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nephron progenitor cells

David Ad Munro, Yishay Wineberg, Julia Tarnick, Chris S Vink, Zhuan Li, Clare Pridans, Elaine Dzierzak, Tomer Kalisky, Peter Hohenstein, Jamie A Davies
The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis...
February 13, 2019: ELife
Pauli Tikka, Franz Schaefer
This chapter reviews some currently available methodologies for constructing mathematical models in kidney development. Mammalian nephrogenesis is a complex biological process, which in its earliest stages involves migration, condensation, proliferation, and differentiation of metanephric mesenchymal (MM) cells interacting with the uroepithelial cells of the ureteric bud (UB). First, the mathematical modelling in biology is generally described. Secondly, some accounts to biological pattern formation in modelling are given in general, including models that transcend the Turing model...
2019: Methods in Molecular Biology
Zhongwei Li, Toshikazu Araoka, Juan Carlos Izpisua Belmonte
During kidney development, Six2+ nephron progenitor cells (NPCs) generate nephrons, the functional units of the kidney. Isolating and expanding NPCs in vitro have enabled wide applications in both basic and translational research. Here we describe the methods to derive NPC lines from mouse embryonic kidneys in a 3D culture format as well as gene editing in the NPC lines.
2019: Methods in Molecular Biology
Yasuhiro Yoshimura, Atsuhiro Taguchi, Ryuichi Nishinakamura
Nephrons, the functional units of the kidney, are derived from nephron progenitor cells (NPCs). Here, we describe methods to reconstruct nephron tissue via induction of NPCs from mouse and human pluripotent stem cells, which mimic multistep developmental signals in vivo. Induced NPCs differentiate into three-dimensional nephron structures, including glomerular podocytes and nephric tubules, which are useful for studying early stages of kidney specification and morphogenetic processes in the context of normal development or disease...
2019: Methods in Molecular Biology
Aaron C Brown, Ashwani K Gupta, Leif Oxburgh
Nephrons differentiate from the cap mesenchyme of the fetal kidney. Nephron progenitor cells that populate the cap mesenchyme efficiently balance self-renewal and epithelial differentiation to enable repeated rounds of nephron formation during development. Here we describe a method to isolate and propagate these cells from the embryonic mouse kidney. Using this method, nephron progenitor cells from a single litter of mice can be propagated to hundreds of millions of cells that express appropriate markers of the undifferentiated state and retain epithelial differentiation capacity in vitro...
2019: Methods in Molecular Biology
Teppei Goto, Hiromasa Hara, Makoto Sanbo, Hideki Masaki, Hideyuki Sato, Tomoyuki Yamaguchi, Shinichi Hochi, Toshihiro Kobayashi, Hiromitsu Nakauchi, Masumi Hirabayashi
Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor...
February 5, 2019: Nature Communications
Ken Hiratsuka, Toshiaki Monkawa, Tomohiko Akiyama, Yuhki Nakatake, Mayumi Oda, Sravan Kumar Goparaju, Hiromi Kimura, Nana Chikazawa-Nohtomi, Saeko Sato, Keiichiro Ishiguro, Shintaro Yamaguchi, Sayuri Suzuki, Ryuji Morizane, Shigeru B H Ko, Hiroshi Itoh, Minoru S H Ko
The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2+ SALL1+ nephron progenitor cells with 92% efficiency within 2 days...
January 29, 2019: Scientific Reports
Kynan T Lawlor, Luke Zappia, James Lefevre, Joo-Seop Park, Nicholas A Hamilton, Alicia Oshlack, Melissa H Little, Alexander Nicholas Combes
Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here we examine how progenitor cell migration impacts regionally induced commitment within the nephrogenic niche in mice. We identify a subset of cells that express Wnt4 , an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction...
January 24, 2019: ELife
Alexander N Combes, Luke Zappia, Pei Xuan Er, Alicia Oshlack, Melissa H Little
BACKGROUND: Human kidney organoids hold promise for studying development, disease modelling and drug screening. However, the utility of stem cell-derived kidney tissues will depend on how faithfully these replicate normal fetal development at the level of cellular identity and complexity. METHODS: Here, we present an integrated analysis of single cell datasets from human kidney organoids and human fetal kidney to assess similarities and differences between the component cell types...
January 23, 2019: Genome Medicine
Yasuhiro Yoshimura, Atsuhiro Taguchi, Shunsuke Tanigawa, Junji Yatsuda, Tomomi Kamba, Satoru Takahashi, Hidetake Kurihara, Masashi Mukoyama, Ryuichi Nishinakamura
BACKGROUND: Previous research has elucidated the signals required to induce nephron progenitor cells (NPCs) from pluripotent stem cells (PSCs), enabling the generation of kidney organoids. However, selectively controlling differentiation of NPCs to podocytes has been a challenge. METHODS: We investigated the effects of various growth factors in cultured mouse embryonic NPCs during three distinct steps of nephron patterning: from NPC to pretubular aggregate, from the latter to epithelial renal vesicle (RV), and from RV to podocyte...
January 11, 2019: Journal of the American Society of Nephrology: JASN
Ming S Tham, Ian M Smyth
Kidneys are bilateral organs required to maintain homeostasis in the body through the regulation of fluid composition and the excretion of metabolic waste products. The initial steps in organ development are characterized by cellular interactions which regulate both the position and number of kidneys formed. Once established, further development is driven by orchestrated interactions between progenitor cell populations which serve to establish both nephrons-the functional unit of the organ which filters the blood-and the complex ramified collecting duct system which transports urine to the bladder...
December 20, 2018: Wiley Interdisciplinary Reviews. Developmental Biology
Kasey Cargill, Sunder Sims-Lucas
The mammalian kidney is a complex organ that has several metabolically active cell types to aid in waste filtration, salt-water balance, and electrolyte homeostasis in the body. These functions are done primarily through the nephron, which relies on strict regulation of various metabolic pathways. Any deviations in the metabolic profile of nephrons or their precursor cells called nephron progenitors can lead to renal pathologies and abnormal development. Metabolism encompasses the mechanisms by which cells generate intermediate molecules and energy in the form of adenosine triphosphate (ATP)...
December 15, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
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
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