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  1. Article ; Online: Towards Modelling Genetic Kidney Diseases with Human Pluripotent Stem Cells.

    Rooney, Kirsty M / Woolf, Adrian S / Kimber, Susan J

    Nephron

    2021  Volume 145, Issue 3, Page(s) 285–296

    Abstract: Background: Kidney disease causes major suffering and premature mortality worldwide. With no cure for kidney failure currently available, and with limited options for treatment, there is an urgent need to develop effective pharmaceutical interventions ... ...

    Abstract Background: Kidney disease causes major suffering and premature mortality worldwide. With no cure for kidney failure currently available, and with limited options for treatment, there is an urgent need to develop effective pharmaceutical interventions to slow or prevent kidney disease progression.
    Summary: In this review, we consider the feasibility of using human pluripotent stem cell-derived kidney tissues, or organoids, to model genetic kidney disease. Notable successes have been made in modelling genetic tubular diseases (e.g., cystinosis), polycystic kidney disease, and medullary cystic kidney disease. Organoid models have also been used to test novel therapies that ameliorate aberrant cell biology. Some progress has been made in modelling congenital glomerular disease, even though glomeruli within organoids are developmentally immature. Less progress has been made in modelling structural kidney malformations, perhaps because sufficiently mature metanephric mesenchyme-derived nephrons, ureteric bud-derived branching collecting ducts, and a prominent stromal cell population are not generated together within a single protocol. Key Messages: We predict that the field will advance significantly if organoids can be generated with a full complement of cell lineages and with kidney components displaying key physiological functions, such as glomerular filtration. The future economic upscaling of reproducible organoid generation will facilitate more widespread research applications, including the potential therapeutic application of these stem cell-based technologies.
    MeSH term(s) Genetic Predisposition to Disease ; Humans ; Kidney Diseases/congenital ; Kidney Diseases/genetics ; Kidney Diseases/pathology ; Pluripotent Stem Cells/metabolism
    Language English
    Publishing date 2021-03-26
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 207121-6
    ISSN 2235-3186 ; 1423-0186 ; 1660-8151 ; 0028-2766
    ISSN (online) 2235-3186 ; 1423-0186
    ISSN 1660-8151 ; 0028-2766
    DOI 10.1159/000514018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The miR-199a/214 Cluster Controls Nephrogenesis and Vascularization in a Human Embryonic Stem Cell Model.

    Bantounas, Ioannis / Lopes, Filipa M / Rooney, Kirsty M / Woolf, Adrian S / Kimber, Susan J

    Stem cell reports

    2020  Volume 16, Issue 1, Page(s) 134–148

    Abstract: MicroRNAs (miRNAs) are gene expression regulators and they have been implicated in acquired kidney diseases and in renal development, mostly through animal studies. We hypothesized that the miR-199a/214 cluster regulates human kidney development. We ... ...

    Abstract MicroRNAs (miRNAs) are gene expression regulators and they have been implicated in acquired kidney diseases and in renal development, mostly through animal studies. We hypothesized that the miR-199a/214 cluster regulates human kidney development. We detected its expression in human embryonic kidneys by in situ hybridization. To mechanistically study the cluster, we used 2D and 3D human embryonic stem cell (hESC) models of kidney development. After confirming expression in each model, we inhibited the miRNAs using lentivirally transduced miRNA sponges. This reduced the WT1
    MeSH term(s) Antagomirs/metabolism ; Capillaries/pathology ; Cell Culture Techniques ; Cell Differentiation ; Down-Regulation ; Human Embryonic Stem Cells/cytology ; Human Embryonic Stem Cells/metabolism ; Humans ; Kidney Tubules, Proximal/blood supply ; Kidney Tubules, Proximal/cytology ; Kidney Tubules, Proximal/metabolism ; MicroRNAs/metabolism ; Models, Biological ; Neovascularization, Physiologic ; Sialoglycoproteins/genetics ; Sialoglycoproteins/metabolism ; WT1 Proteins/genetics ; WT1 Proteins/metabolism
    Chemical Substances Antagomirs ; MIRN214 microRNA, human ; MicroRNAs ; Sialoglycoproteins ; WT1 Proteins ; WT1 protein, human ; mirn199 microRNA, human ; podocalyxin
    Language English
    Publishing date 2020-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2020.11.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Optogenetic manipulation of BMP signaling to drive chondrogenic differentiation of hPSCs.

    Humphreys, Paul E A / Woods, Steven / Bates, Nicola / Rooney, Kirsty M / Mancini, Fabrizio E / Barclay, Cerys / O'Flaherty, Julieta / Martial, Franck P / Domingos, Marco A N / Kimber, Susan J

    Cell reports

    2023  Volume 42, Issue 12, Page(s) 113502

    Abstract: Optogenetics is a rapidly advancing technology combining photochemical, optical, and synthetic biology to control cellular behavior. Together, sensitive light-responsive optogenetic tools and human pluripotent stem cell differentiation models have the ... ...

    Abstract Optogenetics is a rapidly advancing technology combining photochemical, optical, and synthetic biology to control cellular behavior. Together, sensitive light-responsive optogenetic tools and human pluripotent stem cell differentiation models have the potential to fine-tune differentiation and unpick the processes by which cell specification and tissue patterning are controlled by morphogens. We used an optogenetic bone morphogenetic protein (BMP) signaling system (optoBMP) to drive chondrogenic differentiation of human embryonic stem cells (hESCs). We engineered light-sensitive hESCs through CRISPR-Cas9-mediated integration of the optoBMP system into the AAVS1 locus. The activation of optoBMP with blue light, in lieu of BMP growth factors, resulted in the activation of BMP signaling mechanisms and upregulation of a chondrogenic phenotype, with significant transcriptional differences compared to cells in the dark. Furthermore, cells differentiated with light could form chondrogenic pellets consisting of a hyaline-like cartilaginous matrix. Our findings indicate the applicability of optogenetics for understanding human development and tissue engineering.
    MeSH term(s) Humans ; Optogenetics ; Chondrocytes ; Cell Differentiation/genetics ; Cartilage/metabolism ; Pluripotent Stem Cells ; Chondrogenesis/genetics ; Bone Morphogenetic Protein 2/metabolism ; Cells, Cultured
    Chemical Substances Bone Morphogenetic Protein 2
    Language English
    Publishing date 2023-11-28
    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.2023.113502
    Database MEDical Literature Analysis and Retrieval System OnLINE

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