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  1. Artikel ; Online: Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.

    Marchiano, Silvia / Nakamura, Kenta / Reinecke, Hans / Neidig, Lauren / Lai, Michael / Kadota, Shin / Perbellini, Filippo / Yang, Xiulan / Klaiman, Jordan M / Blakely, Leslie P / Karbassi, Elaheh / Fields, Paul A / Fenix, Aidan M / Beussman, Kevin M / Jayabalu, Anu / Kalucki, Faith A / Potter, Jennifer C / Futakuchi-Tsuchida, Akiko / Weber, Gerhard J /
    Dupras, Sarah / Tsuchida, Hiroshi / Pabon, Lil / Wang, Lili / Knollmann, Björn C / Kattman, Steven / Thies, R Scott / Sniadecki, Nathan / MacLellan, W Robb / Bertero, Alessandro / Murry, Charles E

    Cell stem cell

    2023  Band 30, Heft 4, Seite(n) 396–414.e9

    Abstract: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. ...

    Abstract Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.
    Mesh-Begriff(e) Humans ; Animals ; Swine ; Myocytes, Cardiac/metabolism ; Gene Editing ; Cell Line ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/therapy ; Arrhythmias, Cardiac/metabolism ; Cell- and Tissue-Based Therapy ; Cell Differentiation/genetics
    Sprache Englisch
    Erscheinungsdatum 2023-04-06
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2023.03.010
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.

    Marchiano, Silvia / Nakamura, Kenta / Reinecke, Hans / Neidig, Lauren / Lai, Michael / Kadota, Shin / Perbellini, Filippo / Yang, Xiulan / Klaiman, Jordan M / Blakely, Leslie P / Karbassi, Elaheh / Fields, Paul A / Fenix, Aidan M / Beussman, Kevin M / Jayabalu, Anu / Kalucki, Faith A / Potter, Jennifer C / Futakuchi-Tsuchida, Akiko / Weber, Gerhard J /
    Dupras, Sarah / Tsuchida, Hiroshi / Pabon, Lil / Wang, Lili / Knollmann, Björn C / Kattman, Steven / Thies, R Scott / Sniadecki, Nathan / MacLellan, W Robb / Bertero, Alessandro / Murry, Charles E

    Cell stem cell

    2023  Band 30, Heft 5, Seite(n) 741

    Sprache Englisch
    Erscheinungsdatum 2023-04-25
    Erscheinungsland United States
    Dokumenttyp Published Erratum
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2023.04.010
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells.

    Xu, Zhuojin / Robitaille, Aaron M / Berndt, Jason D / Davidson, Kathryn C / Fischer, Karin A / Mathieu, Julie / Potter, Jennifer C / Ruohola-Baker, Hannele / Moon, Randall T

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

    2016  Band 113, Heft 42, Seite(n) E6382–E6390

    Abstract: In both mice and humans, pluripotent stem cells (PSCs) exist in at least two distinct states of pluripotency, known as the naïve and primed states. Our understanding of the intrinsic and extrinsic factors that enable PSCs to self-renew and to transition ... ...

    Abstract In both mice and humans, pluripotent stem cells (PSCs) exist in at least two distinct states of pluripotency, known as the naïve and primed states. Our understanding of the intrinsic and extrinsic factors that enable PSCs to self-renew and to transition between different pluripotent states is important for understanding early development. In mouse embryonic stem cells (mESCs), Wnt proteins stimulate mESC self-renewal and support the naïve state. In human embryonic stem cells (hESCs), Wnt/β-catenin signaling is active in naïve-state hESCs and is reduced or absent in primed-state hESCs. However, the role of Wnt/β-catenin signaling in naïve hESCs remains largely unknown. Here, we demonstrate that inhibition of the secretion of Wnts or inhibition of the stabilization of β-catenin in naïve hESCs reduces cell proliferation and colony formation. Moreover, we show that addition of recombinant Wnt3a partially rescues cell proliferation in naïve hESCs caused by inhibition of Wnt secretion. Notably, inhibition of Wnt/β-catenin signaling in naïve hESCs did not cause differentiation. Instead, it induced primed hESC-like proteomic and metabolic profiles. Thus, our results suggest that naïve hESCs secrete Wnts that activate autocrine or paracrine Wnt/β-catenin signaling to promote efficient self-renewal and inhibit the transition to the primed state.
    Mesh-Begriff(e) Apoptosis ; Benzothiazoles/pharmacology ; Biomarkers ; Cell Cycle/genetics ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Proliferation ; Cell Self Renewal/drug effects ; Cell Self Renewal/genetics ; Colony-Forming Units Assay ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Heterocyclic Compounds, 3-Ring/pharmacology ; Human Embryonic Stem Cells/cytology ; Human Embryonic Stem Cells/drug effects ; Human Embryonic Stem Cells/metabolism ; Humans ; Models, Biological ; Proteomics/methods ; RNA, Small Interfering/genetics ; Wnt Signaling Pathway/drug effects
    Chemische Substanzen Benzothiazoles ; Biomarkers ; Heterocyclic Compounds, 3-Ring ; IWP-2 compound ; RNA, Small Interfering ; XAV939
    Sprache Englisch
    Erscheinungsdatum 2016-10-03
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; 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.1613849113
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4

    Davidson, Kathryn C / Adams, Allison M / Goodson, Jamie M / McDonald, Circe E / Potter, Jennifer C / Berndt, Jason D / Biechele, Travis L / Taylor, Russell J / Moon, Randall T

    Proceedings of the National Academy of Sciences of the United States of America. 2012 Mar. 20, v. 109, no. 12

    2012  

    Abstract: Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a ... ...

    Abstract Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of β-catenin signaling, which led us to postulate that Wnt/β-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses β-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates β-catenin signaling in hESCs. Using a fluorescent reporter of β-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated β-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/β-catenin signaling in the differentiation rather than self-renewal of hESCs.
    Schlagwörter agonists ; embryonic stem cells ; exposure pathways ; fluorescence ; genes ; humans ; signal transduction
    Sprache Englisch
    Erscheinungsverlauf 2012-0320
    Umfang p. 4485-4490.
    Erscheinungsort National Academy of Sciences
    Dokumenttyp Artikel
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1118777109
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  5. Artikel ; Online: Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4.

    Davidson, Kathryn C / Adams, Allison M / Goodson, Jamie M / McDonald, Circe E / Potter, Jennifer C / Berndt, Jason D / Biechele, Travis L / Taylor, Russell J / Moon, Randall T

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

    2012  Band 109, Heft 12, Seite(n) 4485–4490

    Abstract: Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a ... ...

    Abstract Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of β-catenin signaling, which led us to postulate that Wnt/β-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses β-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates β-catenin signaling in hESCs. Using a fluorescent reporter of β-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated β-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/β-catenin signaling in the differentiation rather than self-renewal of hESCs.
    Mesh-Begriff(e) Animals ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Coculture Techniques ; Embryonic Stem Cells/cytology ; Genes, Reporter ; Humans ; Mice ; Models, Biological ; Octamer Transcription Factor-3/metabolism ; Signal Transduction ; Wnt Proteins/metabolism ; beta Catenin/metabolism
    Chemische Substanzen Octamer Transcription Factor-3 ; POU5F1 protein, human ; Wnt Proteins ; beta Catenin
    Sprache Englisch
    Erscheinungsdatum 2012-03-05
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; 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.1118777109
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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