1
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Lee SM, Cichanski SR, Pintozzi NG, Kaufmann M, Jones G, Meyer MB. Kidney deletions of Cyp27b1 fail to reduce serum 1,25(OH) 2D 3. J Steroid Biochem Mol Biol 2025; 250:106734. [PMID: 40096920 DOI: 10.1016/j.jsbmb.2025.106734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/17/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
Vitamin D metabolism is controlled through the kidney mitochondrial P450 enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) that activate and degrade the endocrine vitamin D hormone (1,25(OH)2D3), respectively. We recently demonstrated that extrarenal cells can make 1,25(OH)2D3 with adequate vitamin D supplementation by targeted mass spectrometry imaging in our Cyp27b1 kidney enhancer deletion mouse model that lacks circulating 1,25(OH)2D3 (M1/M21-DIKO mouse). Based on these observations, we selectively deleted Cyp27b1 (Cyp27b1fl/fl) from the mouse kidney using the Six2- and Pax8-cre drivers that target tubule and nephron development to see if we could recapitulate the remarkable phenotype of the M1/M21-DIKO mice. While Six2-cre/Cyp27b1fl/fl mice had a mild phenotype, Pax8-cre/Cyp27b1fl/fl mice had a marked elevation of parathyroid hormone and a reduction in bone mineral density. The vitamin D metabolic profile in the Pax8-cre/Cyp27b1fl/fl clearly indicated a dysfunction in the CYP24A1 enzyme with reductions in 24,25(OH)2D3 and 25(OH)D3-26,23-lactone with an accompanying elevation of 25(OH)D3. However, despite these compensatory reductions in CYP24A1 derived metabolites and apparent deletion of Cyp27b1 in the kidney, the 1,25(OH)2D3 levels were not changed from wildtype in either mouse. Like 24,25(OH)2D3, the 1,24,25(OH)3D3 levels were also reduced. These data highlight the robust homeostatic mechanisms to salvage 1,25(OH)2D3, point towards potential compensatory mechanisms of 1,25(OH)2D3 production from non-kidney tissues, and reinforce the utility of the M1/M21-DIKO model as a non-global deletion of Cyp27b1 with reductions in serum 1,25(OH)2D3 to be used to understand the complexity of vitamin D metabolism in health and inflammatory disease.
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Affiliation(s)
- Seong Min Lee
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Shannon R Cichanski
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Nicolas G Pintozzi
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Martin Kaufmann
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada; Department of Surgery, Queen's University, Kingston, Ontario K7L3N6, Canada
| | - Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada
| | - Mark B Meyer
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
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2
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Xue Z, Xuan H, Lau K, Su Y, Wegener M, Li K, Turner L, Adams M, Shi X, Wen H. Expression of ENL YEATS domain tumor mutations in nephrogenic or stromal lineage impairs kidney development. Nat Commun 2025; 16:2531. [PMID: 40087269 PMCID: PMC11909213 DOI: 10.1038/s41467-025-57926-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 03/05/2025] [Indexed: 03/17/2025] Open
Abstract
Recurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENLT) mutations and show that heterozygous mutant expression in Six2+ nephrogenic or Foxd1+ stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENLT mutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation of Hox and Wnt signaling genes in mutant nephrogenic cells. In contrast, Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, with dysregulated stromal gene expression affecting stroma-epithelium crosstalk. Our findings uncover distinct pathways through which ENL mutations disrupt nephrogenesis, providing a foundation for further investigations into their role in tumorigenesis.
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Affiliation(s)
- Zhaoyu Xue
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Hongwen Xuan
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Kin Lau
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Yangzhou Su
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Marc Wegener
- Genomics Core, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Kuai Li
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Lisa Turner
- Pathology Core, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Marie Adams
- Genomics Core, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Xiaobing Shi
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA
| | - Hong Wen
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA.
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3
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Davies JA. Kidney development and regeneration: An introduction to this volume in Current Topics in Developmental Biology. Curr Top Dev Biol 2025; 163:1-14. [PMID: 40254341 DOI: 10.1016/bs.ctdb.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Mechanistic studies of renal development arguably began 70 years ago, in 1955 when Clifford Grobstein identified an inductive interaction between ureteric bud and metanephric mesenchyme. As an introduction to a special volume of Current Topics in Developmental Biology, this review looks back over the decades since Grobstein's paper to ask how well we have now answered the mechanistic questions raised in his 'pre-molecular' age, and to highlight new questions that have emerged from an increasing understanding of how kidneys develop. I consider that some old questions, such as lineage, have been answered fairly comprehensively. Some questions such as the nature of inductive signalling have become much more complicated, as a notion of 'the signal' has been replaced by hundreds, or possibly thousands, of communications that coordinate renal development. Some old questions, particularly about morphogenesis, remain open. Others, such as metabolism, were ignored for decades but are now being studied again, very profitably. New topics, such as stem cell behaviour, self-organization, epigenetics and congenital abnormalities, join work on the old ones. We have undoubtedly learned much over the last 70 years but, strangely perhaps, the number of questions still to be answered now seems much larger than it did in decades long past.
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Affiliation(s)
- Jamie A Davies
- Deanery of Biomedical Sciences, University of Edinburgh.
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4
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Michalopulos MG, Liu Y, Raju DR, Lafin JT, Ma Y, Gaur D, Khadka S, Xing C, McMahon AP, Carroll TJ, Drake KA. Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.10.637031. [PMID: 39990396 PMCID: PMC11844377 DOI: 10.1101/2025.02.10.637031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about regulation of the stromal progenitor population. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1 c/c ) results in an expansion of Foxd1+ stromal progenitor cells. Analyses of the developing stroma in two additional models, including Wnt4-null mutants (which fail to form nephron structures similar to Six2cre;Wt1 c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTA c/+ ), both phenocopy Six2cre;Wt1 c/c mutants, thus further confirming that defects in the NPC lineage result in abnormal development of the stromal progenitor population. Furthermore, we identify a subcluster of the Foxd1+ stroma that appears expanded in the three mutant mouse models and conserved in human fetal kidneys. Overall, the findings from this study suggest that loss of differentiating nephron structures may result in possible over proliferation of the stromal progenitor population and/or a block in stromal differentiation and further highlight how crosstalk amongst the progenitor cell lineages coordinates multiple aspects of kidney development.
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Affiliation(s)
- Michael G Michalopulos
- Department of Pediatrics, Division of Pediatric Nephrology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Yan Liu
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dinesh Ravindra Raju
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - John T Lafin
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yanru Ma
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dhruv Gaur
- Midwestern University, Chicago College of Osteopathic Medicine, Chicago, IL, USA
| | - Sadiksha Khadka
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chao Xing
- Department of Bioinformatics and O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Andrew P McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Thomas J Carroll
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Keri A Drake
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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5
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Anjum H, Smith JP, Martini AG, Yacu GS, Medrano S, Gomez RA, Sequeira-Lopez MLS, Quaggin SE, Finer G. Tcf21 as a founder transcription factor in specifying Foxd1 cells to the juxtaglomerular cell lineage. Am J Physiol Renal Physiol 2025; 328:F121-F130. [PMID: 39589156 DOI: 10.1152/ajprenal.00235.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/29/2024] [Accepted: 11/14/2024] [Indexed: 01/03/2025] Open
Abstract
Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Forkhead box D1-positive (Foxd1+) stromal progenitors. However, factors guiding these progenitors toward renin-secreting cell fate remain unclear. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Using Foxd1Cre/+;Tcf21f/f and Ren1dCre/+;Tcf21f/f mouse models, we investigated the role of Tcf21 in the differentiation of Foxd1+ progenitor cells into juxtaglomerular (JG) cells. Immunostaining and in situ hybridization demonstrated fewer renin-positive areas and altered renal arterial morphology, including the afferent arteriole, in Foxd1Cre/+;Tcf21f/f kidneys compared with controls, indicating Tcf21's critical role in the emergence of renin-expressing cells. However, Tcf21 inactivation in renin-expressing cells (Ren1dCre/+;Tcf21f/f) did not recapitulate this phenotype, suggesting Tcf21 is dispensable once renin cell identity is established. Using an integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on GFP+ cells (stromal lineage) from E12, E18, P5, and P30 Foxd1Cre/+;Rosa26mTmG control kidneys, we analyzed the temporal dynamics of Tcf21 expression in cells comprising the JG lineage (n = 2,054). A pseudotime trajectory analysis revealed that Tcf21 expression is highest in metanephric mesenchyme and stromal cells at early developmental stages (E12), with a decline in expression as cells mature into renin-expressing JG cells. Motif enrichment analyses supported Tcf21's significant involvement in early kidney development. These findings underscore the critical role of Tcf21 in Foxd1+ cell differentiation into JG cells during early stages of kidney development, offering insights into the molecular mechanisms governing JG cell differentiation and highlighting Tcf21's pivotal role in kidney development.NEW & NOTEWORTHY This manuscript provides novel insights into the role of Tcf21 in the differentiation of Foxd1+ cells into JG cells. Using integrated scRNA-seq and scATAC-seq, the study reveals that Tcf21 expression is crucial during early embryonic stages, with its peak at embryonic day 12. The findings demonstrate that inactivation of Tcf21 leads to fewer renin-positive areas and altered renal arterial morphology, underscoring the importance of Tcf21 in the specification of renin-expressing JG cells and kidney development.
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Affiliation(s)
- Hina Anjum
- Division of Pediatric Nephrology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
| | - Jason P Smith
- Department of Pediatrics, Child Health Research Center, University of Virginia, Charlottesville, Virginia, United States
| | - Alexandre G Martini
- Department of Pediatrics, Child Health Research Center, University of Virginia, Charlottesville, Virginia, United States
| | - George S Yacu
- Division of Pediatric Nephrology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
| | - Silvia Medrano
- Department of Pediatrics, Child Health Research Center, University of Virginia, Charlottesville, Virginia, United States
| | - R Ariel Gomez
- Department of Pediatrics, Child Health Research Center, University of Virginia, Charlottesville, Virginia, United States
| | - Maria Luisa S Sequeira-Lopez
- Department of Pediatrics, Child Health Research Center, University of Virginia, Charlottesville, Virginia, United States
| | - Susan E Quaggin
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Division of Nephrology and Hypertension, Northwestern Memorial Hospital, Chicago, Illinois, United States
| | - Gal Finer
- Division of Pediatric Nephrology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
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6
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Finer G, Khan MD, Zhou Y, Gadhvi G, Yacu GS, Park JS, Gomez RA, Sequeira-Lopez MLS, Quaggin SE, Winter DR. The transcription factor TCF21 is necessary for adoption of cell fates by Foxd1+ stromal progenitors during kidney development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.14.607910. [PMID: 39211232 PMCID: PMC11361084 DOI: 10.1101/2024.08.14.607910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Normal kidney development requires the coordinated interactions between multiple progenitor cell lineages. Among these, Foxd1+ stromal progenitors are essential for nephrogenesis, giving rise to diverse cell types including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms governing their differentiation remain poorly understood. This study investigates the role of Tcf21, a mesoderm-specific bHLH transcription factor, in Foxd1+ cell fate determination. Using single-cell RNA sequencing (scRNA-seq), we analyzed 32,461 GFP+ cells from embryonic day 14.5 (E14.5) Foxd1 Cre/+ ;Rosa26 mTmG ;Tcf21 f/f kidneys ( Tcf21-cKO ) and controls. Clustering identified a predominant stromal population, further divided into six subpopulations associated with healthy kidney development: nephrogenic zone-associated stroma, proliferating stroma, medullary/perivascular stroma, collecting duct-associated stroma, differentiating stroma, and ureteric stroma. Loss of Tcf21 resulted in marked depletion of medullary/perivascular stroma, collecting duct-associated stroma, proliferating stroma, and nephrogenic zone-associated stroma stromal subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces. Additionally, we identified a novel cluster unique to Tcf21-cKO kidneys, characterized by high expression of Endomucin (Emcn), a vascular endothelial marker. These cells spanned across pseudotime trajectories and were distributed broadly across the mutant kidney. The emergence of Emcn-expressing cells in Tcf21-cKO kidneys coincided with a reduction in Acta2-expressing medullary stromal cells, suggesting a population shift. Our findings highlight the critical role of Tcf21 in directing Foxd1+ progenitor differentiation. Loss of Tcf21 disrupts stromal cell fates, leading to aberrant kidney development and providing new insights into the mechanisms underlying congenital kidney anomalies. TRANSLATIONAL STATEMENT This study reveals critical insights into kidney development and congenital anomalies by identifying the developmental origins of stromal heterogeneity and the key role of Tcf21 in stromal progenitor differentiation. These findings enhance our understanding of stromal cell fate decisions and their relevance to congenital disorders. Additionally, this work provides valuable information for improving the recapitulation of the stromal compartment ex vivo, a current challenge in kidney organoid models. The role of Tcf21 in stromal phenotypic modulation underscores its broader significance in tissue repair and fibrotic diseases, suggesting potential avenues for therapeutic intervention.
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7
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Rabelink TJ, Wang G, van der Vlag J, van den Berg BM. The roles of hyaluronan in kidney development, physiology and disease. Nat Rev Nephrol 2024; 20:822-832. [PMID: 39191935 DOI: 10.1038/s41581-024-00883-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2024] [Indexed: 08/29/2024]
Abstract
The hyaluronan (HA) matrix in the tissue microenvironment is crucial for maintaining homeostasis by regulating inflammatory signalling, endothelial-mesenchymal transition and cell migration. During development, covalent modifications and osmotic swelling of HA create mechanical forces that initiate midgut rotation, vascular patterning and branching morphogenesis. Together with its main cell surface receptor, CD44, HA establishes a physicochemical scaffold at the cell surface that facilitates the interaction and clustering of growth factors and receptors that is required for normal physiology. High-molecular-weight HA, tumour necrosis factor-stimulated gene 6, pentraxin 3 and CD44 form a stable pericellular matrix that promotes tissue regeneration and reduces inflammation. By contrast, breakdown of high-molecular-weight HA into depolymerized fragments by hyaluronidases triggers inflammatory signalling, leukocyte migration and angiogenesis, contributing to tissue damage and fibrosis in kidney disease. Targeting HA metabolism is challenging owing to its dynamic regulation and tissue-specific functions. Nonetheless, modulating HA matrix functions by targeting its binding partners holds promise as a therapeutic strategy for restoring tissue homeostasis and mitigating pathological processes. Further research in this area is warranted to enable the development of novel therapeutic approaches for kidney and other diseases characterized by dysregulated HA metabolism.
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Affiliation(s)
- Ton J Rabelink
- Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands.
| | - Gangqi Wang
- Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Johan van der Vlag
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bernard M van den Berg
- Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
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8
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Nishimura Y, Hanada S. Origins and Molecular Mechanisms Underlying Renal Vascular Development. KIDNEY360 2024; 5:1718-1726. [PMID: 39115947 DOI: 10.34067/kid.0000000000000543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Kidneys play a crucial role in maintaining homeostasis within the body, and this function is intricately linked to the vascular structures within them. For vascular cells in the kidney to mature and function effectively, a well-coordinated spatial alignment between the nephrons and complex network of blood vessels is essential. This arrangement ensures efficient blood filtration and regulation of the electrolyte balance, blood pressure, and fluid levels. Additionally, the kidneys are vital in regulating the acid-base balance and producing hormones involved in erythropoiesis and blood pressure control. This article focuses on the vascular development of the kidneys, summarizing the current understanding of the origin and formation of the renal vasculature, and the key molecules involved. A comprehensive review of existing studies has been conducted to elucidate the cellular and molecular mechanisms governing renal vascular development. Specific molecules play a critical role in the development of renal vasculature, contributing to the spatial alignment between nephrons and blood vessels. By elucidating the cellular and molecular mechanisms involved in renal vascular development, this study aims to advance renal regenerative medicine and offer potential avenues for therapeutic interventions in kidney disease.
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Affiliation(s)
- Yusuke Nishimura
- Department of Clinical Engineering, Faculty of Medical Science and Technology, Gunma Paz University, Takasaki, Japan
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9
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McLarnon SR, Honeycutt SE, N’Guetta PEY, Xiong Y, Li X, Abe K, Kitai H, Souma T, O’Brien LL. Altered renal vascular patterning reduces ischemic kidney injury and limits vascular loss associated with aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620969. [PMID: 39553980 PMCID: PMC11565873 DOI: 10.1101/2024.10.29.620969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular pattern altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to recovery from a model of bilateral ischemic injury and measured vascular dynamics in aged mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared to control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with aging compared to a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function; thus, modulating renal vascular patterning may represent an effective therapeutic strategy. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury or aging has important implications for enhancing kidney regeneration and tissue engineering strategies.
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Affiliation(s)
- Sarah R. McLarnon
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Samuel E. Honeycutt
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Pierre-Emmanuel Y. N’Guetta
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yubin Xiong
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Xinwei Li
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
- Cell and Developmental Biology, Rutgers University, Piscataway, NJ 08854, USA
| | - Koki Abe
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hiroki Kitai
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Tomokazu Souma
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Lori L. O’Brien
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
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10
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Anjum H, Smith JP, Martini AG, Yacu GS, Medrano S, Gomez RA, Sequeira-Lopez MLS, Quaggin SE, Finer G. Tcf21 as a Founder Transcription Factor in Specifying Foxd1 Cells to the Juxtaglomerular Cell Lineage. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.25.586641. [PMID: 38585851 PMCID: PMC10996550 DOI: 10.1101/2024.03.25.586641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Foxd1+ stromal progenitors. However, factors guiding these progenitors toward renin-secreting cell fate remain unclear. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Utilizing Foxd1 Cre/+ ;Tcf21 f/f and Ren1 dCre/+ ;Tcf21 f/f mouse models, we investigated the role of Tcf21 in the differentiation of Foxd1+ progenitor cells into juxtaglomerular (JG) cells. Immunostaining and in-situ hybridization demonstrated fewer renin-positive areas and altered renal arterial morphology, including the afferent arteriole, in Foxd1 Cre/+ ;Tcf21 f/f kidneys compared to controls, indicating Tcf21's critical role in the emergence of renin-expressing cells. However, Tcf21 inactivation in renin-expressing cells ( Ren1 dCre/+ ;Tcf21 f/f ) did not recapitulate this phenotype, suggesting Tcf21 is dispensable once renin cell identity is established. Using an integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on GFP+ cells (stromal lineage) from E12, E18, P5, and P30 Foxd1 Cre/+ ;Rosa26 mTmG control kidneys, we analyzed the temporal dynamics of Tcf21 expression in cells comprising the JG lineage ( n =2,054). A pseudotime trajectory analysis revealed that Tcf21 expression is highest in metanephric mesenchyme and stromal cells at early developmental stages (E12), with a decline in expression as cells mature into renin-expressing JG cells. Motif enrichment analyses supported Tcf21's significant involvement in early kidney development. These findings underscore the critical role of Tcf21 in Foxd1+ cell differentiation into JG cells during early stages of kidney development, offering insights into the molecular mechanisms governing JG cell differentiation and highlight Tcf21's pivotal role in kidney development. NEW & NOTEWORTHY This manuscript provides novel insights into the role of Tcf21 in the differentiation of Foxd1+ cells into JG cells. Utilizing integrated scRNA-seq and scATAC-seq, the study reveals that Tcf21 expression is crucial during early embryonic stages, with its peak at embryonic day 12. The findings demonstrate that inactivation of Tcf21 leads to fewer renin-positive areas and altered renal arterial morphology, underscoring the importance of Tcf21 in the specification of renin-expressing JG cells and kidney development.
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11
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Clemons HJ, Hogan DJ, Brown PO. Depot-specific mRNA expression programs in human adipocytes suggest physiological specialization via distinct developmental programs. PLoS One 2024; 19:e0311751. [PMID: 39401200 PMCID: PMC11472956 DOI: 10.1371/journal.pone.0311751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 09/24/2024] [Indexed: 10/17/2024] Open
Abstract
Adipose tissue is distributed in diverse locations throughout the human body. Not much is known about the extent to which anatomically distinct adipose depots are functionally distinct, specialized organs, nor whether depot-specific characteristics result from intrinsic developmental programs, as opposed to reversible physiological responses to differences in tissue microenvironment. We used DNA microarrays to compare mRNA expression patterns of isolated human adipocytes and cultured adipose stem cells, before and after ex vivo adipocyte differentiation, from seven anatomically diverse adipose tissue depots. Adipocytes from different depots display distinct gene expression programs, which are most closely shared with anatomically related depots. mRNAs whose expression differs between anatomically diverse groups of depots (e.g., subcutaneous vs. internal) suggest important functional specializations. These depot-specific differences in gene expression were recapitulated when adipocyte progenitor cells from each site were differentiated ex vivo, suggesting that progenitor cells from specific anatomic sites are deterministically programmed to differentiate into depot-specific adipocytes. Many developmental transcription factors show striking depot-specific patterns of expression, suggesting that adipocytes in each anatomic depot are programmed during early development in concert with anatomically related tissues and organs. Our results support the hypothesis that adipocytes from different depots are functionally distinct and that their depot-specific specialization reflects distinct developmental programs.
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Affiliation(s)
- Heather J. Clemons
- Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America
- Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Daniel J. Hogan
- Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America
- Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Patrick O. Brown
- Department of Biochemistry, Stanford University School of Medicine, Palo Alto, California, United States of America
- Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California, United States of America
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12
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Nagase T, Nagase M. Piezo ion channels: long-sought-after mechanosensors mediating hypertension and hypertensive nephropathy. Hypertens Res 2024; 47:2786-2799. [PMID: 39103520 DOI: 10.1038/s41440-024-01820-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/03/2024] [Accepted: 07/07/2024] [Indexed: 08/07/2024]
Abstract
Recent advances in mechanobiology and the discovery of mechanosensitive ion channels have opened a new era of research on hypertension and related diseases. Piezo1 and Piezo2, first reported in 2010, are regarded as bona fide mechanochannels that mediate various biological and pathophysiological phenomena in multiple tissues and organs. For example, Piezo channels have pivotal roles in blood pressure control, triggering shear stress-induced nitric oxide synthesis and vasodilation, regulating baroreflex in the carotid sinus and aorta, and releasing renin from renal juxtaglomerular cells. Herein, we provide an overview of recent literature on the roles of Piezo channels in the pathogenesis of hypertension and related kidney damage, including our experimental data on the involvement of Piezo1 in podocyte injury and that of Piezo2 in renin expression and renal fibrosis in animal models of hypertensive nephropathy. The mechanosensitive ion channels Piezo1 and Piezo2 play various roles in the pathogenesis of systemic hypertension by acting on vascular endothelial cells, baroreceptors in the carotid artery and aorta, and the juxtaglomerular apparatus. Piezo channels also contribute to hypertensive nephropathy by acting on mesangial cells, podocytes, and perivascular mesenchymal cells.
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Affiliation(s)
- Takashi Nagase
- Kunitachi Aoyagien Tachikawa Geriatric Health Services Facility, Tokyo, Japan
| | - Miki Nagase
- Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan.
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13
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Ibi Y, Nishinakamura R. Generating kidney organoids based on developmental nephrology. Eur J Cell Biol 2024; 103:151450. [PMID: 39137450 DOI: 10.1016/j.ejcb.2024.151450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 08/15/2024] Open
Abstract
Over the past decade, the induction protocols for the two types of kidney organoids (nephron organoids and ureteric bud organoids) from pluripotent stem cells (PSCs) have been established based on the knowledge gained in developmental nephrology. Kidney organoids are now used for disease modeling and drug screening, but they also have potential as tools for clinical transplantation therapy. One of the options to achieve this goal would be to assemble multiple renal progenitor cells (nephron progenitor, ureteric bud, stromal progenitor) to reproduce the organotypic kidney structure from PSCs. At least from mouse PSCs, all the three progenitors have been induced and assembled into such "higher order" kidney organoids. We will provide an overview of the developmental nephrology required for the induction of renal progenitors and discuss recent advances and remaining challenges of kidney organoids for clinical transplantation therapy.
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Affiliation(s)
- Yutaro Ibi
- Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Ryuichi Nishinakamura
- Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
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14
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Song L, Li Q, Xia L, Sahay AE, Qiu Q, Li Y, Li H, Sasaki K, Susztak K, Wu H, Wan L. Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape. Nat Commun 2024; 15:5937. [PMID: 39009564 PMCID: PMC11250843 DOI: 10.1038/s41467-024-50171-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 07/02/2024] [Indexed: 07/17/2024] Open
Abstract
How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL's histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
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Affiliation(s)
- Lele Song
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Qinglan Li
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lingbo Xia
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of the School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Arushi Eesha Sahay
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Qi Qiu
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Yuanyuan Li
- MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Haitao Li
- MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Kotaro Sasaki
- Department of Biomedical Sciences, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Katalin Susztak
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Hao Wu
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Liling Wan
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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15
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Yoon B, Kim H, Jung SW, Park J. Single-cell lineage tracing approaches to track kidney cell development and maintenance. Kidney Int 2024; 105:1186-1199. [PMID: 38554991 DOI: 10.1016/j.kint.2024.01.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/06/2023] [Accepted: 01/09/2024] [Indexed: 04/02/2024]
Abstract
The kidney is a complex organ consisting of various cell types. Previous studies have aimed to elucidate the cellular relationships among these cell types in developing and mature kidneys using Cre-loxP-based lineage tracing. However, this methodology falls short of fully capturing the heterogeneous nature of the kidney, making it less than ideal for comprehensively tracing cellular progression during kidney development and maintenance. Recent technological advancements in single-cell genomics have revolutionized lineage tracing methods. Single-cell lineage tracing enables the simultaneous tracing of multiple cell types within complex tissues and their transcriptomic profiles, thereby allowing the reconstruction of their lineage tree with cell state information. Although single-cell lineage tracing has been successfully applied to investigate cellular hierarchies in various organs and tissues, its application in kidney research is currently lacking. This review comprehensively consolidates the single-cell lineage tracing methods, divided into 4 categories (clustered regularly interspaced short palindromic repeat [CRISPR]/CRISPR-associated protein 9 [Cas9]-based, transposon-based, Polylox-based, and native barcoding methods), and outlines their technical advantages and disadvantages. Furthermore, we propose potential future research topics in kidney research that could benefit from single-cell lineage tracing and suggest suitable technical strategies to apply to these topics.
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Affiliation(s)
- Baul Yoon
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Hayoung Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Su Woong Jung
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, Republic of Korea; Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
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16
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Song L, Li Q, Xia L, Sahay A, Qiu Q, Li Y, Li H, Sasaki K, Susztak K, Wu H, Wan L. Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.09.591709. [PMID: 38766219 PMCID: PMC11100752 DOI: 10.1101/2024.05.09.591709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Cell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly the HOX clusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolution in vivo . It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.
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17
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Greenberg D, Rosenblum ND, Tonelli M. The multifaceted links between hearing loss and chronic kidney disease. Nat Rev Nephrol 2024; 20:295-312. [PMID: 38287134 DOI: 10.1038/s41581-024-00808-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 01/31/2024]
Abstract
Hearing loss affects nearly 1.6 billion people and is the third-leading cause of disability worldwide. Chronic kidney disease (CKD) is also a common condition that is associated with adverse clinical outcomes and high health-care costs. From a developmental perspective, the structures responsible for hearing have a common morphogenetic origin with the kidney, and genetic abnormalities that cause familial forms of hearing loss can also lead to kidney disease. On a cellular level, normal kidney and cochlea function both depend on cilial activities at the apical surface, and kidney tubular cells and sensory epithelial cells of the inner ear use similar transport mechanisms to modify luminal fluid. The two organs also share the same collagen IV basement membrane network. Thus, strong developmental and physiological links exist between hearing and kidney function. These theoretical considerations are supported by epidemiological data demonstrating that CKD is associated with a graded and independent excess risk of sensorineural hearing loss. In addition to developmental and physiological links between kidney and cochlear function, hearing loss in patients with CKD may be driven by specific medications or treatments, including haemodialysis. The associations between these two common conditions are not commonly appreciated, yet have important implications for research and clinical practice.
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Affiliation(s)
- Dina Greenberg
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, Toronto, Ontario, Canada
| | - Norman D Rosenblum
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, Toronto, Ontario, Canada
- Department of Paediatrics, Temerty Faculty of Medicine, Toronto, Ontario, Canada
| | - Marcello Tonelli
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
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18
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Shen Y, Lotenberg K, Zaworski J, Broeker KAE, Vasseur F, Louedec L, Placier S, Frère P, Verpont MC, Galichon P, Buob D, Hadchouel J, Terzi F, Chatziantoniou C, Calmont A. Neuropilin-1 regulates renin synthesis in juxtaglomerular cells. J Physiol 2024; 602:1815-1833. [PMID: 38381008 DOI: 10.1113/jp285422] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/06/2024] [Indexed: 02/22/2024] Open
Abstract
Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.
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Affiliation(s)
- Yunzhu Shen
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Kenza Lotenberg
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Jeremy Zaworski
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | | | - Florence Vasseur
- Institut Necker Enfants Malades, Growth and Signalling departement, Université Paris Cité, INSERM U1151, CNRS UMR 8253, Paris, France
| | - Liliane Louedec
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Sandrine Placier
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Perrine Frère
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Marie-Christine Verpont
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Pierre Galichon
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - David Buob
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Juliette Hadchouel
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Fabiola Terzi
- Institut Necker Enfants Malades, Growth and Signalling departement, Université Paris Cité, INSERM U1151, CNRS UMR 8253, Paris, France
| | - Christos Chatziantoniou
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
| | - Amélie Calmont
- Sorbonne Université, INSERM, Unité mixte de Recherche 1155, Kidney Research Centre, Hôpital Tenon, Paris, France
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19
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Long HY, Qian ZP, Lan Q, Xu YJ, Da JJ, Yu FX, Zha Y. Human pluripotent stem cell-derived kidney organoids: Current progress and challenges. World J Stem Cells 2024; 16:114-125. [PMID: 38455108 PMCID: PMC10915962 DOI: 10.4252/wjsc.v16.i2.114] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
Human pluripotent stem cell (hPSC)-derived kidney organoids share similarities with the fetal kidney. However, the current hPSC-derived kidney organoids have some limitations, including the inability to perform nephrogenesis and lack of a corticomedullary definition, uniform vascular system, and coordinated exit pathway for urinary filtrate. Therefore, further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development, regeneration, disease modeling, and drug screening. In this review, we discussed recent advances in the generation of hPSC-derived kidney organoids, how these organoids contribute to the understanding of human kidney development and research in disease modeling. Additionally, the limitations, future research focus, and applications of hPSC-derived kidney organoids were highlighted.
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Affiliation(s)
- Hong-Yan Long
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Zu-Ping Qian
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Qin Lan
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yong-Jie Xu
- Department of Laboratory Medicine, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Jing-Jing Da
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Fu-Xun Yu
- Key Laboratory of Diagnosis and Treatment of Pulmonary Immune Diseases, National Health Commission, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Yan Zha
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China.
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20
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Qiu C, Martin BK, Welsh IC, Daza RM, Le TM, Huang X, Nichols EK, Taylor ML, Fulton O, O'Day DR, Gomes AR, Ilcisin S, Srivatsan S, Deng X, Disteche CM, Noble WS, Hamazaki N, Moens CB, Kimelman D, Cao J, Schier AF, Spielmann M, Murray SA, Trapnell C, Shendure J. A single-cell time-lapse of mouse prenatal development from gastrula to birth. Nature 2024; 626:1084-1093. [PMID: 38355799 PMCID: PMC10901739 DOI: 10.1038/s41586-024-07069-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024]
Abstract
The house mouse (Mus musculus) is an exceptional model system, combining genetic tractability with close evolutionary affinity to humans1,2. Mouse gestation lasts only 3 weeks, during which the genome orchestrates the astonishing transformation of a single-cell zygote into a free-living pup composed of more than 500 million cells. Here, to establish a global framework for exploring mammalian development, we applied optimized single-cell combinatorial indexing3 to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation (embryonic day 8) to birth (postnatal day 0). From these data, we annotate hundreds of cell types and explore the ontogenesis of the posterior embryo during somitogenesis and of kidney, mesenchyme, retina and early neurons. We leverage the temporal resolution and sampling depth of these whole-embryo snapshots, together with published data4-8 from earlier timepoints, to construct a rooted tree of cell-type relationships that spans the entirety of prenatal development, from zygote to birth. Throughout this tree, we systematically nominate genes encoding transcription factors and other proteins as candidate drivers of the in vivo differentiation of hundreds of cell types. Remarkably, the most marked temporal shifts in cell states are observed within one hour of birth and presumably underlie the massive physiological adaptations that must accompany the successful transition of a mammalian fetus to life outside the womb.
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Affiliation(s)
- Chengxiang Qiu
- Department of Genome Sciences, University of Washington, Seattle, WA, USA.
| | - Beth K Martin
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | | | - Riza M Daza
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Truc-Mai Le
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
| | - Xingfan Huang
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
| | - Eva K Nichols
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Megan L Taylor
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
| | - Olivia Fulton
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Diana R O'Day
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
| | | | - Saskia Ilcisin
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
| | - Sanjay Srivatsan
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Medical Scientist Training Program, University of Washington, Seattle, WA, USA
| | - Xinxian Deng
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Christine M Disteche
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - William Stafford Noble
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
| | - Nobuhiko Hamazaki
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Howard Hughes Medical Institute, Seattle, WA, USA
| | - Cecilia B Moens
- Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - David Kimelman
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Department of Biochemistry, University of Washington, Seattle, WA, USA
| | - Junyue Cao
- Laboratory of Single-Cell Genomics and Population dynamics, The Rockefeller University, New York, NY, USA
| | - Alexander F Schier
- Biozentrum, University of Basel, Basel, Switzerland
- Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA
| | - Malte Spielmann
- Max Planck Institute for Molecular Genetics, Berlin, Germany
- Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg, Lübeck, Kiel, Lübeck, Germany
| | | | - Cole Trapnell
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
- Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA
- Seattle Hub for Synthetic Biology, Seattle, WA, USA
| | - Jay Shendure
- Department of Genome Sciences, University of Washington, Seattle, WA, USA.
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
- Howard Hughes Medical Institute, Seattle, WA, USA.
- Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA.
- Seattle Hub for Synthetic Biology, Seattle, WA, USA.
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21
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Luo PM, Gu X, Chaney C, Carroll T, Cleaver O. Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation. Development 2023; 150:dev201884. [PMID: 37823339 PMCID: PMC10690105 DOI: 10.1242/dev.201884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/02/2023] [Indexed: 10/13/2023]
Abstract
The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation.
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Affiliation(s)
- Peter M. Luo
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Xiaowu Gu
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Christopher Chaney
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Thomas Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Internal Medicine and Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Ondine Cleaver
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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22
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Honeycutt SE, N'Guetta PEY, Hardesty DM, Xiong Y, Cooper SL, Stevenson MJ, O'Brien LL. Netrin 1 directs vascular patterning and maturity in the developing kidney. Development 2023; 150:dev201886. [PMID: 37818607 PMCID: PMC10690109 DOI: 10.1242/dev.201886] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 10/02/2023] [Indexed: 10/12/2023]
Abstract
The intricate vascular system of the kidneys 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 that is crucial for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing mouse 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 Ntn1 to proper vascularization and kidney development.
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Affiliation(s)
- Samuel E. Honeycutt
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Pierre-Emmanuel Y. N'Guetta
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Deanna M. Hardesty
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yubin Xiong
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shamus L. Cooper
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Matthew J. Stevenson
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lori L. O'Brien
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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23
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Matsui K, Yamanaka S, Chen S, Matsumoto N, Morimoto K, Kinoshita Y, Inage Y, Saito Y, Takamura T, Fujimoto T, Tajiri S, Matsumoto K, Kobayashi E, Yokoo T. Long-term viable chimeric nephrons generated from progenitor cells are a reliable model in cisplatin-induced toxicity. Commun Biol 2023; 6:1097. [PMID: 37898693 PMCID: PMC10613230 DOI: 10.1038/s42003-023-05484-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/18/2023] [Indexed: 10/30/2023] Open
Abstract
Kidney organoids have shown promise as evaluation tools, but their in vitro maturity remains limited. Transplantation into adult mice has aided in maturation; however, their lack of urinary tract connection limits long-term viability. Thus, long-term viable generated nephrons have not been demonstrated. In this study, we present an approachable method in which mouse and rat renal progenitor cells are injected into the developing kidneys of neonatal mice, resulting in the generation of chimeric nephrons integrated with the host urinary tracts. These chimeric nephrons exhibit similar maturation to the host nephrons, long-term viability with excretion and reabsorption functions, and cisplatin-induced renal injury in both acute and chronic phases, as confirmed by single-cell RNA-sequencing. Additionally, induced human nephron progenitor cells differentiate into nephrons within the neonatal kidneys. Collectively, neonatal injection represents a promising approach for in vivo nephron generation, with potential applications in kidney regeneration, drug screening, and pathological analysis.
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Affiliation(s)
- Kenji Matsui
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Shuichiro Yamanaka
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
| | - Sandy Chen
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Naoto Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Keita Morimoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Yoshitaka Kinoshita
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8654, Japan
| | - Yuka Inage
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
- Department of Pediatrics, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Yatsumu Saito
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Tsuyoshi Takamura
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Toshinari Fujimoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Susumu Tajiri
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Kei Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Eiji Kobayashi
- Department of Kidney Regenerative Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
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24
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Xu J, Zhou X, Zhang T, Zhang B, Xu PX. Smarca4 deficiency induces Pttg1 oncogene upregulation and hyperproliferation of tubular and interstitial cells during kidney development. Front Cell Dev Biol 2023; 11:1233317. [PMID: 37727504 PMCID: PMC10506413 DOI: 10.3389/fcell.2023.1233317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 08/17/2023] [Indexed: 09/21/2023] Open
Abstract
Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific transcription factors and epigenetic/chromatin regulators. However, the roles of epigenetic/chromatin regulators in kidney development and disease remain poorly understood. In this study, we investigated the impact of deleting the chromatin remodeling factor Smarca4 (Brg1), a human Wilms tumor-associated gene, in Wnt4-expressing cells. Smarca4 deficiency led to severe tubular defects and a shortened medulla. Through unbiased single-cell RNA sequencing analyses, we identified multiple types of Wnt4 Cre-labeled interstitial cells, along with nephron-related cells. Smarca4 deficiency increased interstitial cells but markedly reduced tubular cells, resulting in cells with mixed identity and elevated expression of cell-cycle regulators and genes associated with extracellular matrix and epithelial-to-mesenchymal transition/fibrosis. We found that Smarca4 loss induced a significant upregulation of the oncogene Pttg1 and hyperproliferation of Wnt4 Cre-labeled cells. These changes in the cellular state could hinder the cellular transition into characteristic tubular structures, eventually leading to fibrosis. In conclusion, our findings shed light on novel cell types and genes associated with Wnt4 Cre-labeled cells and highlight the critical role of Smarca4 in regulating tubular cell differentiation and the expression of the cancer-causing gene Pttg1 in the kidney. These findings may provide valuable insights into potential therapeutic strategies for renal cell carcinoma resulting from SMARCA4 deficiency.
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Affiliation(s)
- Jinshu Xu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Xianxiao Zhou
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Ting Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Pin-Xian Xu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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25
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Ibi Y, Nishinakamura R. Kidney Bioengineering for Transplantation. Transplantation 2023; 107:1883-1894. [PMID: 36717963 DOI: 10.1097/tp.0000000000004526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The kidney is an important organ for maintenance of homeostasis in the human body. As renal failure progresses, renal replacement therapy becomes necessary. However, there is a chronic shortage of kidney donors, creating a major problem for transplantation. To solve this problem, many strategies for the generation of transplantable kidneys are under investigation. Since the first reports describing that nephron progenitors could be induced from human induced pluripotent stem cells, kidney organoids have been attracting attention as tools for studying human kidney development and diseases. Because the kidney is formed through the interactions of multiple renal progenitors, current studies are investigating ways to combine these progenitors derived from human induced pluripotent stem cells for the generation of transplantable kidney organoids. Other bioengineering strategies, such as decellularization and recellularization of scaffolds, 3-dimensional bioprinting, interspecies blastocyst complementation and progenitor replacement, and xenotransplantation, also have the potential to generate whole kidneys, although each of these strategies has its own challenges. Combinations of these approaches will lead to the generation of bioengineered kidneys that are transplantable into humans.
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Affiliation(s)
- Yutaro Ibi
- Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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26
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Deacon E, Li A, Boivin F, Dvorkin-Gheva A, Cunanan J, Bridgewater D. β-Catenin in the kidney stroma modulates pathways and genes to regulate kidney development. Dev Dyn 2023; 252:1224-1239. [PMID: 37227110 DOI: 10.1002/dvdy.603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Kidney development is regulated by cellular interactions between the ureteric epithelium, mesenchyme, and stroma. Previous studies demonstrate essential roles for stromal β-catenin in kidney development. However, how stromal β-catenin regulates kidney development is not known. We hypothesize that stromal β-catenin modulates pathways and genes that facilitate communications with neighboring cell populations to regulate kidney development. RESULTS We isolated purified stromal cells with wild type, deficient, and overexpressed β-catenin by fluorescence-activated cell sorting and conducted RNA Sequencing. A Gene Ontology network analysis demonstrated that stromal β-catenin modulates key kidney developmental processes, including branching morphogenesis, nephrogenesis and vascular formation. Specific stromal β-catenin candidate target genes that may mediate these effects included secreted, cell-surface and transcriptional factors that regulate branching morphogenesis and nephrogenesis (Wnts, Bmp, Fgfr, Tcf/Lef) and secreted vascular guidance cues (Angpt1, VEGF, Sema3a). We validated established β-catenin targets including Lef1 and novel candidate β-catenin targets including Sema3e which have unknown roles in kidney development. CONCLUSIONS These studies advance our understanding of gene and biological pathway dysregulation in the context of stromal β-catenin misexpression during kidney development. Our findings suggest that during normal kidney development, stromal β-catenin may regulate secreted and cell-surface proteins to communicate with adjacent cell populations.
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Affiliation(s)
- Erin Deacon
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Anna Li
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Felix Boivin
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Anna Dvorkin-Gheva
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Joanna Cunanan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Darren Bridgewater
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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27
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Abstract
Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood-brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer's disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.
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Affiliation(s)
| | - Hongkuan Fan
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
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28
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Huang B, Zeng Z, Li H, Li Z, Chen X, Guo J, Zhang CC, Schreiber ME, Vonk AC, Xiang T, Patel T, Li Y, Parvez RK, Der B, Chen JH, Liu Z, Thornton ME, Grubbs BH, Diao Y, Dou Y, Gnedeva K, Lindström NO, Ying Q, Pastor-Soler NM, Fei T, Hallows KR, McMahon AP, Li Z. Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.25.542343. [PMID: 37293038 PMCID: PMC10245960 DOI: 10.1101/2023.05.25.542343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
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, identifying novel genes associated with kidney development and disease. A rapid, efficient, and scalable 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.
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Affiliation(s)
- Biao Huang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- These authors contributed equally
| | - Zipeng Zeng
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- These authors contributed equally
| | - Hui Li
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Zexu Li
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R. China
| | - Xi Chen
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Jinjin Guo
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Chennan C. Zhang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Megan E. Schreiber
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Ariel C. Vonk
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Tianyuan Xiang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Tadrushi Patel
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yidan Li
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Riana K. Parvez
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Balint Der
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Jyun Hao Chen
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Zhenqing Liu
- Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Matthew E. Thornton
- Division of Maternal Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Brendan H. Grubbs
- Division of Maternal Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yarui Diao
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yali Dou
- Department of Medicine, Department of Biochemistry and Molecular Medicine, University of Southern California, CA 90033, USA
| | - Ksenia Gnedeva
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033, USA
| | - Nils O. Lindström
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Qilong Ying
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Nuria M. Pastor-Soler
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Teng Fei
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R. China
| | - Kenneth R. Hallows
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Andrew P. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Zhongwei Li
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Lead contact
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29
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Kumegawa K, Yang L, Miyata K, Maruyama R. FOXD1 is associated with poor outcome and maintains tumor-promoting enhancer-gene programs in basal-like breast cancer. Front Oncol 2023; 13:1156111. [PMID: 37234983 PMCID: PMC10206236 DOI: 10.3389/fonc.2023.1156111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Breast cancer biology varies markedly among patients. Basal-like breast cancer is one of the most challenging subtypes to treat because it lacks effective therapeutic targets. Despite numerous studies on potential targetable molecules in this subtype, few targets have shown promise. However, the present study revealed that FOXD1, a transcription factor that functions in both normal development and malignancy, is associated with poor prognosis in basal-like breast cancer. We analyzed publicly available RNA sequencing data and conducted FOXD1-knockdown experiments, finding that FOXD1 maintains gene expression programs that contribute to tumor progression. We first conducted survival analysis of patients grouped via a Gaussian mixture model based on gene expression in basal-like tumors, finding that FOXD1 is a prognostic factor specific to this subtype. Then, our RNA sequencing and chromatin immunoprecipitation sequencing experiments using the basal-like breast cancer cell lines BT549 and Hs578T with FOXD1 knockdown revealed that FOXD1 regulates enhancer-gene programs related to tumor progression. These findings suggest that FOXD1 plays an important role in basal-like breast cancer progression and may represent a promising therapeutic target.
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Affiliation(s)
- Kohei Kumegawa
- Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Liying Yang
- Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kenichi Miyata
- Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Reo Maruyama
- Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo, Japan
- Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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30
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Greenberg D, D’Cruz R, Lacanlale JL, Rowan CJ, Rosenblum ND. Hedgehog-GLI mediated control of renal formation and malformation. FRONTIERS IN NEPHROLOGY 2023; 3:1176347. [PMID: 37675356 PMCID: PMC10479618 DOI: 10.3389/fneph.2023.1176347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 03/31/2023] [Indexed: 09/08/2023]
Abstract
CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling is critical to normal embryogenesis, including kidney development. Hh signaling mediates the physiological development of the ureter and stroma and has adverse pathophysiological effects on the metanephric mesenchyme, ureteric, and nephrogenic lineages. Further, disruption of Hh signaling is causative of numerous human developmental disorders associated with renal malformation; Pallister-Hall Syndrome (PHS) is characterized by a diverse spectrum of malformations including CAKUT and caused by truncating variants in the middle-third of the Hh signaling effector GLI3. Here, we outline the roles of Hh signaling in regulating murine kidney development, and review human variants in Hh signaling genes in patients with renal malformation.
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Affiliation(s)
- Dina Greenberg
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Robert D’Cruz
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Jon L. Lacanlale
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Christopher J. Rowan
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Norman D. Rosenblum
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Division of Nephrology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Pediatrics, University of Toronto, Toronto, ON, Canada
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Honeycutt SE, N’Guetta PEY, Hardesty DM, Xiong Y, Cooper SL, O’Brien LL. Netrin-1 directs vascular patterning and maturity in the developing kidney. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.14.536975. [PMID: 37131589 PMCID: PMC10153117 DOI: 10.1101/2023.04.14.536975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Blood filtering by the kidney requires the establishment of an intricate vascular system that works to support body fluid and organ homeostasis. Despite these critical roles, 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 stromal progenitors in the developing kidney, and conditional deletion of Ntn1 from Foxd1+ stromal progenitors (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys that display extended nephrogenesis. Despite expression of the netrin-1 receptor Unc5c in the adjacent nephron progenitor niche, Unc5c knockout kidneys develop normally. The netrin-1 receptor Unc5b is expressed by embryonic kidney endothelium and therefore we interrogated the vascular networks of Foxd1GC/+;Ntn1fl/fl kidneys. Wholemount, 3D analyses revealed the loss of a predictable vascular pattern in mutant kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization in these mutants. 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 these results, whole kidney RNA-seq showed upregulation of angiogenic programs and downregulation of muscle-related programs which included smooth muscle-associated genes. Together, our findings highlight the significance of netrin-1 to proper vascularization and kidney development.
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Affiliation(s)
- Samuel Emery Honeycutt
- Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Deanna Marie Hardesty
- Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yubin Xiong
- Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shamus Luke Cooper
- Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lori Lynn O’Brien
- Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Lipp SN, Jacobson KR, Schwaderer AL, Hains DS, Calve S. FOXD1 is required for 3D patterning of the kidney interstitial matrix. Dev Dyn 2023; 252:463-482. [PMID: 36335435 DOI: 10.1002/dvdy.545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The interstitial extracellular matrix (ECM) is comprised of proteins and glycosaminoglycans and provides structural and biochemical information during development. Our previous work revealed the presence of transient ECM-based structures in the interstitial matrix of developing kidneys. Stromal cells are the main contributors to interstitial ECM synthesis, and the transcription factor Forkhead Box D1 (Foxd1) is critical for stromal cell function. To investigate the role of Foxd1 in interstitial ECM patterning, we combined 3D imaging and proteomics to explore how the matrix changes in the murine developing kidney when Foxd1 is knocked out. RESULTS We found that COL26A1, FBN2, EMILIN1, and TNC, interstitial ECM proteins that are transiently upregulated during development, had a similar distribution perinatally but then diverged in patterning in the adult. Abnormally clustered cortical vertical fibers and fused glomeruli were observed when Foxd1 was knocked out. The changes in the interstitial ECM of Foxd1 knockout kidneys corresponded to disrupted Foxd1+ cell patterning but did not precede branching dysmorphogenesis. CONCLUSIONS The transient ECM networks affected by Foxd1 knockout may provide support for later-stage nephrogenic structures.
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Affiliation(s)
- Sarah N Lipp
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
- The Indiana University Medical Scientist/Engineer Training Program, Indianapolis, Indiana, USA
| | - Kathryn R Jacobson
- Purdue University Interdisciplinary Life Science Program, Purdue University, West Lafayette, Indiana, USA
| | - Andrew L Schwaderer
- Department of Pediatrics, Indiana University School of Medicine, Riley Children's Hospital, Indianapolis, Indiana, USA
| | - David S Hains
- Department of Pediatrics, Indiana University School of Medicine, Riley Children's Hospital, Indianapolis, Indiana, USA
| | - Sarah Calve
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
- Purdue University Interdisciplinary Life Science Program, Purdue University, West Lafayette, Indiana, USA
- Department of Mechanical Engineering, University of Colorado--Boulder, Boulder, Colorado, USA
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Wojcik HM, Lovvorn HN, Hollingshead M, Pierce J, Stotler H, Murphy AJ, Borgel S, Phelps HM, Correa H, Perantoni AO. Exploiting embryonic niche conditions to grow Wilms tumor blastema in culture. Front Oncol 2023; 13:1091274. [PMID: 37007076 PMCID: PMC10061139 DOI: 10.3389/fonc.2023.1091274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
IntroductionWilms Tumor (WT), or nephroblastoma, is the most common pediatric kidney cancer. Most WTs display a “favorable” triphasic histology, in which the tumor is comprised of blastemal, stromal, and epithelial cell types. Blastemal predominance after neoadjuvant chemotherapy or diffuse anaplasia (“unfavorable” histology; 5-8%) portend a worse prognosis. Blastema likely provide the putative cancer stem cells (CSCs), which retain molecular and histologic features characteristic of nephron progenitor cells (NPCs), within WTs. NPCs arise in the metanephric mesenchyme (MM) and populate the cap mesenchyme (CM) in the developing kidney. WT blastemal cells, like NPCs, similarly express markers, SIX2 and CITED1. Tumor xenotransplantation is currently the only dependable method to propagate tumor tissue for research or therapeutic screening, since efforts to culture tumors in vitro as monolayers have invariably failed. Therefore, a critical need exists to propagate WT stem cells rapidly and efficiently for high-throughput, real-time drug screening.MethodsPreviously, our lab developed niche conditions that support the propagation of murine NPCs in culture. Applying similar conditions to WTs, we assessed our ability to maintain key NPC "stemness" markers, SIX2, NCAM, and YAP1, and CSC marker ALDHI in cells from five distinct untreated patient tumors.ResultsAccordingly, our culture conditions maintained the expression of these markers in cultured WT cells through multiple passages of rapidly dividing cells.DiscussionThese findings suggest that our culture conditions sustain the WT blastemal population, as previously shown for normal NPCs. As a result, we have developed new WT cell lines and a multi-passage in vitro model for studying the blastemal lineage/CSCs in WTs. Furthermore, this system supports growth of heterogeneous WT cells, upon which potential drug therapies could be tested for efficacy and resistance.
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Affiliation(s)
- Heather M. Wojcik
- Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD, United States
| | - Harold N. Lovvorn
- Department of Pediatric Surgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
| | - Melinda Hollingshead
- Biological Testing Branch/Developmental Therapeutics Program, National Cancer Institute, Frederick, MD, United States
| | - Janene Pierce
- Department of Pediatric Surgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
| | - Howard Stotler
- Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, MD, United States
| | - Andrew J. Murphy
- Department of Pediatric Surgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
| | - Suzanne Borgel
- Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, MD, United States
| | - Hannah M. Phelps
- Department of Pediatric Surgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
| | - Hernan Correa
- Division of Pediatric Pathology, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
| | - Alan O. Perantoni
- Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD, United States
- *Correspondence: Alan O. Perantoni,
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Yu J, Yu C, Bayliss G, Zhuang S. Protein arginine methyltransferases in renal development, injury, repair, and fibrosis. Front Pharmacol 2023; 14:1123415. [PMID: 36817133 PMCID: PMC9935595 DOI: 10.3389/fphar.2023.1123415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Protein arginine methyltransferases (PRMTs) methylate a range of histone and non-histone substrates and participate in multiple biological processes by regulating gene transcription and post-translational modifications. To date, most studies on PRMTs have focused on their roles in tumors and in the physiological and pathological conditions of other organs. Emerging evidence indicates that PRMTs are expressed in the kidney and contribute to renal development, injury, repair, and fibrosis. In this review, we summarize the role and the mechanisms of PRMTs in regulating these renal processes and provide a perspective for future clinical applications.
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Affiliation(s)
- Jianjun Yu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chao Yu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Georgia Bayliss
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, United States
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, United States
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Zhang PL, Macknis JK. Immunohistochemical Panels to Evaluate Important Immunophenotypes of Human Mesonephros. Fetal Pediatr Pathol 2023; 42:1-17. [PMID: 35289709 DOI: 10.1080/15513815.2022.2045402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Background. The immunophenotypes and potential excretory function of human mesonephros are not well studied. Methods. Five mesonephros specimens of human embryos from the 6th to 10th weeks of gestation were stained with immunohistochemical markers. Results. PAX8 was universally expressed in all renal tubules, while α-methyacyl-CoA racemase (AMACAR) was positive in proximal tubules and GATA3 was positive in distal tubular mesonephric structures. At the 8th weeks of gestation, the mesonephric glomeruli were characterized by opened glomerular capillary loops with Periodic Acid Schiff (PAS)-positive glomerular basement membranes and GATA3-positive mesangial-like cells. By the 8th week, proximal tubules showed PAS-positive brush borders, indicating reabsorption capacity, and the proximal tubules also demonstrated positivity with kidney injury molecule-1 (KIM-1), representing tubular response to injury. Conclusion. Our overall findings show detailed phenotypes of the glomerular and tubular structures of the mesonephros and indicate that at the 8th week of gestation, the mesonephros may carry out temporary excretory function before metanephros becomes fully functional.
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Affiliation(s)
- Ping L Zhang
- Division of Anatomic Pathology, Beaumont Labs, Beaumont Health, Royal Oak, MI, USA
| | - Jacqueline K Macknis
- Division of Anatomic Pathology, Beaumont Labs, Beaumont Health, Royal Oak, MI, USA
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36
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Royer-Pokora B, Wruck W, Adjaye J, Beier M. Gene expression studies of WT1 mutant Wilms tumor cell lines in the frame work of published kidney development data reveals their early kidney stem cell origin. PLoS One 2023; 18:e0270380. [PMID: 36689432 PMCID: PMC9870146 DOI: 10.1371/journal.pone.0270380] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 11/21/2022] [Indexed: 01/24/2023] Open
Abstract
In order to get a better insight into the timing of WT1 mutant Wilms tumor development, we compared the gene expression profiles of nine established WT1 mutant Wilms tumor cell lines with published data from different kidney cell types during development. Publications describing genes expressed in nephrogenic precursor cells, ureteric bud cells, more mature nephrogenic epithelial cells and interstitial cell types were used. These studies uncovered that the WT1 mutant Wilms tumor cells lines express genes from the earliest nephrogenic progenitor cells, as well as from more differentiated nephron cells with the highest expression from the stromal/interstitial compartment. The expression of genes from all cell compartments points to an early developmental origin of the tumor in a common stem cell. Although variability of the expression of specific genes was evident between the cell lines the overall expression pattern was very similar. This is likely dependent on their different genetic backgrounds with distinct WT1 mutations and the absence/presence of mutant CTNNB1.
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Affiliation(s)
- Brigitte Royer-Pokora
- Institute of Human Genetics, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Wasco Wruck
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Manfred Beier
- Institute of Human Genetics, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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37
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Kumar S, Fan X, Rasouly HM, Sharma R, Salant DJ, Lu W. ZEB2 controls kidney stromal progenitor differentiation and inhibits abnormal myofibroblast expansion and kidney fibrosis. JCI Insight 2023; 8:e158418. [PMID: 36445780 PMCID: PMC9870089 DOI: 10.1172/jci.insight.158418] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 11/21/2022] [Indexed: 11/30/2022] Open
Abstract
FOXD1+ cell-derived stromal cells give rise to pericytes and fibroblasts that support the kidney vasculature and interstitium but are also major precursors of myofibroblasts. ZEB2 is a SMAD-interacting transcription factor that is expressed in developing kidney stromal progenitors. Here we show that Zeb2 is essential for normal FOXD1+ stromal progenitor development. Specific conditional knockout of mouse Zeb2 in FOXD1+ stromal progenitors (Zeb2 cKO) leads to abnormal interstitial stromal cell development, differentiation, and kidney fibrosis. Immunofluorescent staining analyses revealed abnormal expression of interstitial stromal cell markers MEIS1/2/3, CDKN1C, and CSPG4 (NG2) in newborn and 3-week-old Zeb2-cKO mouse kidneys. Zeb2-deficient FOXD1+ stromal progenitors also took on a myofibroblast fate that led to kidney fibrosis and kidney failure. Cell marker studies further confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers, including PDGFRβ, CSPG4, desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, SMAD4, and AXIN2. Thus, our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development, whereas loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.
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Dorison A, Forbes TA, Little MH. What can we learn from kidney organoids? Kidney Int 2022; 102:1013-1029. [PMID: 35970244 DOI: 10.1016/j.kint.2022.06.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/15/2022] [Accepted: 06/24/2022] [Indexed: 12/14/2022]
Abstract
The ability to generate 3-dimensional models of the developing human kidney via the directed differentiation of pluripotent stem cells-termed kidney organoids-has been hailed as a major advance in experimental nephrology. Although these provide an opportunity to interrogate human development, model-specific kidney diseases facilitate drug screening and even deliver bioengineered tissue; most of these prophetic end points remain to be realized. Indeed, at present we are still finding out what we can learn and what we cannot learn from this approach. In this review, we will summarize the approaches available to generate models of the human kidney from stem cells, the existing successful applications of kidney organoids, their limitations, and remaining challenges.
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Affiliation(s)
- Aude Dorison
- Murdoch Children's Research Institute, Parkville, Melbourne, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Melbourne, Australia; Novo Nordisk Foundation Centre for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Thomas A Forbes
- Murdoch Children's Research Institute, Parkville, Melbourne, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Melbourne, Australia; Department of Nephrology, Royal Children's Hospital, Parkville, Melbourne, Australia
| | - Melissa H Little
- Murdoch Children's Research Institute, Parkville, Melbourne, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Melbourne, Australia; Novo Nordisk Foundation Centre for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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Motojima M, Tanaka M, Kume T. Foxc1 and Foxc2 are indispensable for maintenance of progenitors of nephron and stroma in the developing kidney. J Cell Sci 2022; 135:276938. [PMID: 36073617 DOI: 10.1242/jcs.260356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Nephron development proceeds with reciprocal interactions among three layers: nephron progenitors (NPs), ureteric buds, and stromal progenitors (SPs). We found Foxc1 and Foxc2 (Foxc1/2) expression in NPs and SPs. Systemic deletion of Foxc1/2 two days after the onset of metanephros development (E13.5) resulted in epithelialization of NPs and ectopic formation of renal vesicles. NP-specific deletion did not cause these phenotypes, indicating that Foxc1/2 in other cells (likely in SPs) contributed to the maintenance of NPs. Single-cell RNA-seq analysis revealed NP and SP subpopulations, the border between committed NPs and renewing NPs, and similarity among cortical interstitium and vascular smooth muscle type cells. Integrated analysis of the control and knockout data indicated transformation of some NPs to strange cells expressing markers of vascular endothelium, reduced numbers of self-renewing NP and SP populations, downregulation of crucial genes for kidney development such as Fgf20 and Frem1 in NPs, and Foxd1 and Sall1 in SPs. It also revealed upregulation of genes that were not usually expressed in NPs and SPs. Thus, Foxc1/2 maintains NPs and SPs by regulating the expression of multiple genes.
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Affiliation(s)
- Masaru Motojima
- Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Masayuki Tanaka
- Medical Science College Office, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Tsutomu Kume
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
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40
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Drake KA, Chaney C, Patel M, Das A, Bittencourt J, Cohn M, Carroll TJ. Transcription Factors YAP/TAZ and SRF Cooperate To Specify Renal Myofibroblasts in the Developing Mouse Kidney. J Am Soc Nephrol 2022; 33:1694-1707. [PMID: 35918150 PMCID: PMC9529188 DOI: 10.1681/asn.2021121559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/23/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells. METHODS In embryonic mouse kidneys, we identified a subpopulation of stromal cells with enriched activity in YAP and TAZ. To evaluate the function of these cell types, we genetically ablated both Yap and Taz from the stromal progenitor population and examined how gene activity and development of YAP/TAZ mutant kidneys are affected over a developmental time course. RESULTS We found that YAP and TAZ are active in a subset of renal interstitium and that stromal-specific coablation of YAP/TAZ disrupts cortical fibroblast, pericyte, and myofibroblast development, with secondary effects on peritubular capillary differentiation. We also demonstrated that the transcription factor SRF cooperates with YAP/TAZ to drive expression of at least a subset of renal myofibroblast target genes and to specify myofibroblasts but not cortical fibroblasts or pericytes. CONCLUSIONS These findings reveal a critical role for YAP/TAZ in specific embryonic stromal cells and suggest that interaction with cofactors, such as SRF, influence the expression of cell type-specific target genes, thus driving stromal heterogeneity. Further, this work reveals functional roles for renal stroma heterogeneity in creating unique microenvironments that influence the differentiation and maintenance of the renal parenchyma.
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Affiliation(s)
- Keri A Drake
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Christopher Chaney
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mohita Patel
- Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Amrita Das
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Julia Bittencourt
- Department of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida, Gainesville, Florida
| | - Martin Cohn
- Department of Molecular Genetics and Microbiology, University of Florida Genetics Institute, University of Florida, Gainesville, Florida
| | - Thomas J Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas
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Minuth WW. The interstitium at the developing nephron in the fetal kidney during advanced pregnancy - a microanatomical inventory. Mol Cell Pediatr 2022; 9:17. [PMID: 36008693 PMCID: PMC9411487 DOI: 10.1186/s40348-022-00149-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 08/15/2022] [Indexed: 11/10/2022] Open
Abstract
Background A series of noxae can evoke the termination of nephron formation in preterm and low birth weight babies. This results in oligonephropathy with severe consequences for health in the later life. Although the clinical parameters have been extensively investigated, little is known about the initial damage. Previous pathological findings indicate the reduction in width of the nephrogenic zone and the lack of S-shaped bodies. Current morphological investigations suggest that due to the mutual patterning beside the forming nephron, also its structural neighbors, particularly the interjacent interstitium, must be affected. However, beside the findings on integrative and mastering functions, systematic microanatomical data explaining the configuration of the interstitium at the developing nephron in the fetal kidney during advanced pregnancy is not available. Therefore, this work explains the typical features. Results The generated data depicts that the progenitor cells, nephrogenic niche, pretubular aggregate, and mesenchymal-to-epithelial transition are restricted to the subcapsular interstitium. During the proceeding development, only the distal pole of the renal vesicles and comma- and S-shaped bodies stays in further contact with it. The respective proximal pole is positioned opposite the peritubular interstitium at the connecting tubule of an underlying but previously formed nephron. The related medial aspect faces the narrow peritubular interstitium of a collecting duct (CD) ampulla first only at its tip, then at its head, conus, and neck, and finally at the differentiating CD tubule. The lateral aspect starts at the subcapsular interstitium, but then it is positioned along the wide perivascular interstitium of the neighboring ascending perforating radiate artery. When the nephron matures, the interstitial configuration changes again. Conclusions The present investigation illustrates that the interstitium at the forming nephron in the fetal kidney consists of existing, transient, stage-specific, and differently far matured compartments. According to the developmental needs, it changes its shape by formation, degradation, fusion, and rebuilding.
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Affiliation(s)
- Will W Minuth
- Institute of Anatomy, University of Regensburg, 93053, Regensburg, Germany.
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Kobayashi H, Davidoff O, Pujari-Palmer S, Drevin M, Haase VH. EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis. Acta Physiol (Oxf) 2022; 235:e13826. [PMID: 35491502 PMCID: PMC9329237 DOI: 10.1111/apha.13826] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/14/2022] [Accepted: 04/28/2022] [Indexed: 12/22/2022]
Abstract
AIM Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. METHODS We investigated Epo transcription in myofibroblasts and characterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF-PHI molidustat. Lectin absorption chromatography was used to assess liver-derived EPO. In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy. RESULTS In AN, molidustat-induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α-smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin-expressing, kidney injury molecule 1-negative nephron segments and contingent on residual renal function. Liver-derived EPO did not contribute to serum EPO in molidustat-treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy. CONCLUSIONS Our studies suggest that HIF-PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function.
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Affiliation(s)
- Hanako Kobayashi
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Olena Davidoff
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | | | | | - Volker H Haase
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Department of Molecular Physiology & Biophysics and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Finer G, Maezawa Y, Ide S, Onay T, Souma T, Scott R, Liang X, Zhao X, Gadhvi G, Winter DR, Quaggin SE, Hayashida T. Stromal Transcription Factor 21 Regulates Development of the Renal Stroma via Interaction with Wnt/ β-Catenin Signaling. KIDNEY360 2022; 3:1228-1241. [PMID: 35919523 PMCID: PMC9337899 DOI: 10.34067/kid.0005572021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 04/12/2022] [Indexed: 01/11/2023]
Abstract
Background Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that transcription factor 21 (Tcf21) is required for ureteric bud branching. Here, we show that Tcf21 in Foxd1+ interstitial progenitors regulates stromal formation and differentiation via interaction with β-catenin. Methods We utilized the Foxd1Cre;Tcf21f/f murine kidney for morphologic analysis. We used the murine clonal mesenchymal cell lines MK3/M15 to study Tcf21 interaction with Wnt/β-catenin. Results Absence of Tcf21 from Foxd1+ stromal progenitors caused a decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in the Foxd1+ stromal cells also led to defective differentiation of interstitial cells to smooth-muscle cells, perivascular pericytes, and mesangial cells. Foxd1Cre;Tcf21f/f kidney showed an abnormal pattern of the renal vascular tree. The stroma of Foxd1Cre;Tcf21f/f kidney demonstrated marked reduction in β-catenin protein expression compared with wild type. Tcf21 was bound to β-catenin both upon β-catenin stabilization and at basal state as demonstrated by immunoprecipitation in vitro. In MK3/M15 metanephric mesenchymal cells, Tcf21 enhanced TCF/LEF promoter activity upon β-catenin stabilization, whereas DNA-binding deficient mutated Tcf21 did not enhance TCF/LEF promoter activity. Kidney explants of Foxd1Cre;Tcf21f/f showed low mRNA expression of stromal Wnt target genes. Treatment of the explants with CHIR, a Wnt ligand mimetic, restored Wnt target gene expression. Here, we also corroborated previous evidence that normal development of the kidney stroma is required for normal development of the Six2+ nephron progenitor cells, loop of Henle, and the collecting ducts. Conclusions These findings suggest that stromal Tcf21 facilitates medullary stroma development by enhancing Wnt/β-catenin signaling and promotes stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.
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Affiliation(s)
- Gal Finer
- Division of Nephrology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Yoshiro Maezawa
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shintaro Ide
- Department of Medicine, Duke University, Durham, North Carolina
| | - Tuncer Onay
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Tomokazu Souma
- Department of Medicine, Duke University, Durham, North Carolina
| | - Rizaldy Scott
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xiaoyan Liang
- Division of Nephrology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xiangmin Zhao
- Division of Nephrology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
| | - Gaurav Gadhvi
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Deborah R. Winter
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Susan E. Quaggin
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Tomoko Hayashida
- Division of Nephrology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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44
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Huang B, Zeng Z, Zhang CC, Schreiber ME, Li Z. Approaches to kidney replacement therapies—opportunities and challenges. Front Cell Dev Biol 2022; 10:953408. [PMID: 35982852 PMCID: PMC9380013 DOI: 10.3389/fcell.2022.953408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
One out of seven people develop chronic kidney disease (CKD). When kidney function continues to decline, CKD patients may develop end-stage renal disease (ESRD, or kidney failure). More than 2 out of 1,000 adults develop ESRD and these patients must live on dialysis or get a kidney transplant to survive. Each year, more than $51 billion is spent to treat patients with ESRD in the United States. In addition, ESRD greatly reduces longevity and quality of life for patients. Compared to dialysis, kidney transplant offers the best chance of survival, but few donor organs are available. Thus, there is an urgent need for innovative solutions that address the shortage of kidneys available for transplantation. Here we summarize the status of current approaches that are being developed to solve the shortage of donor kidneys. These include the bioartificial kidney approach which aims to make a portable dialysis device, the recellularization approach which utilizes native kidney scaffold to make an engineered kidney, the stem cell-based approach which aims to generate a kidney de novo by recapitulating normal kidney organogenesis, the xenotransplantation approach which has the goal to make immunocompatible pig kidneys for transplantation, and the interspecies chimera approach which has potential to generate a human kidney in a host animal. We also discuss the interconnections among the different approaches, and the remaining challenges of translating these approaches into novel therapies.
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Affiliation(s)
- Biao Huang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Zipeng Zeng
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Chennan C. Zhang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Megan E. Schreiber
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Zhongwei Li
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Zhongwei Li,
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45
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Lebeau G, Ah-Pine F, Daniel M, Bedoui Y, Vagner D, Frumence E, Gasque P. Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses? Int J Mol Sci 2022; 23:ijms23148038. [PMID: 35887383 PMCID: PMC9317325 DOI: 10.3390/ijms23148038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/16/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.
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Affiliation(s)
- Grégorie Lebeau
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Franck Ah-Pine
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Service Anatomo-Pathologie, CHU de la Réunion, 97400 Saint-Denis, France
| | - Matthieu Daniel
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Yosra Bedoui
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Damien Vagner
- Service de Médecine Interne, CHU de la Réunion, 97400 Saint-Denis, France;
| | - Etienne Frumence
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Philippe Gasque
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
- Correspondence:
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Kobayashi A, Nishinakamura R. Building kidney organoids from pluripotent stem cells. Curr Opin Nephrol Hypertens 2022; 31:367-373. [PMID: 35727170 DOI: 10.1097/mnh.0000000000000807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW During embryogenesis, the kidney is mainly generated from three progenitor cells; nephron progenitors, ureteric bud progenitors and stromal progenitors. Mutual interactions of the all three progenitor populations are essential to form a functional kidney with the higher-order structure. Pluripotent stem cells have potential to differentiate into all cell types of the animal body, including the kidney. In this review, we will summarize recent advances in reconstructing kidney organoids from pluripotent stem cells. RECENT FINDINGS In the past years, major advances were reported to induce nephron and ureteric bud progenitors from pluripotent stem cells in mice and humans, and to create kidney organoids of nephron and/or ureteric bud-derived collecting duct tissues in vitro. These kidney organoid technologies were applied to high-throughput genetic screenings and small chemical screenings to identify key factors for kidney development and disease. Furthermore, a novel method was established to induce stromal progenitors from pluripotent stem cells, leading to creation of kidney organoids with the higher-order structures completely derived from pluripotent stem cells. SUMMARY These advances in kidney organoids from pluripotent stem cells should lay a foundation to establish a novel therapy for kidney disease, which ultimately eliminate the need of dialysis and kidney transplantation for patients with kidney disease in the future.
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Affiliation(s)
- Akio Kobayashi
- Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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47
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Röck R, Rizzo L, Lienkamp SS. Kidney Development: Recent Insights from Technological Advances. Physiology (Bethesda) 2022; 37:0. [PMID: 35253460 DOI: 10.1152/physiol.00041.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The kidney is a complex organ, and how it forms is a fascinating process. New technologies, such as single-cell transcriptomics, and enhanced imaging modalities are offering new approaches to understand the complex and intertwined processes during embryonic kidney development.
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Affiliation(s)
- Ruth Röck
- Institute of Anatomy, University of Zurich, Zurich, Switzerland.,Swiss National Centres of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), Zurich, Switzerland
| | - Ludovica Rizzo
- Institute of Anatomy, University of Zurich, Zurich, Switzerland.,Swiss National Centres of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), Zurich, Switzerland.,PhD program "Molecular and Translational Biomedicine," Life Science Zurich Graduate School, Zurich, Switzerland
| | - Soeren S Lienkamp
- Institute of Anatomy, University of Zurich, Zurich, Switzerland.,Swiss National Centres of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), Zurich, Switzerland
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48
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Ferician AM, Ferician OC, Cumpanas AD, Berzava PL, Nesiu A, Barmayoun A, Cimpean AM. Heterogeneity of Platelet Derived Growth Factor Pathway Gene Expression Profile Defines Three Distinct Subgroups of Renal Cell Carcinomas. Cancer Genomics Proteomics 2022; 19:477-489. [PMID: 35732321 PMCID: PMC9247877 DOI: 10.21873/cgp.20334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/18/2022] [Accepted: 05/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM We previously described four different vascular patterns (reticular, diffuse, fasciculate, and trabecular) in renal cell carcinoma (RCC) suggesting an early and heterogeneous acquisition of perivascular cells most probably due to a particular PDGF pathway gene expression profile. The aim of the study was to study PDGF pathway gene expression profiles, separately for each vascular pattern. MATERIALS AND METHODS TaqMan assay for the PDGF pathway was performed on twelve cases of ccRCC previously evaluated by histopathology, immunohistochemistry, and RNAscope. Gene expression profile was correlated with grade, invasion, vascular patterns, and VEGF. RESULTS PIK3C3 and SLC9A3 genes were overexpressed in all vascular patterns, but they were significantly correlated with high VEGF mRNA in the reticular and diffuse pattern. STAT1, JAK2, SHC2, SRF and CHUK (IKK) were exclusively overexpressed in cases with diffuse vascular pattern. SLC9A3, CHUK and STAT3 were overexpressed in G2 tumors. CONCLUSION Three ccRCC subgroups were defined: 1) PIK3C3 (VSP34)/SLC9A3 which may be proper for anti PIK3C3 inhibitors; 2) VEGFhigh subgroup where association of anti VEGF may be a benefit and 3) JAK2/STAT1 subgroup, potentially being eligible for anti JAK/STAT therapy associated with IKK inhibitors.
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Affiliation(s)
- Adela Maria Ferician
- Department of Orthopedy and Traumatology/Urology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Ovidiu Catalin Ferician
- Department of Orthopedy and Traumatology/Urology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania;
| | - Andrei Dragos Cumpanas
- Department of Microscopic Morphology/Histology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Patricia Lorena Berzava
- Department of Microscopic Morphology/Histology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Alexandru Nesiu
- Department of Urology, Faculty of Medicine "Vasile Goldiş" Western University, Arad, Romania
| | - Ariana Barmayoun
- Klinik fur Psychiatrie, Psychosomatik und Psychotherapie, Uniklinikum Frankfurt, Frankfurt, Germany
| | - Anca Maria Cimpean
- Department of Microscopic Morphology/Histology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Center of Expertise for Rare Vascular Disease in Children, Emergency Hospital for Children Louis Turcanu, Timisoara, Romania
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49
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Saito Y, Yamanaka S, Matsumoto N, Takamura T, Fujimoto T, Matsui K, Tajiri S, Matsumoto K, Kobayashi E, Yokoo T. Generation of functional chimeric kidney containing exogenous progenitor-derived stroma and nephron via a conditional empty niche. Cell Rep 2022; 39:110933. [PMID: 35705028 DOI: 10.1016/j.celrep.2022.110933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/31/2022] [Accepted: 05/18/2022] [Indexed: 11/17/2022] Open
Abstract
Generation of new kidneys can be useful in various research fields, including organ transplantation. However, generating renal stroma, an important component tissue for structural support, endocrine function, and kidney development, remains difficult. Organ generation using an animal developmental niche can provide an appropriate in vivo environment for renal stroma differentiation. Here, we generate rat renal stroma with endocrine capacity by removing mouse stromal progenitor cells (SPCs) from the host developmental niche and transplanting rat SPCs. Furthermore, we develop a method to replace both nephron progenitor cells (NPCs) and SPCs, called the interspecies dual replacement of the progenitor (i-DROP) system, and successfully generate functional chimeric kidneys containing rat nephrons and stroma. This method can generate renal tissue from progenitors and reduce xenotransplant rejection. Moreover, it is a safe method, as donor cells do not stray into nontarget organs, thus accelerating research on stem cells, chimeras, and xenotransplantation.
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Affiliation(s)
- Yatsumu Saito
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Shuichiro Yamanaka
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoto Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Takamura
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toshinari Fujimoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenji Matsui
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Susumu Tajiri
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kei Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Eiji Kobayashi
- Department of Kidney Regenerative Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
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50
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Abstract
MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.
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Affiliation(s)
- Débora Malta Cerqueira
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Maliha Tayeb
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jacqueline Ho
- Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- John G. Rangos Sr. Research Center, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
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