The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Iain A Drummond - One of the best experts on this subject based on the ideXlab platform.
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fibroblast growth factor signaling mediates progenitor cell aggregation and Nephron regeneration in the adult zebrafish kidney
Developmental Biology, 2019Co-Authors: Thomas F Gallegos, Caramai N Kamei, Michael Rohly, Iain A DrummondAbstract:Abstract The zebrafish kidney regenerates after injury by development of new Nephrons from resident adult kidney stem cells. Although adult kidney progenitor cells have been characterized by transplantation and single cell RNA seq, signals that stimulate new Nephron formation are not known. Here we demonstrate that fibroblast growth factors and FGF signaling is rapidly induced after kidney injury and that FGF signaling is required for recruitment of progenitor cells to sites of new Nephron formation. Chemical or dominant negative blockade of Fgfr1 prevented formation of Nephron progenitor cell aggregates after injury and during kidney development. Implantation of FGF soaked beads induced local aggregation of lhx1a:EGFP + kidney progenitor cells. Our results reveal a previously unexplored role for FGF signaling in recruitment of renal progenitors to sites of new Nephron formation and suggest a role for FGF signaling in maintaining cell adhesion and cell polarity in newly forming kidney epithelia.
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wnt signaling mediates new Nephron formation during zebrafish kidney regeneration
Development, 2019Co-Authors: Caramai N Kamei, Thomas F Gallegos, Yan Liu, Neil A Hukriede, Iain A DrummondAbstract:ABSTRACT Zebrafish kidneys use resident kidney stem cells to replace damaged tubules with new Nephrons: the filtration units of the kidney. What stimulates kidney progenitor cells to form new Nephrons is not known. Here, we show that wnt9a and wnt9b are induced in the injured kidney at sites where frizzled9b- and lef1-expressing progenitor cells form new Nephrons. New Nephron aggregates are patterned by Wnt signaling, with high canonical Wnt-signaling cells forming a single cell thick rosette that demarcates: domains of cell proliferation in the elongating Nephron; and tubule fusion where the new Nephron plumbs into the distal tubule and establishes blood filtrate drainage. Pharmacological blockade of canonical Wnt signaling inhibited new Nephron formation after injury by inhibiting cell proliferation, and resulted in loss of polarized rosette structures in the aggregates. Mutation in frizzled9b reduced total kidney Nephron number, caused defects in tubule morphology and reduced regeneration of new Nephrons after injury. Our results demonstrate an essential role for Wnt/frizzled signaling in adult zebrafish kidney development and regeneration, highlighting conserved mechanisms underlying both mammalian kidney development and kidney stem cell-directed neonephrogenesis in zebrafish.
Andrew P Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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repression of interstitial identity in Nephron progenitor cells by pax2 establishes the Nephron interstitium boundary during kidney development
Developmental Cell, 2017Co-Authors: Natalie Naiman, Kaoru Fujioka, Mari Fujino, Todd M Valerius, Steven S Potter, Andrew P Mcmahon, Akio KobayashiAbstract:Summary 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 fail to differentiate into Nephron cells but can switch fates into renal interstitium-like cell types. These data suggest that Pax2 function maintains Nephron progenitor cells by repressing a renal interstitial cell program. Thus, the lineage boundary between the Nephron and renal interstitial compartments is maintained by the Pax2 activity in Nephron progenitor cells during kidney organogenesis.
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Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney.
Cell Reports, 2015Co-Authors: Sanjeev Kumar, Jing Liu, Paul Pang, A Michaela Krautzberger, Antoine Reginensi, Haruhiko Akiyama, Andreas Schedl, Benjamin D Humphreys, Andrew P McmahonAbstract:After acute kidney injury (AKI), surviving cells within the Nephron proliferate and repair. We identify Sox9 as an acute epithelial stress response in renal regeneration. Translational profiling after AKI revealed a rapid upregulation of Sox9 within proximal tubule (PT) cells, the Nephron cell type most vulnerable to AKI. Descendants of Sox9(+) cells generate the bulk of the Nephron during development and regenerate functional PT epithelium after AKI-induced reactivation of Sox9 after renal injury. After restoration of renal function post-AKI, persistent Sox9 expression highlights regions of unresolved damage within injured Nephrons. Inactivation of Sox9 in PT cells pre-injury indicates that Sox9 is required for the normal course of post-AKI recovery. These findings link Sox9 to cell intrinsic mechanisms regulating development and repair of the mammalian Nephron.
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Induction and patterning of the metanephric Nephron
Seminars in Cell & Developmental Biology, 2014Co-Authors: Lori L. O'brien, Andrew P McmahonAbstract:The functional unit of the mammalian metanephric kidney is the Nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important physiological functions. Nephrons are assembled from a Nephron-restricted pool of mesenchymal progenitors over an extensive developmental period that is completed prior to (human), or shortly after (mouse), birth. An appropriate balance in the expansion and commitment of Nephron progenitors to Nephron formation is essential for normal kidney function. Too few Nephrons increase risk of kidney disease later in life while the failure of normal progenitor differentiation in Wilm's tumor patients leads to massive growth of a nephroblast population often necessitating surgical removal of the kidney. An inductive process within the metanephric mesenchyme leads to the formation of a pretubular aggregate which transitions into an epithelial renal vesicle: the precursor for Nephron assembly. Growth, morphogenesis and patterning transform this simple cyst-like structure into a highly elongated mature Nephron with distinct cell types positioned along a proximal (glomerular) to distal (connecting segment) axis of functional organization. This review discusses our current understanding of the specification, maintenance and commitment of Nephron progenitors, and the regulatory processes that transform the renal vesicle into a Nephron.
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high resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the Nephron progenitor population
Developmental Biology, 2009Co-Authors: Joshua W Mugford, Akio Kobayashi, Andrew P McmahonAbstract:The functional unit of the kidney is the Nephron. During its organogenesis, the mammalian metanephric kidney generates thousands of Nephrons over a protracted period of fetal life. All Nephrons are derived from a population of self-renewing multi-potent progenitor cells, termed the cap mesenchyme. However, our understanding of the molecular and cellular mechanisms underlying Nephron development is at an early stage. In order to identify factors involved in nephrogenesis, we performed a high-resolution, spatial profiling of a number of transcriptional regulators expressed within the cap mesenchyme and early developing Nephron. Our results demonstrate novel, stereotypic, spatially defined cellular sub-domains within the cap mesenchyme, which may, in part, reflect induction of Nephron precursors. These results suggest a hitherto unappreciated complexity of cell states that accompany the assembly of the metanephric kidney, likely reflecting diverse regulatory actions such as the maintenance and induction of Nephron progenitors.
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six2 defines and regulates a multipotent self renewing Nephron progenitor population throughout mammalian kidney development
Cell Stem Cell, 2008Co-Authors: Akio Kobayashi, Todd M Valerius, Joshua W Mugford, Thomas J Carroll, Michelle Self, Guillermo Oliver, Andrew P McmahonAbstract:Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to Nephrons and how multiple Nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent Nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the Nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing Nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the Nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic Nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent Nephron progenitor population.
Melissa H Little - One of the best experts on this subject based on the ideXlab platform.
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Recreating, expanding and using Nephron progenitor populations.
Nature Reviews Nephrology, 2019Co-Authors: Melissa H Little, Kynan T. LawlorAbstract:2019 saw advances in the generation of induced pluripotent stem cell (iPSC)-derived Nephron progenitors and in our understanding of how Nephrons form in a kidney organoid. Fundamental studies of regeneration in zebrafish continue to provide vital clues as to how we might use iPSC-derived cells to regenerate a human Nephron in vivo.
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Reporter‐based fate mapping in human kidney organoids confirms Nephron lineage relationships and reveals synchronous Nephron formation
EMBO Reports, 2019Co-Authors: Sara E. Howden, Jessica M Vanslambrouck, Sean Wilson, Ker Sin Tan, Melissa H LittleAbstract:Nephron formation continues throughout kidney morphogenesis in both mice and humans. Lineage tracing studies in mice identified a self-renewing Six2-expressing Nephron progenitor population able to give rise to the full complement of Nephrons throughout kidney morphogenesis. To investigate the origin of Nephrons within human pluripotent stem cell-derived kidney organoids, we performed a similar fate-mapping analysis of the SIX2-expressing lineage in induced pluripotent stem cell (iPSC)-derived kidney organoids to explore the feasibility of investigating lineage relationships in differentiating iPSCs Using CRISPR/Cas9 gene-edited lineage reporter lines, we show that SIX2-expressing cells give rise to Nephron epithelial cell types but not to presumptive ureteric epithelium. The use of an inducible (CreERT2) line revealed a declining capacity for SIX2 cells to contribute to Nephron formation over time, but retention of Nephron-forming capacity if provided an exogenous WNT signal. Hence, while human iPSC-derived kidney tissue appears to maintain lineage relationships previously identified in developing mouse kidney, unlike the developing kidney , kidney organoids lack a Nephron progenitor niche capable of both self-renewal and ongoing nephrogenesis.
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The Life Cycle of the Nephron Progenitor
Developmental Cell, 2015Co-Authors: Melissa H LittleAbstract:Although we know that mesenchymal progenitors give rise to Nephrons in the kidney, how they balance self-renewal versus differentiation is still unclear. In this issue of Developmental Cell, Chen et al. (2015) show that Nephron progenitors age, but not necessarily irreversibly: old progenitors can be "rejuvenated" by a young crowd.
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directing human embryonic stem cell differentiation towards a renal lineage generates a self organizing kidney
Nature Cell Biology, 2014Co-Authors: Minoru Takasato, Jessica M Vanslambrouck, Pei Xuan Er, M Becroft, Edouard G Stanley, Andrew G Elefanty, Melissa H LittleAbstract:With the prevalence of end-stage renal disease rising 8% per annum globally, there is an urgent need for renal regenerative strategies. The kidney is a mesodermal organ that differentiates from the intermediate mesoderm (IM) through the formation of a ureteric bud (UB) and the interaction between this bud and the adjacent IM-derived metanephric mesenchyme (MM). The Nephrons arise from a Nephron progenitor population derived from the MM (ref. ). The IM itself is derived from the posterior primitive streak. Although the developmental origin of the kidney is well understood, Nephron formation in the human kidney is completed before birth. Hence, there is no postnatal stem cell able to replace lost Nephrons. In this study, we have successfully directed the differentiation of human embryonic stem cells (hESCs) through posterior primitive streak and IM under fully chemically defined monolayer culture conditions using growth factors used during normal embryogenesis. This differentiation protocol results in the synchronous induction of UB and MM that forms a self-organizing structure, including Nephron formation, in vitro. Such hESC-derived components show broad renal potential ex vivo, illustrating the potential for pluripotent-stem-cell-based renal regeneration.
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Nephron formation adopts a novel spatial topology at cessation of nephrogenesis
Developmental Biology, 2011Co-Authors: Bree Rumballe, Thierry Gilbert, Kylie Georgas, Alexander N Combes, Melissa H LittleAbstract:Nephron number in the mammalian kidney is known to vary dramatically, with postnatal renal function directly influenced by Nephron complement. What determines final Nephron number is poorly understood but Nephron formation in the mouse kidney ceases within the first few days after birth, presumably due to the loss of all remaining Nephron progenitors via epithelial differentiation. What initiates this event is not known. Indeed, whether Nephron formation occurs in the same way at this time as during embryonic development has also not been examined. In this study, we investigate the key cellular compartments involved in Nephron formation; the ureteric tip, cap mesenchyme and early Nephrons; from postnatal day (P) 0 to 6 in the mouse. High resolution analyses of gene and protein expression indicate that loss of Nephron progenitors precedes loss of ureteric tip identity, but show spatial shifts in the expression of cap mesenchyme genes during this time. In addition, cap mesenchymal volume and rate of proliferation decline prior to birth. Section-based 3D modeling and Optical Projection Tomography revealed a burst of ectopic Nephron induction, with the formation of multiple (up to 5) Nephrons per ureteric tip evident from P2. While the distal–proximal patterning of these Nephrons occurred normally, their spatial relationship with the ureteric compartment was altered. We propose that this phase of Nephron formation represents an acceleration of differentiation within the cap mesenchyme due to a displacement of signals within the nephrogenic niche.
Akio Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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repression of interstitial identity in Nephron progenitor cells by pax2 establishes the Nephron interstitium boundary during kidney development
Developmental Cell, 2017Co-Authors: Natalie Naiman, Kaoru Fujioka, Mari Fujino, Todd M Valerius, Steven S Potter, Andrew P Mcmahon, Akio KobayashiAbstract:Summary 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 fail to differentiate into Nephron cells but can switch fates into renal interstitium-like cell types. These data suggest that Pax2 function maintains Nephron progenitor cells by repressing a renal interstitial cell program. Thus, the lineage boundary between the Nephron and renal interstitial compartments is maintained by the Pax2 activity in Nephron progenitor cells during kidney organogenesis.
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high resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the Nephron progenitor population
Developmental Biology, 2009Co-Authors: Joshua W Mugford, Akio Kobayashi, Andrew P McmahonAbstract:The functional unit of the kidney is the Nephron. During its organogenesis, the mammalian metanephric kidney generates thousands of Nephrons over a protracted period of fetal life. All Nephrons are derived from a population of self-renewing multi-potent progenitor cells, termed the cap mesenchyme. However, our understanding of the molecular and cellular mechanisms underlying Nephron development is at an early stage. In order to identify factors involved in nephrogenesis, we performed a high-resolution, spatial profiling of a number of transcriptional regulators expressed within the cap mesenchyme and early developing Nephron. Our results demonstrate novel, stereotypic, spatially defined cellular sub-domains within the cap mesenchyme, which may, in part, reflect induction of Nephron precursors. These results suggest a hitherto unappreciated complexity of cell states that accompany the assembly of the metanephric kidney, likely reflecting diverse regulatory actions such as the maintenance and induction of Nephron progenitors.
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six2 defines and regulates a multipotent self renewing Nephron progenitor population throughout mammalian kidney development
Cell Stem Cell, 2008Co-Authors: Akio Kobayashi, Todd M Valerius, Joshua W Mugford, Thomas J Carroll, Michelle Self, Guillermo Oliver, Andrew P McmahonAbstract:Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to Nephrons and how multiple Nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent Nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the Nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing Nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the Nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic Nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent Nephron progenitor population.
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Gene expression profiles in developing Nephrons using Lim1 metanephric mesenchyme-specific conditional mutant mice
BMC Nephrology, 2006Co-Authors: You-tzung Chen, Akio Kobayashi, Kin Ming Kwan, Randy L Johnson, Richard R BehringerAbstract: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. Conclusion 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.
Ryuichi Nishinakamura - One of the best experts on this subject based on the ideXlab platform.
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pax2 is dispensable for in vitro Nephron formation from human induced pluripotent stem cells
Scientific Reports, 2017Co-Authors: Yusuke Kaku, Shunsuke Tanigawa, Atsuhiro Taguchi, Fahim Haque, Tetsushi Sakuma, Takashi Yamamoto, Ryuichi NishinakamuraAbstract:The kidney is formed by reciprocal interactions between the Nephron progenitor and the ureteric bud, the former of which gives rise to the epithelia of Nephrons consisting of glomeruli and renal tubules. The transcription factor PAX2 is essential for this mesenchymal-to-epithelial transition of Nephron progenitors, as well as ureteric bud lineage development, in mice. PAX2 mutations in humans cause renal coloboma syndrome. We previously reported the induction of Nephron progenitors and three-dimensional Nephron structures from human induced pluripotent stem (iPS) cells. Here we generate iPS cells lacking PAX2, and address the role of PAX2 in our in vitro induction protocol. While PAX2-null human Nephron progenitors were properly formed, they unexpectedly became epithelialised to form glomeruli and renal tubules. However, the mutant glomerular parietal epithelial cells failed to transit to the squamous morphology, retaining the shape and markers of columnar epithelia. Therefore, PAX2 is dispensable for mesenchymal-to-epithelial transition of Nephron progenitors, but is required for morphological development of glomerular parietal epithelial cells, during Nephron formation from human iPS cells in vitro.
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Induction of Nephron progenitors and glomeruli from human pluripotent stem cells
Pediatric Nephrology, 2017Co-Authors: Ryuichi Nishinakamura, Sazia Sharmin, Atsuhiro TaguchiAbstract:Studies of kidney regeneration using stem cells have progressed rapidly in recent years. Our group has developed a protocol to induce Nephron progenitors from both mouse and human pluripotent stem cells which is based on a revised model of early stage kidney specification. The induced progenitors readily reconstitute three-dimensional Nephron structures, including glomeruli and renal tubules, in vitro. We can further generate human induced pluripotent stem cells (iPSCs), in which nephrin-expressing glomerular podocytes are tagged with green fluorescent protein (GFP). The sorted GFP-positive cells retain the podocyte-specific molecular and structural features. Upon transplantation, mouse endothelial cells of the host animals are integrated into the human iPSC-derived glomeruli, and the podocytes show further maturation. Other laboratories have reported different protocols to induce Nephron structures from human iPSCs in vitro. These findings will accelerate our understanding of kidney development and diseases in humans.
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selective in vitro propagation of Nephron progenitors derived from embryos and pluripotent stem cells
Cell Reports, 2016Co-Authors: Shunsuke Tanigawa, Atsuhiro Taguchi, Alan O. Perantoni, Nirmala Sharma, Ryuichi NishinakamuraAbstract:Nephron progenitors in the embryonic kidney propagate while generating differentiated Nephrons. However, in mice, the progenitors terminally differentiate shortly after birth. Here, we report a method for selectively expanding Nephron progenitors in vitro in an undifferentiated state. Combinatorial and concentration-dependent stimulation with LIF, FGF2/9, BMP7, and a WNT agonist is critical for expansion. The purified progenitors proliferated beyond the physiological limits observed in vivo, both for cell numbers and lifespan. Neonatal progenitors were maintained for a week, while progenitors from embryonic day 11.5 expanded 1,800-fold for nearly 20 days and still reconstituted 3D Nephrons containing glomeruli and renal tubules. Furthermore, progenitors generated from mouse embryonic stem cells and human induced pluripotent cells could be expanded with retained Nephron-forming potential. Thus, we have established in vitro conditions for promoting the propagation of Nephron progenitors, which will be essential for dissecting the mechanisms of kidney organogenesis and for regenerative medicine.