024-06-21 | GSE232480 | GEO

Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development [human ATAC-seq]

2024-06-21 | GSE232478 | GEO

Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development [mouse scRNA-seq]

2024-06-21 | GSE232481 | GEO

Lgr5+ve stem cells in nephrogenesis

Project description:Multipotent stem cells and their lineage-restricted progeny drive nephron formation within the developing kidney. Validated markers of these early stem/progenitor populations are essential for deciphering their in vivo function and for evaluating their clinical potential for treating adult kidney disease. Here, we document expression of the adult stem cell marker Lgr5 in the developing kidney and assess the stem/progenitor identity of Lgr5+ve cells via in vivo lineage tracing. The appearance and localization of Lgr5+ve cells coincided with that of the S-shaped body around E14. Lgr5 expression remained restricted to cell clusters within developing nephrons in the cortex until P7, when expression was permanently silenced. In vivo lineage tracing identified Lgr5 as a marker of a novel progenitor population within nascent nephrons dedicated to generating the thick ascending limb of Henle's loop and distal convoluted tubule. The Lgr5 surface marker and experimental models described here will be invaluable for deciphering the contribution of early nephron stem cells to developmental defects and for isolating human nephron progenitors as a prerequisite to evaluating their therapeutic potential. Metanephric kidneys of timed pregnancies of ~14 days of gestation were harvested and cultured for ~10 days. Lgr5-EGFP-Ires-CreERT2-positive embryonic kidneys were identified by fluorescence microscopy and enzymatically digested to a single cell solution. GFPhi and GFPneg cells were sorted by flow cytometry (MoFlo; Dako). RNA, isolated using RNeasy (Qiagen), was analyzed using the Affymetrix platform.

2012-09-04 | E-GEOD-39881 | biostudies-arrayexpress

Gene expression profiles in developing nephrons using Lim1 metanephric mesenchyme-specific conditional mutant mice

Project description:BACKGROUND: Lim1 is a homeobox gene that is essential for nephrogenesis. During metanephric kidney development, Lim1 is expressed in the nephric duct, ureteric buds, and the induced metanephric mesenchyme. Conditional ablation of Lim1 in the metanephric mesenchyme blocks the formation of nephrons at the nephric vesicle stage, leading to the production of small, non-functional kidneys that lack nephrons. METHODS: In the present study, we used Affymetrix probe arrays to screen for nephron-specific genes by comparing the expression profiles of control and Lim1 conditional mutant kidneys. Kidneys from two developmental stages, embryonic day 14.5 (E14.5) and 18.5 (E18.5), were examined. RESULTS: Comparison of E18.5 kidney expression profiles generated a list of 465 nephron-specific gene candidates that showed a more than 2-fold increase in their expression level in control kidney versus the Lim1 conditional mutant kidney. Computational analysis confirmed that this screen enriched for kidney-specific genes. Furthermore, at least twenty-eight of the top fifty (56%) candidates (or their vertebrate orthologs) were previously reported to have a nephron-specific expression pattern. Our analysis of E14.5 expression data yielded 41 candidate genes that are up-regulated in the control kidneys compared to the conditional mutants. Three of them are related to the Notch signaling pathway that is known to be important in cell fate determination and nephron patterning. CONCLUSIONS: Therefore, we demonstrate that Lim1 conditional mutant kidneys serve as a novel tissue source for comprehensive expression studies and provide a means to identify nephron-specific genes. Keywords: tissue specificity, time course, development, kidney, metanephric mesenchyme, nephron, Lim1, knockout mice, conditional knockout

2006-02-13 | GSE4230 | GEO

Netrin-1 directs vascular patterning and maturity in the developing kidney

Project description:The kidneys intricate vascular system supports body fluid and organ homeostasis. However, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin-1 (Ntn1) is a secreted ligand critical for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing kidney and conditional deletion (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys with extended nephrogenesis. Wholemount 3D analyses additionally revealed the loss of a predictable vascular pattern in Foxd1GC/+;Ntn1fl/fl kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of our observed phenotypes, whole kidney RNA-seq revealed disruptions to genes and programs associated with stromal cells, vasculature, and differentiating nephrons. Together, our findings highlight the significance of netrin-1 to proper vascularization and kidney development.

2023-10-19 | GSE245506 | GEO

Transcriptional profile of mouse nephron progenitor cells

Project description:In developing mammalian kidney, nephron progenitor cells (NPC) give rise to all cells in mature nephrons. Expression of the transcription factor Six2 marks NPC in developing mouse kidneys. Within the Six2+ cell population, uncommitted NPC is marked by Cited1 expression. Towards the depletion of NPC in P2, most of the Cited1+ NPC is committed. Therefore, most of the Six2+ cells in kidney represents committed NPC. In order to explore the mechanism of NPC self-renewal and differentiation, hereby we generated transcriptionl profiles of uncommitted NPC (Cited1RFP+ cells from kidneys of E16.5 Cited1tagRFP transgenic mice) and committed NPC (Six2GFP+ cells from kidneys of P2 Six2TGC transgenic mice).

2018-01-18 | GSE89264 | GEO

Identifying the molecular mechanisms that underlie impaired kidney development due to maternal diabetes.

Project description:The prevalence of diabetes has significantly increased among women of childbearing age worldwide, and it is known that infants who are exposed to maternal diabetes in utero are at increased risk of congenital anomalies of the kidney and urinary tract. The primary role of the kidney is to filter blood through the nephrons. These anomalies can result in a reduction in the number of nephrons that are formed during kidney development, or decreased congenital nephron endowment, which is linked to hypertension and chronic kidney disease. It is unknown how exposure to maternal diabetes in utero results in abnormal kidney development and the long-term health consequences of this exposure remain ill-defined. In this study, we profiled gene expression in the developing mouse kidney from C57BL/6J control and maternal diabetes exposed (DM_Exp) mice at single cell resolution. Consistent with previous studies, clusters with distinct transcriptional signatures clearly identify major compartments and cell types of the developing kidney.

2024-11-01 | GSE162298 | GEO

Characterization of splice isoform switching during human kidney development

Project description:Background: Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme – a transient kidney-specific progenitor state – undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms’ tumor that mimics normal kidney development. While human kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. Methods: We performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms’ tumor patient-derived xenografts. Results: We identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms’ tumors. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate mRNA splice isoform switching during human kidney development. Conclusions: These findings illuminate new molecular mechanisms involved in human kidney development and pediatric kidney tumors.

2022-11-14 | GSE150684 | GEO

Ex vivo expanded human 3D Nephrospheres engraft long term and repair chronic renal injury in mice

Project description:End-stage renal disease is a worldwide epidemic requiring renal replacement therapy. Harvesting tissue from failing kidneys and autotransplantation of expanded committed progenitors giving rise to renal parenchyma could theoretically allow for the restoration of kidney function delaying or preventing the need for dialysis or a renal allograft. Here we utilized healthy and end-stage human adult kidneys to robustly expand proliferative kidney epithelial cells and establish 3D-kidney epithelial cultures termed nephrospheres (nSPH). Formation of nephrospheres recapitulates renal developmental programs to reestablish renal identity and revitalize renal epithelia in primary cultures. Transplantation into NOD/SCID mice show that 3D-nSPH restore self-organogenetic properties lost in adherent cultures, allowing in turn efficient engraftment and long-term survival as tubular structures and demonstrating self-organization as critical to prolonged in vivo cell survival. Moreover, long-term tubular engraftment of human nSPH proved to be functionally beneficial in murine models of chronic kidney disease. Remarkably, in vitro, nSPH inhibited pro-fibrotic collagen production in cultured fibroblasts via paracrine modulation of STAT6/IL13 while in vivo, transplanted nSPH induced transcriptional signatures of proliferation and a release from the quiescent state in host tubules potentially re-activating endogenous regeneration. These data support the use of human nSPH for autologous renal cell therapy.

2019-12-03 | GSE141257 | GEO

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