The Rhesus Macaque serves a model for Human Lateral Branching Nephrogenesis
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE158304 | GEO | 2021/02/18
REPOSITORIES: GEO
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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
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.
2012-09-04 | GSE39881 | GEO
Project description:The kidney contains the functional units, the nephrons, surrounded by the renal interstitium. Previously, we discovered that, once Six2-expressing nephron progenitor cells and Foxd1-expressing renal interstitial progenitor cells form at the onset of kidney development, descendant cells from these populations contribute exclusively to the main body of nephrons and renal interstitial tissues, respectively, indicating a lineage boundary between the nephron and renal interstitial compartments. Currently, it is unclear how lineages are regulated during kidney organogenesis. We demonstrate that nephron progenitor cells lacking Pax2 activity failed to differentiate into nephron cells, but can switch fates into renal interstitium cell types. These data suggest that Pax2 function maintains nephron progenitor cells by repressing transdifferentiation into renal interstitial cell states. Thus, the lineage boundary between the nephron and renal interstitial compartments is maintained by the Pax2 activity in nephron progenitor cells during kidney organogenesis.
2017-03-11 | GSE79137 | GEO
Project description:Preterm neonates are at high risk for nephron loss under adverse clinical conditions (e.g., cardiocirculatory decompensation, nephrotoxic drugs). Importantly, the onset of renal damage potentially collides with the proceeding nephrogenesis of prematurity prior 36 weeks of gestation. Recent animal studies suggest that early nephron loss within this vulnerable phase is associated with more severe glomerular and tubulointerstitial alterations later in life, irrespective of the occurrence of arterial hypertension. It is known that nephrogenic pathways are reactivated after acute kidney injury supporting renal repair and regeneration. In this study we hypothesized that nephron loss during nephrogenesis leads to an alteration of the kidney developmental program which in turn impairs homeostasis and repair and thus aggravates kidney injury later in life. Preterm infants prior to 36 weeks of gestation show an active nephrogenesis after birth. In rats, nephrogenesis is still active until day 10 of life. Mimicking the human situation of acute nephron loss in preterm neonates with ongoing nephrogenesis, rats were uninephrectomized at day 1 of life (UNXd1). A second group of animals was uninephrectomized at day 14 of life (UNXd14), which resembles a nephron loss after terminated nephrogenesis. Age-matched control groups were sham operated. Three days after uninephrectomy the animals were sacrificed. Transcriptional renal changes were analyzed by RNAseqencing, followed by in silico functional pathway analysis. In UNXd1 animals 1182 genes were differentially regulated compared to the respective control group. The functional groups “renal development” and “kidney injury” were among the most differentially regulated groups and revealed distinctive alterations in UNXd1 animals. Reduced expression levels of candidate genes concerning renal development (Bmp7, Gdnf, Pdgf-B, Wt1) and kidney injury (nephrin, podocin, Tgf-β1) were detected in the kidney of UNXd1 animals. The downregulation of Bmp7 and Gdnf expression in the remaining kidney of UNXd1 animals persisted until day 28 of life. In UNXd14 rats Six2 was upregulated and Pax22 downregulated compared to controls. We conclude that neonatal nephron loss during active nephrogenesis affects renal development and induces persistently reduced expression levels of genes which in turn might hinder tissue repair after kidney injury later in life.
2021-06-09 | GSE176395 | GEO
Project description:All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost after birth. The recreation of nephron progenitors (NPs) and/or their maintenance in culture has been a major focus of renal regenerative strategies. Using a lentiviral screening approach, we previously generated an induced nephron progenitor (iNP) state in vitro using a pool of six transcription factors (SIX1, SIX2, HOXA11, OSR1, EYA1, SNAI2). Here, using an inducible piggyBac transposon system, we demonstrate efficient reprogramming to iNPs with only three transcription factors (SNAI2, EYA1 and SIX1). Coupled with maintenance in culture conditions supportive of this progenitor state, the resulting population can contribute to developing nephrons in vitro, ex vivo and in vivo. This approach provides a rapid and efficient method for the generation of NPs from human somatic cells.
2019-11-28 | GSE107410 | GEO
Project description:During development, nephron progenitor forming one million nephrons, a functional unit in the kidney. However, nephron progenitor ceases before birth in human when they terminally differentiated to the nephron. Our lab established the method for induction of nephron progenitors from mouse Embryonic Stem (ES) cells and/or human induced Pluripotent Stem Cells (iPSCs) (Taguchi et al., Cell Stem Cell. 2014, 2017). For application of induced nephron progenitors to regenerative medicine, a large number of cells are required such as disease modeling and drug screening. To selectively propagate human iPS-derived nephron progenitors in vitro in an undifferentiated state, we developed SIX2-GFP iPS line and optimized culture condition of induced nephron progenitors by modifying our previously developed condition (Tanigawa et al., Cell Rep. 2016). To understand how whole gene expression profiles of human iPS-derived nephron progenitor cells are changed during culture, we isolated nephron progenitor cells by FACS and cultured in our defined culture condition. Purified RNAs from cultured cells at day 7 or un-cultured nephron progenitor cells were analyzed by RNA-seq.
2019-08-01 | GSE118729 | GEO
Project description:During development, distinct progenitors contribute to the nephrons versus the ureteric epithelium of the kidney. Indeed, previous pluripotent stem cell-derived models of kidney tissue either contain nephrons or pattern specifically to the ureteric epithelium. By reanalysing the transcriptional distinction between distal nephron and ureteric epithelium in human fetal kidney, we show here that while existing nephron-containing kidney organoids contain distal nephron epithelium and no ureteric epithelium, this distal nephron segment alone displays significant in vitro plasticity and can adopt a ureteric epithelial tip identity when isolated and cultured in defined conditions. “Induced” ureteric epithelium cultures can be cryopreserved, serially passaged without loss of identity and transitioned towards a collecting duct fate. Indeed, cultures harbouring loss-of-function mutations in PKHD1 recapitulate the cystic phenotype associated with autosomal recessive polycystic kidney disease.
2021-01-15 | GSE161255 | GEO
Project description:Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identi-fying novel genes associated with kidney development and disease. A rapid, efficient, and scala-ble organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.
2024-03-14 | GSE251862 | GEO
Project description:In developing mammalian kidney, nephron progenitor cells (NPC) give rise to all cells in mature nephrons. Several transcription factors, including Six2, Hoxd11, Osr1 and Wt1, are expressed in NPC and are essential for its maintenance and/or specification. In order to understand the regulatory functions of these factors, we mapped binding sites of Six2, Hoxd11 and Osr1 in NPC using a novel transgenic strategy, and of Wt1 in wild-type developing kidney.
2018-01-18 | GSE90016 | GEO
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