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  1. Article ; 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  Volume 30, Issue 4, Page(s) 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 term(s) 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
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; 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  Volume 30, Issue 5, Page(s) 741

    Language English
    Publishing date 2023-04-25
    Publishing country United States
    Document type 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Production and transplantation of retinal cells from human and mouse embryonic stem cells.

    La Torre, Anna / Lamba, Deepak A / Jayabalu, Anu / Reh, Thomas A

    Methods in molecular biology (Clifton, N.J.)

    2012  Volume 884, Page(s) 229–246

    Abstract: Over the last few years, numerous studies have introduced strategies for the generation of neuronal populations from embryonic stem cells. These techniques are valuable both in the study of early neurogenesis and in the generation of an unlimited source ... ...

    Abstract Over the last few years, numerous studies have introduced strategies for the generation of neuronal populations from embryonic stem cells. These techniques are valuable both in the study of early neurogenesis and in the generation of an unlimited source of donor cells for replacement therapies. We have developed a protocol to direct mouse and human embryonic stem cells to retinal fates by using the current model of eye specification. Our method is a multistep protocol in which the cultures are treated with IGF1 and a combination of BMP and Wnt inhibitors to promote the expression of key retinal progenitor genes, as assayed by RT-PCR and immunofluorescence microscopy. The retinal progenitor population spontaneously undergoes differentiation towards various types of retinal neurons, including photoreceptors.
    MeSH term(s) Animals ; Cell Culture Techniques ; Cell Differentiation ; Embryonic Stem Cells/cytology ; Humans ; Immunohistochemistry ; Mice ; Microinjections ; Real-Time Polymerase Chain Reaction ; Retina/cytology ; Retina/metabolism ; Stem Cell Transplantation
    Language English
    Publishing date 2012-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-61779-848-1_16
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes.

    Nakamura, Kenta / Neidig, Lauren E / Yang, Xiulan / Weber, Gerhard J / El-Nachef, Danny / Tsuchida, Hiroshi / Dupras, Sarah / Kalucki, Faith A / Jayabalu, Anu / Futakuchi-Tsuchida, Akiko / Nakamura, Daisy S / Marchianò, Silvia / Bertero, Alessandro / Robinson, Melissa R / Cain, Kevin / Whittington, Dale / Tian, Rong / Reinecke, Hans / Pabon, Lil /
    Knollmann, Björn C / Kattman, Steven / Thies, R Scott / MacLellan, W Robb / Murry, Charles E

    Stem cell reports

    2021  Volume 16, Issue 10, Page(s) 2473–2487

    Abstract: Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore ... ...

    Abstract Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0-0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.
    MeSH term(s) Amiodarone/therapeutic use ; Animals ; Anti-Arrhythmia Agents/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Cell Line ; Cell- and Tissue-Based Therapy/adverse effects ; Disease Models, Animal ; Drug Combinations ; Humans ; Ivabradine/therapeutic use ; Male ; Myocardial Infarction/drug therapy ; Myocytes, Cardiac/transplantation ; Pluripotent Stem Cells/transplantation ; Stem Cell Transplantation/adverse effects ; Swine ; Tachycardia/drug therapy
    Chemical Substances Anti-Arrhythmia Agents ; Drug Combinations ; Ivabradine (3H48L0LPZQ) ; Amiodarone (N3RQ532IUT)
    Language English
    Publishing date 2021-09-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2021.08.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate.

    Chao, Jennifer R / Lamba, Deepak A / Klesert, Todd R / Torre, Anna La / Hoshino, Akina / Taylor, Russell J / Jayabalu, Anu / Engel, Abbi L / Khuu, Thomas H / Wang, Ruikang K / Neitz, Maureen / Neitz, Jay / Reh, Thomas A

    Translational vision science & technology

    2017  Volume 6, Issue 3, Page(s) 4

    Abstract: Purpose: Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether ... ...

    Abstract Purpose: Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether these cells can also survive and integrate into the retina of a nonhuman primate,
    Methods: hESCs were differentiated toward retinal neuronal fates using our previously published technique and cultured for 60 to 70 days. Differentiated cells were further treated with 20 μM N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) for a period of 5 days immediately prior to subretinal transplantation. Differentiated cells were labeled with a lentivirus expressing GFP. One million cells (10,000 cells/μL) were injected into the submacular space into a squirrel monkey eye, using an ab externo technique.
    Results: RetCam imaging demonstrated the presence and survival of human donor cells 3 months after transplantation in the
    Conclusions: Human ES cell-derived retinal neurons injected into the submacular space of a squirrel monkey survive at least 3 months postinjection without immunosuppression. Some donor cells appeared to integrate into the host inner retina, and numerous donor axonal projections were noted throughout, with some projecting into the optic nerve.
    Translational relevance: These data illustrate the feasibility of hESC-derived retinal cell replacement in the nonhuman primate eye.
    Language English
    Publishing date 2017-05-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2674602-5
    ISSN 2164-2591
    ISSN 2164-2591
    DOI 10.1167/tvst.6.3.4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development.

    Yao, Zizhen / Mich, John K / Ku, Sherman / Menon, Vilas / Krostag, Anne-Rachel / Martinez, Refugio A / Furchtgott, Leon / Mulholland, Heather / Bort, Susan / Fuqua, Margaret A / Gregor, Ben W / Hodge, Rebecca D / Jayabalu, Anu / May, Ryan C / Melton, Samuel / Nelson, Angelique M / Ngo, N Kiet / Shapovalova, Nadiya V / Shehata, Soraya I /
    Smith, Michael W / Tait, Leah J / Thompson, Carol L / Thomsen, Elliot R / Ye, Chaoyang / Glass, Ian A / Kaykas, Ajamete / Yao, Shuyuan / Phillips, John W / Grimley, Joshua S / Levi, Boaz P / Wang, Yanling / Ramanathan, Sharad

    Cell stem cell

    2017  Volume 20, Issue 1, Page(s) 120–134

    Abstract: During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early ... ...

    Abstract During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/β-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.
    MeSH term(s) Animals ; Brain/embryology ; Brain/metabolism ; Cell Line ; Cell Lineage/genetics ; Clone Cells ; Embryonic Development/genetics ; Human Embryonic Stem Cells/cytology ; Humans ; Mice ; Models, Biological ; Neurons/cytology ; Neurons/metabolism ; Reproducibility of Results ; Sequence Analysis, RNA ; Single-Cell Analysis/methods ; Transcription Factors/metabolism ; Transcriptome/genetics ; Wnt Signaling Pathway/genetics
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2017-01-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2016.09.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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