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  1. Article ; Online: Fount, fate, features, and function of renal erythropoietin-producing cells.

    Dahl, Sophie L / Bapst, Andreas M / Khodo, Stellor Nlandu / Scholz, Carsten C / Wenger, Roland H

    Pflugers Archiv : European journal of physiology

    2022  Volume 474, Issue 8, Page(s) 783–797

    Abstract: Renal erythropoietin (Epo)-producing (REP) cells represent a rare and incompletely understood cell type. REP cells are fibroblast-like cells located in close proximity to blood vessels and tubules of the corticomedullary border region. Epo mRNA in REP ... ...

    Abstract Renal erythropoietin (Epo)-producing (REP) cells represent a rare and incompletely understood cell type. REP cells are fibroblast-like cells located in close proximity to blood vessels and tubules of the corticomedullary border region. Epo mRNA in REP cells is produced in a pronounced "on-off" mode, showing transient transcriptional bursts upon exposure to hypoxia. In contrast to "ordinary" fibroblasts, REP cells do not proliferate ex vivo, cease to produce Epo, and lose their identity following immortalization and prolonged in vitro culture, consistent with the loss of Epo production following REP cell proliferation during tissue remodelling in chronic kidney disease. Because Epo protein is usually not detectable in kidney tissue, and Epo mRNA is only transiently induced under hypoxic conditions, transgenic mouse models have been developed to permanently label REP cell precursors, active Epo producers, and inactive descendants. Future single-cell analyses of the renal stromal compartment will identify novel characteristic markers of tagged REP cells, which will provide novel insights into the regulation of Epo expression in this unique cell type.
    MeSH term(s) Animals ; Erythropoietin/metabolism ; Hypoxia/metabolism ; Kidney/metabolism ; Mice ; Mice, Transgenic ; RNA, Messenger/metabolism ; Renal Insufficiency, Chronic/metabolism
    Chemical Substances RNA, Messenger ; Erythropoietin (11096-26-7)
    Language English
    Publishing date 2022-06-24
    Publishing country Germany
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 6380-0
    ISSN 1432-2013 ; 0031-6768
    ISSN (online) 1432-2013
    ISSN 0031-6768
    DOI 10.1007/s00424-022-02714-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cre-mediated, loxP independent sequential recombination of a tripartite transcriptional stop cassette allows for partial read-through transcription.

    Bapst, Andreas M / Dahl, Sophie L / Knöpfel, Thomas / Wenger, Roland H

    Biochimica et biophysica acta. Gene regulatory mechanisms

    2020  Volume 1863, Issue 8, Page(s) 194568

    Abstract: One of the widely used applications of the popular Cre-loxP method for targeted recombination is the permanent activation of marker genes, such as reporter genes or antibiotic resistance genes, by excision of a preceding transcriptional stop signal. The ... ...

    Abstract One of the widely used applications of the popular Cre-loxP method for targeted recombination is the permanent activation of marker genes, such as reporter genes or antibiotic resistance genes, by excision of a preceding transcriptional stop signal. The STOP cassette consists of three identical SV40-derived poly(A) signal repeats and is flanked by two loxP sites. We found that in addition to complete loxP-mediated recombination, limiting levels of the Cre recombinase also cause incomplete recombination of the STOP cassette. Partial recombination leads to the loss of only one or two of the three identical poly(A) repeats with recombination breakpoints always precisely matching the end/start of each poly(A) signal repeat without any relevant similarity to the canonical or known cryptic loxP sequences, suggesting that this type of Cre-mediated recombination is loxP-independent. Incomplete deletion of the STOP cassette results in partial read-through transcription, explaining at least some of the variability often observed in marker gene expression from an otherwise identical locus.
    MeSH term(s) Animals ; CHO Cells ; Cricetulus ; Female ; Gene Expression ; Genes, Reporter/genetics ; Genetic Markers ; Integrases/genetics ; Integrases/metabolism ; Kidney ; Male ; Mice ; Recombination, Genetic ; Transcriptome
    Chemical Substances Genetic Markers ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
    Language English
    Publishing date 2020-04-25
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2918786-2
    ISSN 1876-4320 ; 1874-9399
    ISSN (online) 1876-4320
    ISSN 1874-9399
    DOI 10.1016/j.bbagrm.2020.194568
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism.

    Ruiz-Serrano, Amalia / Boyle, Christina N / Monné Rodríguez, Josep M / Günter, Julia / Jucht, Agnieszka E / Pfundstein, Svende / Bapst, Andreas M / Lutz, Thomas A / Wenger, Roland H / Scholz, Carsten C

    International journal of molecular sciences

    2022  Volume 23, Issue 3

    Abstract: Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the ... ...

    Abstract Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (
    MeSH term(s) Adenosine Triphosphate/metabolism ; Adenylate Kinase/metabolism ; Animals ; Blood Glucose ; Body Weight ; Cell Size ; Cells, Cultured ; Cysteine Endopeptidases/genetics ; Cysteine Endopeptidases/metabolism ; Energy Metabolism ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Deletion ; Insulin/administration & dosage ; Insulin/adverse effects ; Insulin Resistance/genetics ; Mice ; Mixed Function Oxygenases/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism
    Chemical Substances Blood Glucose ; Insulin ; Adenosine Triphosphate (8L70Q75FXE) ; Mixed Function Oxygenases (EC 1.-) ; factor inhibiting hypoxia-inducible factor 1, mouse (EC 1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Adenylate Kinase (EC 2.7.4.3) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Otub1 protein, mouse (EC 3.4.22.-)
    Language English
    Publishing date 2022-01-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23031536
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Neurogenic and pericytic plasticity of conditionally immortalized cells derived from renal erythropoietin-producing cells.

    Bapst, Andreas M / Knöpfel, Thomas / Nolan, Karen A / Imeri, Faik / Schuh, Claus D / Hall, Andrew M / Guo, Jia / Katschinski, Dörthe M / Wenger, Roland H

    Journal of cellular physiology

    2022  Volume 237, Issue 5, Page(s) 2420–2433

    Abstract: In adult mammals, the kidney is the main source of circulating erythropoietin (Epo), the master regulator of erythropoiesis. In vivo data in mice demonstrated multiple subtypes of interstitial renal Epo-producing (REP) cells. To analyze the ... ...

    Abstract In adult mammals, the kidney is the main source of circulating erythropoietin (Epo), the master regulator of erythropoiesis. In vivo data in mice demonstrated multiple subtypes of interstitial renal Epo-producing (REP) cells. To analyze the differentiation plasticity of fibroblastoid REP cells, we used a transgenic REP cell reporter mouse model to generate conditionally immortalized REP-derived (REPD) cell lines. Under nonpermissive conditions, REPD cells ceased from proliferation and acquired a stem cell-like state, with strongly enhanced hypoxia-inducible factor 2 (HIF-2α), stem cell antigen 1 (SCA-1), and CD133 expression, but also enhanced alpha-smooth muscle actin (αSMA) expression, indicating myofibroblastic signaling. These cells maintained the "on-off" nature of Epo expression observed in REP cells in vivo, whereas other HIF target genes showed a more permanent regulation. Like REP cells in vivo, REPD cells cultured in vitro generated long tunneling nanotubes (TNTs) that aligned with endothelial vascular structures, were densely packed with mitochondria and became more numerous under hypoxic conditions. Although inhibition of mitochondrial oxygen consumption blunted HIF signaling, removal of the TNTs did not affect or even enhance the expression of HIF target genes. Apart from pericytes, REPD cells readily differentiated into neuroglia but not adipogenic, chondrogenic, or osteogenic lineages, consistent with a neuronal origin of at least a subpopulation of REP cells. In summary, these results suggest an unprecedented combination of differentiation features of this unique cell type.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Line ; Erythropoiesis ; Erythropoietin/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Kidney/metabolism ; Mammals/metabolism ; Mice ; Mice, Transgenic ; Pericytes/metabolism
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1, alpha Subunit ; Erythropoietin (11096-26-7)
    Language English
    Publishing date 2022-01-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3116-1
    ISSN 1097-4652 ; 0021-9541
    ISSN (online) 1097-4652
    ISSN 0021-9541
    DOI 10.1002/jcp.30677
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  5. Article ; Online: The transcriptional and regulatory identity of erythropoietin producing cells.

    Kragesteen, Bjørt K / Giladi, Amir / David, Eyal / Halevi, Shahar / Geirsdóttir, Laufey / Lempke, Olga M / Li, Baoguo / Bapst, Andreas M / Xie, Ken / Katzenelenbogen, Yonatan / Dahl, Sophie L / Sheban, Fadi / Gurevich-Shapiro, Anna / Zada, Mor / Phan, Truong San / Avellino, Roberto / Wang, Shuang-Yin / Barboy, Oren / Shlomi-Loubaton, Shir /
    Winning, Sandra / Markwerth, Philipp P / Dekalo, Snir / Keren-Shaul, Hadas / Kedmi, Merav / Sikora, Martin / Fandrey, Joachim / Korneliussen, Thorfinn S / Prchal, Josef T / Rosenzweig, Barak / Yutkin, Vladimir / Racimo, Fernando / Willerslev, Eske / Gur, Chamutal / Wenger, Roland H / Amit, Ido

    Nature medicine

    2023  Volume 29, Issue 5, Page(s) 1191–1200

    Abstract: Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective ... ...

    Abstract Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies.
    MeSH term(s) Animals ; Humans ; Mice ; Anemia/genetics ; Erythropoiesis/genetics ; Erythropoietin/genetics ; Kidney/metabolism ; RNA/metabolism
    Chemical Substances Erythropoietin (11096-26-7) ; RNA (63231-63-0) ; EPO protein, human ; Epo protein, mouse
    Language English
    Publishing date 2023-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02314-7
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    Zs.A 4212: Show issues Location:
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  6. Article: Knee Extensors Muscle Plasticity Over a 5-Years Rehabilitation Process After Open Knee Surgery.

    Flück, Martin / Viecelli, Claudio / Bapst, Andreas M / Kasper, Stephanie / Valdivieso, Paola / Franchi, Martino V / Ruoss, Severin / Lüthi, Jean-Marc / Bühler, Martin / Claassen, Helgard / Hoppeler, Hans / Gerber, Christian

    Frontiers in physiology

    2018  Volume 9, Page(s) 1343

    Abstract: We investigated molecular and cellular parameters which set metabolic and mechanical functioning of knee extensor muscles in the operated and contralateral control leg of 9 patients with a chronically insufficient anterior cruciate ligament (ACL; 26.6 ± ... ...

    Abstract We investigated molecular and cellular parameters which set metabolic and mechanical functioning of knee extensor muscles in the operated and contralateral control leg of 9 patients with a chronically insufficient anterior cruciate ligament (ACL; 26.6 ± 8.3 years, 8 males, 1 female) after open reconstructive surgery (week 0), after ambulant physiotherapy under cast immobilization (week 9), succeeding rehabilitation training (up to week 26), and subsequent voluntary physical activity (week 260). Clinical indices of knee function in the operated leg were improved at 52 weeks and remained at a comparable level at week 260. CSA of the quadriceps (-18%), MCSA of muscle fibers (-24%), and capillary-to-fiber ratio (-24%) in
    Language English
    Publishing date 2018-09-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2018.01343
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  7. Article ; Online: Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype.

    Imeri, Faik / Nolan, Karen A / Bapst, Andreas M / Santambrogio, Sara / Abreu-Rodríguez, Irene / Spielmann, Patrick / Pfundstein, Svende / Libertini, Silvana / Crowther, Lisa / Orlando, Ilaria M C / Dahl, Sophie L / Keodara, Anna / Kuo, Willy / Kurtcuoglu, Vartan / Scholz, Carsten C / Qi, Weihong / Hummler, Edith / Hoogewijs, David / Wenger, Roland H

    Kidney international

    2018  Volume 95, Issue 2, Page(s) 375–387

    Abstract: Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney ...

    Abstract Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.
    MeSH term(s) Anemia/etiology ; Anemia/pathology ; Animals ; Cell Hypoxia ; Cell Line ; Erythropoietin/genetics ; Erythropoietin/metabolism ; Feedback, Physiological ; Kidney/cytology ; Kidney/pathology ; Mice ; Mice, Transgenic ; Primary Cell Culture ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/pathology ; Telocytes/metabolism ; Telocytes/pathology ; Transcription Factors/metabolism
    Chemical Substances Epo protein, mouse ; HIF-2 protein, mouse ; Transcription Factors ; Erythropoietin (11096-26-7)
    Language English
    Publishing date 2018-11-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2018.08.043
    Database MEDical Literature Analysis and Retrieval System OnLINE

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