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nephron progenitor cells

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 Combes, Valerie Lisnyak, James Lefevre, Lynelle Jones, Melissa H Little, Nicholas Hamilton, Ian Macleod 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
Le Zhang, Sandrine Ettou, Myda Khalid, Mary Taglienti, Dhawal Jain, Youngsook L Jung, Catherine Seager, Yongqing Liu, Kar-Hui Ng, Peter J Park, Jordan A Kreidberg
Epigenetic regulation of gene expression has a crucial role allowing for the self-renewal and differentiation of stem and progenitor populations during organogenesis. The mammalian kidney maintains a population of self-renewing stem cells that differentiate to give rise to thousands of nephrons, which are the functional units that carry out filtration to maintain physiological homeostasis. The polycomb repressive complex 2 (PRC2) epigenetically represses gene expression during development by placing the H3K27me3 mark on histone H3 at promoter and enhancer sites, resulting in gene silencing...
July 18, 2018: Development
Francesca Becherucci, Benedetta Mazzinghi, Marco Allinovi, Maria Lucia Angelotti, Paola Romagnani
Chronic kidney disease is a major health-care problem worldwide and its cost is becoming no longer affordable. Indeed, restoring damaged renal structures or building a new kidney represents an ambitious and ideal alternative to renal replacement therapy. Streams of research have explored the possible application of pluripotent stem cells (SCs) (embryonic SCs and induced pluripotent SCs) in different strategies aimed at regenerate functioning nephrons and at understanding the mechanisms of kidney regeneration...
July 2018: Expert Opinion on Biological Therapy
Nils O Lindström, Guilherme De Sena Brandine, Tracy Tran, Andrew Ransick, Gio Suh, Jinjin Guo, Albert D Kim, Riana K Parvez, Seth W Ruffins, Elisabeth A Rutledge, Matthew E Thornton, Brendan Grubbs, Jill A McMahon, Andrew D Smith, Andrew P McMahon
Mammalian nephrons arise from a limited nephron progenitor pool through a reiterative inductive process extending over days (mouse) or weeks (human) of kidney development. Here, we present evidence that human nephron patterning reflects a time-dependent process of recruitment of mesenchymal progenitors into an epithelial nephron precursor. Progressive recruitment predicted from high-resolution image analysis and three-dimensional reconstruction of human nephrogenesis was confirmed through direct visualization and cell fate analysis of mouse kidney organ cultures...
June 4, 2018: Developmental Cell
Oded Volovelsky, Thi Nguyen, Alison E Jarmas, Alexander N Combes, Sean B Wilson, Melissa H Little, David P Witte, Eric W Brunskill, Raphael Kopan
Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth...
June 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Masaki Nishikawa, Hiroshi Kimura, Naomi Yanagawa, Morgan Hamon, Peter Hauser, Lifu Zhao, Oak D Jo, Norimoto Yanagawa
Kidney organoid is an emerging topic of importance for research in kidney development and regeneration. Conventional culture systems for kidney organoids reported thus far use culture media containing serum, which may compromise our understanding and the potential clinical applicability of the organoid system. In our present study, we tested two serum-free culture conditions and compared their suitability for the maintenance and growth of kidney organoids in culture. One of the serum-free culture conditions was the combination of keratinocytes serum free medium (KSFM) with knockout serum replacement (KSR) (KSFM + KSR), and the other was the combination of knockout DMEM/F12 (KD/F12) and KSR (KD/F12 + KSR)...
July 2, 2018: Biochemical and Biophysical Research Communications
Hongbing Liu, Shaowei Chen, Xiao Yao, Yuwen Li, Chao-Hui Chen, Jiao Liu, Zubaida Saifudeen, Samir S El-Dahr
Nephron progenitor cells (NPCs) are Six2-positive metanephric mesenchyme cells, which undergo self-renewal and differentiation to give rise to nephrons until the end of nephrogenesis. Histone deacetylases (HDACs) are a group of epigenetic regulators that control cell fate, but their role in balancing NPC renewal and differentiation is unknown. Here, we report that NPC-specific deletion of Hdac1 and Hdac2 genes in mice results in early postnatal lethality owing to renal hypodysplasia and loss of NPCs. HDAC1/2 interact with the NPC renewal regulators Six2, Osr1 and Sall1, and are co-bound along with Six2 on the Six2 enhancer...
May 18, 2018: Development
Harini Ramalingam, Alicia R Fessler, Amrita Das, M Todd Valerius, Jeannine Basta, Lynn Robbins, Aaron C Brown, Leif Oxburgh, Andrew P McMahon, Michael Rauchman, Thomas J Carroll
Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear...
August 1, 2018: Developmental Biology
Keri A Drake, Mike Adam, Robert Mahoney, S Steven Potter
Hox genes are important regulators of development. The 39 mammalian Hox genes have considerable functional overlap, greatly confounding their study. In this report, we generated mice with multiple combinations of paralogous and flanking Abd-B Hox gene mutations to investigate functional redundancies in kidney development. The resulting mice developed a number of kidney abnormalities, including hypoplasia, agenesis, and severe cysts, with distinct Hox functions observed in early metanephric kidney formation and nephron progenitor maintenance...
April 20, 2018: Scientific Reports
Edward Daniel, D Berfin Azizoglu, Anne R Ryan, Tezin A Walji, Christopher P Chaney, Gabrielle I Sutton, Thomas J Carroll, Denise K Marciano, Ondine Cleaver
The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3-dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10...
August 2018: Angiogenesis
Renfang Song, Laura Kidd, Adam Janssen, Ihor V Yosypiv
Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells (NPCs) of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V-ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (Six2PRR -/- ) causes early neonatal death. Here, we identified genes that are regulated by PRR in Six2+ NPCs FACS-isolated from Six2PRR -/- and control kidneys on embryonic day E15...
April 2018: Physiological Reports
Bliss Magella, Robert Mahoney, Mike Adam, S Steven Potter
Hox genes can function as key drivers of segment identity, with Hox mutations in Drosophila often resulting in dramatic homeotic transformations. In addition, however, they can serve other essential functions. In mammals, the study of Hox gene roles in development is complicated by the presence of four Hox clusters with a total of 39 genes showing extensive functional overlap. In this study, in order to better understand shared core Hox functions, we examined kidney development in mice with frameshift mutations of multiple Abd-B type Hox genes...
June 15, 2018: Developmental Biology
Karen L Price, Maria Kolatsi-Joannou, Chiara Mari, David A Long, Paul J D Winyard
Kidney function is directly linked to the number of nephrons which are generated until 32-36 weeks gestation in humans. Failure to make nephrons during development leads to congenital renal malformations, whilst nephron loss in adulthood occurs in progressive renal disease. Therefore, an understanding of the molecular processes which underlie human nephron development may help design new treatments for renal disease. Mesenchyme to epithelial transition (MET) is critical for forming nephrons, and molecular pathways which control rodent MET have been identified...
December 2018: Cell Death Discovery
Nils O Lindström, Jill A McMahon, Jinjin Guo, Tracy Tran, Qiuyu Guo, Elisabeth Rutledge, Riana K Parvez, Gohar Saribekyan, Robert E Schuler, Christopher Liao, Albert D Kim, Ahmed Abdelhalim, Seth W Ruffins, Matthew E Thornton, Laurence Basking, Brendan Grubbs, Carl Kesselman, Andrew P McMahon
Human kidney function is underpinned by approximately 1,000,000 nephrons, although the number varies substantially, and low nephron number is linked to disease. Human kidney development initiates around 4 weeks of gestation and ends around 34-37 weeks of gestation. Over this period, a reiterative inductive process establishes the nephron complement. Studies have provided insightful anatomic descriptions of human kidney development, but the limited histologic views are not readily accessible to a broad audience...
March 2018: Journal of the American Society of Nephrology: JASN
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