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Lgr5+ve stem cells in nephrogenesis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Rogier Versteeg

PROVIDER: E-GEOD-39881 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2012-09-04 | GSE39881 | GEO

Repression of interstitial cell identity in nephron progenitor cells by Pax2 establishes the nephron-interstitium lineage boundary throughout mammalian kidney development

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

Inducible three-factor direct reprogramming to nephron progenitors using piggyBac transposons

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

Mapping of transcription factor binding sites in mouse nephron progenitor cells

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

LGR6 marks nephron progenitor cells

Project description:Background: Nephron progenitor cells (NPCs) undergo a stepwise process to generate all mature nephron structures. Mesenchymal to epithelial transition (MET) is considered a multi-step process of NPC differentiation to ensure progressive establishment of new nephrons. However, despite this important role, to date, no marker for NPCs undergoing MET in the nephron exists. Results: Here, we identify LGR6 as a NPC marker, expressed in very early cap mesenchyme, pre-tubular aggregates, renal vesicles and in segments of S-shaped bodies, following the trajectory of MET. By using a lineage tracing approach in embryonic explants in combination with confocal imaging and single-cell RNA sequencing, we provide evidence for the multiple fates of LGR6+ cells during embryonic nephrogenesis. Moreover, by using long-term in vivo lineage tracing, we show that postnatal LGR6+ cells are capable of generating the multiple lineages of the nephrons. Conclusion: Given the profound early mesenchymal expression and MET signature of LGR6+ cells, together with the lineage tracing of mesenchymal LGR6+ cells, we conclude that LGR6+ cells contribute to all nephrogenic segments by undergoing MET. LGR6+ cells can therefore be considered an early committed NPC population during embryonic and postnatal nephrogenesis with potential regenerative capability.

2021-05-25 | GSE164795 | GEO

Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids

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

Gene expression profile of human iPSC-derived nephron progenitor cells

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

p53 Enables Self Renewal of Nephron Progenitor Cells

Project description:p53 limits the self-renewing ability of a variety of stem cells. Here, contrary to its classical role in restraining cell proliferation, we demonstrate a divergent function of p53 in maintenance of self-renewal of the nephron progenitor population in the embryonic mouse kidney. p53-null nephron progenitor cells (NPC) exhibit progressive loss of the self-renewing progenitor niche in the cap mesenchyme, identified by Cited1 and Six2 expression, and loss of cap integrity. Nephron endowment is regulated by NPC availability and their differentiation to nephrons. Quantitatively, the Six2p53-/- cap has 30% fewer Six2GFP+ cells. While the apoptotic index is unchanged the proliferation index is significantly lower, in accordance with cell cycle analysis data showing less mutant Six2p53-/-;GFP+ cells in S and G2/M phases in comparison to Six2p53+/+;GFP+ cells. The mutant kidneys also show nephron deficit and decreased Fgf8 expression. To investigate the underlying changes in gene expression in the cap mesenchyme that contribute to the Six2p53-/- phenotype, we utilized RNA-Seq for transcriptome comparison. Top biological processes affected by p53 loss are development and morphogenesis, cell adhesion/migration, cell survival and metabolism. Cells from the mutant CM showed increased cellular ROS levels as well as deregulated expression of energy metabolism and mitochondrial genes suggesting metabolic dysfunction. Adhesion defects are visualized by decreased immunostaining of adhesion marker NCAM, and may possibly contribute to the differentiation defect as well. Altogether our data suggest a novel role for p53 in enabling self-renewal of the NPC and preservation of the progenitor niche, and thus regulating nephron endowment. mRNA profiles of wild-type (WT) and conditional p53 knockout (KO) of Six2+ mouse nephron progenitor cells (NPC) at embryonic day 15.5

2015-02-16 | E-GEOD-56253 | biostudies-arrayexpress

Gene expression profiles of E8.5, E9.5 and E11.5 kidney precursors

Project description:Understanding processes how the early stage kidney precursor gives rise to metanephric mesenchyme, which is a committed progenitor cells of adult kidney is important for the regeneration of kidney in vitro. The combination of fluorescent activated cell sorting (FACS) plus microarray analysis offers a powerful, efficient and effective method for the creation of global gene expression profiles of the developing kidney precursors. Those gene expression data provides insights into not only the stage specific marker genes but also the signals working in each population, which should be informative for the directed differentiation of pluripotent stem cells in vitro. Osr1-GFP knock-in mice were used to isolate kidney precursor cells from embryos at E8.5, E9.5 and E11.5. At E9.5 and E11.5 embryos, to identify the differences between nephron progenitors and surrounding mesenchyme, nephron progenitor populations were further enriched by gating Osr1-GFP positive Integrin alpha8 positive Pdgfr alpha negative population and compared with Osr1-GFP positive cells other than that gate. RNA was isolated from cells and the gene expression profiles were determined by microarrays.

2015-01-13 | E-GEOD-51054 | biostudies-arrayexpress

Distal nephron plasticity allows the induction of ureteric tip and stalk for the modelling of collecting duct disease

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

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