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nephron progenitor cells

Lori L O'Brien, Alexander N Combes, Kieran M Short, Nils O Lindström, Peter H Whitney, Luise A Cullen-McEwen, Adler Ju, Ahmed Abdelhalim, Odyssé Michos, John F Bertram, Ian M Smyth, Melissa H Little, Andrew P McMahon
A normal endowment of nephrons in the mammalian kidney requires a balance of nephron progenitor self-renewal and differentiation throughout development. Here, we provide evidence for a novel action of ureteric branch tip-derived Wnt11 in progenitor cell organization and interactions within the nephrogenic niche, ultimately determining nephron endowment. In Wnt11 mutants, nephron progenitors dispersed from their restricted niche, intermixing with interstitial progenitors. Nephron progenitor differentiation was accelerated, kidneys were significantly smaller, and the nephron progenitor pool was prematurely exhausted, halving the final nephron count...
December 5, 2018: ELife
Masaki Nishikawa, Shunsuke Yuri, Hiroshi Kimura, Naomi Yanagawa, Morgan Hamon, Peter Hauser, Lifu Zhao, Oak D Jo, Norimoto Yanagawa
Emerging evidence from recent studies has unraveled the roles of long noncoding RNAs (lncRNAs) in the function of various tissues. However, little is known about the roles of lncRNAs in kidney development. In our present study, we aimed to identify functional lncRNAs in one of the three lineages of kidney progenitor cells, i.e., metanephric mesenchymal (MM) cells. We conducted comprehensive analyses of the chromatin signature and transcriptome by RNA-seq and ChIP-seq. We found seventeen lncRNAs that were expressed specifically in MM cells with an active chromatin signature, while remaining silenced in a bivalent chromatin state in non-MM cells...
September 14, 2018: Biochimica et biophysica acta. Gene regulatory mechanisms
Simone Romoli, Maria Lucia Angelotti, Giulia Antonelli, Santhosh Kumar Vr, Shrikant R Mulay, Jyaysi Desai, Lidia Anguiano Gomez, Dana Thomasova, Dirk Eulberg, Sven Klussmann, Maria Elena Melica, Carolina Conte, Duccio Lombardi, Laura Lasagni, Hans-Joachim Anders, Paola Romagnani
Insufficient podocyte regeneration after injury is a central pathomechanism of glomerulosclerosis and chronic kidney disease. Podocytes constitutively secrete the chemokine CXCL12, which is known to regulate homing and activation of stem cells; hence we hypothesized a similar effect of CXCL12 on podocyte progenitors. CXCL12 blockade increased podocyte numbers and attenuated proteinuria in mice with Adriamycin-induced nephropathy. Similar studies in lineage-tracing mice revealed enhanced de novo podocyte formation from parietal epithelial cells in the setting of CXCL12 blockade...
October 22, 2018: Kidney International
Philip Kruber, Oguzhan Angay, Anja Winkler, Michael R Bösl, Susanne Kneitz, Katrin G Heinze, Manfred Gessler
Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes DROSHA and DGCR8 have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the in vivo role of DROSHA mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA carrying a tumor-specific E1147K mutation that acts in a dominant negative manner...
October 27, 2018: International Journal of Cancer. Journal International du Cancer
Krithika Hariharan, Harald Stachelscheid, Bella Rossbach, Su-Jun Oh, Nancy Mah, Kai Schmidt-Ott, Andreas Kurtz, Petra Reinke
Human pluripotent stem cells (hPSCs) provide a source for the generation of defined kidney cells and renal organoids applicable in regenerative medicine, disease modeling, and drug screening. These applications require the provision of hPSC-derived renal cells by reproducible, scalable, and efficient methods. We established a chemically defined protocol by application of Activin A, BMP4, and Retinoic acid followed by GDNF, which steered hPSCs to the renal lineage and resulted in populations of SIX2+ /CITED1+ metanephric mesenchyme- (MM) and of HOXB7+ /GRHL2+ ureteric bud (UB)-like cells already by 6 days...
October 11, 2018: Cellular and Molecular Life Sciences: CMLS
Susumu Tajiri, Shuichiro Yamanaka, Toshinari Fujimoto, Kei Matsumoto, Atsuhiro Taguchi, Ryuichi Nishinakamura, Hirotaka James Okano, Takashi Yokoo
Kidney regeneration from pluripotent stem cells is receiving a lot of attention because limited treatments are currently available for chronic kidney disease (CKD). It has been shown that uremic state in CKD is toxic to somatic stem/progenitor cells, such as endothelial progenitor and mesenchymal stem cells, affecting their differentiation and angiogenic potential. Recent studies reported that specific abnormalities caused by the non-inherited disease are often retained in induced pluripotent stem cell (iPSC)-derived products obtained from patients...
October 8, 2018: Scientific Reports
Ping Wang, Yidong Chen, Jun Yong, Yueli Cui, Rui Wang, Lu Wen, Jie Qiao, Fuchou Tang
Healthy renal function depends on normal nephrogenesis during embryonic development. However, a comprehensive gene expression profile of human fetal kidney development remains largely unexplored. Here, using a single-cell RNA-sequencing technique, we analyzed >3,000 human fetal renal cells spanning 4 months of development in utero. Unsupervised analysis identified two progenitor subtypes during cap mesenchyme development, suggesting a mechanism for sustaining their progenitor states. Furthermore, we identified critical transcriptional regulators and signaling pathways involved in the segmentation of nephron tubules...
September 25, 2018: Cell Reports
Anneliis Ihermann-Hella, Tsuyoshi Hirashima, Jussi Kupari, Kristen Kurtzeborn, Hao Li, Hyuk Nam Kwon, Cristina Cebrian, Abdul Soofi, Arvydas Dapkunas, Ilkka Miinalainen, Gregory R Dressler, Michiyuki Matsuda, Satu Kuure
The in vivo niche and basic cellular properties of nephron progenitors are poorly described. Here we studied the cellular organization and function of the MAPK/ERK pathway in nephron progenitors. Live-imaging of ERK activity by a Förster resonance energy transfer biosensor revealed a dynamic activation pattern in progenitors, whereas differentiating precursors exhibited sustained activity. Genetic experiments demonstrate that MAPK/ERK activity controls the thickness, coherence, and integrity of the nephron progenitor niche...
October 9, 2018: Stem Cell Reports
Melissa H Little, Santhosh V Kumar, Thomas Forbes
Decades of research into the molecular and cellular regulation of kidney morphogenesis in rodent models, particularly the mouse, has provided both an atlas of the mammalian kidney and a roadmap for recreating kidney cell types with potential applications for the treatment of kidney disease. With advances in both our capacity to maintain nephron progenitors in culture, reprogram to kidney cell types and direct the differentiation of human pluripotent stem cells to kidney endpoints, renal regeneration via cellular therapy or tissue engineering may be possible...
September 20, 2018: Seminars in Cell & Developmental Biology
Samir S El-Dahr, Zubaida Saifudeen
Developmental changes in cell fate are tightly regulated by cell-type specific transcription factors. Chromatin reorganization during organismal development ensures dynamic access of developmental regulators to their cognate DNA sequences. Thus, understanding the epigenomic states of promoters and enhancers is of key importance. Recent years have witnessed significant advances in our knowledge of the transcriptional mechanisms of kidney development. Emerging evidence suggests that histone deacetylation by class I HDACs and H3 methylation on lysines 4, 27 and 79 play important roles in regulation of early and late gene expression in the developing kidney...
September 5, 2018: Seminars in Cell & Developmental Biology
Rajasree Menon, Edgar A Otto, Austin Kokoruda, Jian Zhou, Zidong Zhang, Euisik Yoon, Yu-Chih Chen, Olga Troyanskaya, Jason R Spence, Matthias Kretzler, Cristina Cebrián
The mammalian kidney develops through reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons. Most of our knowledge of the developmental regulators driving this process arises from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used single-cell transcriptomics to characterize gene expression in different cell populations, and to study individual cell dynamics and lineage trajectories during development...
August 30, 2018: Development
Jiayi Wang, Jianyong Zhong, Hai-Chun Yang, Agnes B Fogo
Tubular injury sensitizes glomeruli to injury. We review potential mechanisms of this tubuloglomerular cross talk. In the same nephron, tubular injury can cause stenosis of the glomerulotubular junction and finally result in atubular glomeruli. Tubular injury also affects glomerular filtration function through tubuloglomerular feedback. Progenitor cells, that is, parietal epithelial cells and renin positive cells, can be involved in repair of injured glomeruli and also may be modulated by tubular injury. Loss of nephrons induces additional workload and stress on remaining nephrons...
August 29, 2018: Toxicologic Pathology
Leif Oxburgh
The nephron is a multifunctional filtration device equipped with an array of sophisticated sensors. For appropriate physiological function in the human and mouse, nephrons must be stereotypically arrayed in large numbers, and this essential structural property that defines the kidney is determined during its fetal development. This review explores the process of nephron determination in the fetal kidney, providing an overview of the foundational literature in the field as well as exploring new developments in this dynamic research area...
October 6, 2018: Annual Review of Cell and Developmental Biology
Cecilia Boreström, Anna Jonebring, Jing Guo, Henrik Palmgren, Linda Cederblad, Anna Forslöw, Anna Svensson, Magnus Söderberg, Anna Reznichenko, Jenny Nyström, Jaakko Patrakka, Ryan Hicks, Marcello Maresca, Barbara Valastro, Anna Collén
Development of physiologically relevant cellular models with strong translatability to human pathophysiology is critical for identification and validation of novel therapeutic targets. Herein we describe a detailed protocol for generation of an advanced 3-dimensional kidney cellular model using induced pluripotent stem cells, where differentiation and maturation of kidney progenitors and podocytes can be monitored in live cells due to CRISPR/Cas9-mediated fluorescent tagging of kidney lineage markers (SIX2 and NPHS1)...
July 20, 2018: Kidney International
Kieran M Short, Alexander N Combes, Valerie Lisnyak, James G Lefevre, Lynelle K Jones, Melissa H Little, Nicholas A Hamilton, Ian M Smyth
Branching morphogenesis of the ureteric bud is integral to kidney development; establishing the collecting ducts of the adult organ and driving organ expansion via peripheral interactions with nephron progenitor cells. A recent study suggested that termination of tip branching within the developing kidney involved stochastic exhaustion in response to nephron formation, with such a termination event representing a unifying developmental process evident in many organs. To examine this possibility, we have profiled the impact of nephron formation and maturation on elaboration of the ureteric bud during mouse kidney development...
July 31, 2018: ELife
Lori L O'Brien
The filtering component of the kidney, the nephron, arises from a single progenitor population. These nephron progenitor cells (NPCs) both self-renew and differentiate throughout the course of kidney development ensuring sufficient nephron endowment. An appropriate balance of these processes must be struck as deficiencies in nephron numbers are associated with hypertension and kidney disease. This review will discuss the mechanisms and molecules supporting NPC maintenance and differentiation. A focus on recent work will highlight new molecular insights into NPC regulation and their dynamic behavior in both space and time...
July 30, 2018: Seminars in Cell & Developmental Biology
Samira Musah, Nikolaos Dimitrakakis, Diogo M Camacho, George M Church, Donald E Ingber
Protocols have been established to direct the differentiation of human induced pluripotent stem (iPS) cells into nephron progenitor cells and organoids containing many types of kidney cells, but it has been difficult to direct the differentiation of iPS cells to form specific types of mature human kidney cells with high yield. Here, we describe a detailed protocol for the directed differentiation of human iPS cells into mature, post-mitotic kidney glomerular podocytes with high (>90%) efficiency within 26 d and under chemically defined conditions, without genetic manipulations or subpopulation selection...
July 2018: Nature Protocols
Silvia Ferrè, Peter Igarashi
Hepatocyte nuclear factor-1β (HNF-1β) is an essential transcription factor that regulates the development and function of epithelia in the kidney, liver, pancreas, and genitourinary tract. Humans who carry HNF1B mutations develop heterogeneous renal abnormalities, including multicystic dysplastic kidneys, glomerulocystic kidney disease, renal agenesis, renal hypoplasia, and renal interstitial fibrosis. In the embryonic kidney, HNF-1β is required for ureteric bud branching, initiation of nephrogenesis, and nephron segmentation...
July 1, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Ryan W Hunter, Yangjian Liu, Hema Manjunath, Asha Acharya, Benjamin T Jones, He Zhang, Beibei Chen, Harini Ramalingam, Robert E Hammer, Yang Xie, James A Richardson, Dinesh Rakheja, Thomas J Carroll, Joshua T Mendell
Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels...
July 1, 2018: Genes & Development
Christopher J Rowan, Winny Li, Hovhannes Martirosyan, Steven Erwood, Di Hu, Yun-Kyo Kim, Sepideh Sheybani-Deloui, Jaap Mulder, Joshua Blake, Lin Chen, Norman D Rosenblum
Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened ( Smo -deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization...
July 9, 2018: Development
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