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  1. Article ; Online: Tubuloid culture enables long-term expansion of functional human kidney tubule epithelium from iPSC-derived organoids.

    Yousef Yengej, Fjodor A / Jansen, Jitske / Ammerlaan, Carola M E / Dilmen, Emre / Pou Casellas, Carla / Masereeuw, Rosalinde / Hoenderop, Joost G / Smeets, Bart / Rookmaaker, Maarten B / Verhaar, Marianne C / Clevers, Hans

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 6, Page(s) e2216836120

    Abstract: Kidney organoids generated from induced pluripotent stem cells (iPSC) have proven valuable for studies of kidney development, disease, and therapeutic screening. However, specific applications have been hampered by limited expansion capacity, immaturity, ...

    Abstract Kidney organoids generated from induced pluripotent stem cells (iPSC) have proven valuable for studies of kidney development, disease, and therapeutic screening. However, specific applications have been hampered by limited expansion capacity, immaturity, off-target cells, and inability to access the apical side. Here, we apply recently developed tubuloid protocols to purify and propagate kidney epithelium from d7+18 (post nephrogenesis) iPSC-derived organoids. The resulting 'iPSC organoid-derived (iPSCod)' tubuloids can be exponentially expanded for at least 2.5 mo, while retaining expression of important tubular transporters and segment-specific markers. This approach allows for selective propagation of the mature tubular epithelium, as immature cells, stroma, and undesirable off-target cells rapidly disappeared. iPSCod tubuloids provide easy apical access, which enabled functional evaluation and demonstration of essential secretion and electrolyte reabsorption processes. In conclusion, iPSCod tubuloids provide a different, complementary human kidney model that unlocks opportunities for functional characterization, disease modeling, and regenerative nephrology.
    MeSH term(s) Humans ; Induced Pluripotent Stem Cells/metabolism ; Kidney/metabolism ; Epithelium ; Organoids/metabolism ; Kidney Tubules ; Cell Differentiation
    Language English
    Publishing date 2023-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2216836120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease.

    Yousef Yengej, Fjodor A / Pou Casellas, Carla / Ammerlaan, Carola M E / Olde Hanhof, Charlotte J A / Dilmen, Emre / Beumer, Joep / Begthel, Harry / Meeder, Elise M G / Hoenderop, Joost G / Rookmaaker, Maarten B / Verhaar, Marianne C / Clevers, Hans

    Cell reports

    2023  Volume 43, Issue 1, Page(s) 113614

    Abstract: Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. ...

    Abstract Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model the distal nephron and collecting ducts, essential functional parts of the kidney. Differentiation suppresses progenitor traits and upregulates genes required for function. A single-cell atlas reveals that differentiation predominantly generates thick ascending limb and principal cells. Differentiated human tubuloids express luminal NKCC2 and ENaC capable of diuretic-inhibitable electrolyte uptake and enable disease modeling as demonstrated by a lithium-induced tubulopathy model. Lithium causes hallmark AQP2 loss, induces proliferation, and upregulates inflammatory mediators, as seen in vivo. Lithium also suppresses electrolyte transport in multiple segments. In conclusion, this tubuloid model enables modeling of the human distal nephron and collecting duct in health and disease and provides opportunities to develop improved therapies.
    MeSH term(s) Adult ; Humans ; Lithium/pharmacology ; Aquaporin 2 ; Nephrons ; Kidney ; Electrolytes ; Organoids
    Chemical Substances Lithium (9FN79X2M3F) ; Aquaporin 2 ; Electrolytes
    Language English
    Publishing date 2023-12-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.113614
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Differentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids.

    Lindoso, Rafael Soares / Yousef Yengej, Fjodor A / Voellmy, Franziska / Altelaar, Maarten / Mancheño Juncosa, Estela / Tsikari, Theano / Ammerlaan, Carola M E / Van Balkom, Bas W M / Rookmaaker, Maarten B / Verhaar, Marianne C / Masereeuw, Rosalinde

    Journal of nanobiotechnology

    2022  Volume 20, Issue 1, Page(s) 326

    Abstract: The prevalence of end-stage kidney disease (ESKD) is rapidly increasing with the need for regenerative therapies. Adult stem cell derived kidney tubuloids have the potential to functionally mimic the adult kidney tubule, but still lack the expression of ... ...

    Abstract The prevalence of end-stage kidney disease (ESKD) is rapidly increasing with the need for regenerative therapies. Adult stem cell derived kidney tubuloids have the potential to functionally mimic the adult kidney tubule, but still lack the expression of important transport proteins needed for waste removal. Here, we investigated the potential of extracellular vesicles (EVs) obtained from matured kidney tubular epithelial cells to modulate in vitro tubuloids functional maturation. We focused on organic anion transporter 1 (OAT1), one of the most important proteins involved in endogenous waste excretion. First, we show that EVs from engineered proximal tubule cells increased the expression of several transcription factors and epithelial transporters, resulting in improved OAT1 transport capacity. Next, a more in-depth proteomic data analysis showed that EVs can trigger various biological pathways, including mesenchymal-to-epithelial transition, which is crucial in the tubular epithelial maturation. Moreover, we demonstrated that the combination of EVs and tubuloid-derived cells can be used as part of a bioartificial kidney to generate a tight polarized epithelial monolayer with formation of dense cilia structures. In conclusion, EVs from kidney tubular epithelial cells can phenotypically improve in vitro tubuloid maturation, thereby enhancing their potential as functional units in regenerative or renal replacement therapies.
    MeSH term(s) Epithelial Cells ; Extracellular Vesicles/metabolism ; Kidney/metabolism ; Kidney Tubules, Proximal/metabolism ; Proteomics
    Language English
    Publishing date 2022-07-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2100022-0
    ISSN 1477-3155 ; 1477-3155
    ISSN (online) 1477-3155
    ISSN 1477-3155
    DOI 10.1186/s12951-022-01506-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Culture and analysis of kidney tubuloids and perfused tubuloid cells-on-a-chip.

    Gijzen, Linda / Yousef Yengej, Fjodor A / Schutgens, Frans / Vormann, Marianne K / Ammerlaan, Carola M E / Nicolas, Arnaud / Kurek, Dorota / Vulto, Paul / Rookmaaker, Maarten B / Lanz, Henriette L / Verhaar, Marianne C / Clevers, Hans

    Nature protocols

    2021  Volume 16, Issue 4, Page(s) 2023–2050

    Abstract: Advanced in vitro kidney models are of great importance to the study of renal physiology and disease. Kidney tubuloids can be established from primary cells derived from adult kidney tissue or urine. Tubuloids are three-dimensional multicellular ... ...

    Abstract Advanced in vitro kidney models are of great importance to the study of renal physiology and disease. Kidney tubuloids can be established from primary cells derived from adult kidney tissue or urine. Tubuloids are three-dimensional multicellular structures that recapitulate tubular function and have been used to study infectious, malignant, metabolic, and genetic diseases. For tubuloids to more closely represent the in vivo kidney, they can be integrated into an organ-on-a-chip system that has a more physiological tubular architecture and allows flow and interaction with vasculature or epithelial and mesenchymal cells from other organs. Here, we describe a detailed protocol for establishing tubuloid cultures from tissue and urine (1-3 weeks), as well as for generating and characterizing tubuloid cell-derived three-dimensional tubular structures in a perfused microfluidic multi-chip platform (7 d). The combination of the two systems yields a powerful in vitro tool that better recapitulates the complexity of the kidney tubule with donor-specific properties.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Cell Fractionation ; Child ; Child, Preschool ; Electric Impedance ; Female ; Fluorescent Dyes/chemistry ; Humans ; Infant ; Kidney Tubules/growth & development ; Lab-On-A-Chip Devices ; Male ; Membrane Transport Proteins/metabolism ; Microfluidics ; Middle Aged ; Organoids/growth & development ; Perfusion ; Rats ; Tissue Culture Techniques/methods ; Young Adult
    Chemical Substances Fluorescent Dyes ; Membrane Transport Proteins
    Language English
    Publishing date 2021-03-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-020-00479-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

    Claus, Laura R / Chen, Chuan / Stallworth, Jennifer / Turner, Joshua L / Slaats, Gisela G / Hawks, Alexandra L / Mabillard, Holly / Senum, Sarah R / Srikanth, Sujata / Flanagan-Steet, Heather / Louie, Raymond J / Silver, Josh / Lerner-Ellis, Jordan / Morel, Chantal / Mighton, Chloe / Sleutels, Frank / van Slegtenhorst, Marjon / van Ham, Tjakko / Brooks, Alice S /
    Dorresteijn, Eiske M / Barakat, Tahsin Stefan / Dahan, Karin / Demoulin, Nathalie / Goffin, Eric Jean / Olinger, Eric / Larsen, Martin / Hertz, Jens Michael / Lilien, Marc R / Obeidová, Lena / Seeman, Tomas / Stone, Hillarey K / Kerecuk, Larissa / Gurgu, Mihai / Yousef Yengej, Fjodor A / Ammerlaan, Carola M E / Rookmaaker, Maarten B / Hanna, Christian / Rogers, R Curtis / Duran, Karen / Peters, Edith / Sayer, John A / van Haaften, Gijs / Harris, Peter C / Ling, Kun / Mason, Jennifer M / van Eerde, Albertien M / Steet, Richard

    Kidney international

    2023  Volume 104, Issue 5, Page(s) 995–1007

    Abstract: Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the ... ...

    Abstract Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
    MeSH term(s) Animals ; Humans ; Infant, Newborn ; Mice ; Carrier Proteins/metabolism ; Cilia/pathology ; Kidney/metabolism ; Mutation ; NIMA-Related Kinases/genetics ; NIMA-Related Kinases/metabolism ; Polycystic Kidney Diseases/genetics ; Polycystic Kidney, Autosomal Dominant/pathology ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Serine/genetics ; Serine/metabolism ; TRPP Cation Channels/genetics ; TRPP Cation Channels/metabolism
    Chemical Substances ANKS6 protein, mouse ; Carrier Proteins ; NEK8 protein, human (EC 2.7.11.1) ; NIMA-Related Kinases (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Serine (452VLY9402) ; TRPP Cation Channels ; Nek8 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2023-08-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2023.07.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 797: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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