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  1. Article ; Online: MSC-Derived Small Extracellular Vesicles Exert Cardioprotective Effect Through Reducing VLCFAs and Apoptosis in Human Cardiac Organoid IRI Model.

    Poh, Boon Min / Liew, Lee Chuen / Soh, Yan Ni Annie / Lai, Ruenn Chai / Lim, Sai Kiang / Ho, Ying Swan / Soh, Boon Seng

    Stem cells (Dayton, Ohio)

    2024  Volume 42, Issue 5, Page(s) 416–429

    Abstract: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, accounting for 31% of all deaths globally. Myocardial ischemia-reperfusion injury (IRI), a common complication of CVDs, is a major cause of mortality and morbidity. Studies have ... ...

    Abstract Cardiovascular diseases (CVDs) are the leading cause of death worldwide, accounting for 31% of all deaths globally. Myocardial ischemia-reperfusion injury (IRI), a common complication of CVDs, is a major cause of mortality and morbidity. Studies have shown efficacious use of mesenchymal stem cells-derived small extracellular vesicles (MSCs-EVs) to mitigate IRI in animals, but few research has been done on human-related models. In this study, human embryonic stem cell-derived chambered cardiac organoid (CCO) was used as a model system to study the effects of MSC-EVs on myocardial IRI. The results revealed that MSC-EVs treatment reduced apoptosis and improved contraction resumption of the CCOs. Metabolomics analysis showed that this effect could be attributed to EVs' ability to prevent the accumulation of unsaturated very long-chain fatty acids (VLCFAs). This was corroborated when inhibition of fatty acid synthase, which was reported to reduce VLCFAs, produced a similar protective effect to EVs. Overall, this study uncovered the mechanistic role of MSC-EVs in mitigating IRI that involves preventing the accumulation of unsaturated VLCFA, decreasing cell death, and improving contraction resumption in CCOs.
    MeSH term(s) Humans ; Extracellular Vesicles/metabolism ; Apoptosis ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/cytology ; Organoids/metabolism ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/prevention & control ; Fatty Acids/metabolism ; Cardiotonic Agents/metabolism ; Cardiotonic Agents/pharmacology
    Language English
    Publishing date 2024-02-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 1143556-2
    ISSN 1549-4918 ; 1066-5099
    ISSN (online) 1549-4918
    ISSN 1066-5099
    DOI 10.1093/stmcls/sxae015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: JAK2 as a surface marker for enrichment of human pluripotent stem cells-derived ventricular cardiomyocytes.

    Liew, Lee Chuen / Poh, Boon Min / An, Omer / Ho, Beatrice Xuan / Lim, Christina Ying Yan / Pang, Jeremy Kah Sheng / Beh, Leslie Y / Yang, Henry He / Soh, Boon-Seng

    Stem cell research & therapy

    2023  Volume 14, Issue 1, Page(s) 367

    Abstract: Background: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for cardiac disease modelling, drug discovery and regenerative medicine. Despite the advancement in various differentiation protocols, the heterogeneity of ... ...

    Abstract Background: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for cardiac disease modelling, drug discovery and regenerative medicine. Despite the advancement in various differentiation protocols, the heterogeneity of the generated population composed of diverse cardiac subtypes poses a significant challenge to their practical applications. Mixed populations of cardiac subtypes can compromise disease modelling and drug discovery, while transplanting them may lead to undesired arrhythmias as they may not integrate and synchronize with the host tissue's contractility. It is therefore crucial to identify cell surface markers that could enable high purity of ventricular CMs for subsequent applications.
    Methods: By exploiting the fact that immature CMs expressing myosin light chain 2A (MLC2A) will gradually express myosin light chain 2 V (MLC2V) protein as they mature towards ventricular fate, we isolated signal regulatory protein alpha (SIRPA)-positive CMs expressing intracellular MLC2A or MLC2V using MARIS (method for analysing RNA following intracellular sorting). Subsequently, RNA sequencing analysis was performed to examine the gene expression profile of MLC2A + and MLC2V + sorted CMs. We identified genes that were significantly up-regulated in MLC2V + samples to be potential surface marker candidates for ventricular specification. To validate these surface markers, we performed immunostaining and western blot analysis to measure MLC2A and MLC2V protein expressions in SIRPA + CMs that were either positive or negative for the putative surface markers, JAK2 (Janus kinase 2) or CD200. We then characterized the electrophysiological properties of surface marker-sorted CMs, using fluo-4 AM, a green-fluorescent calcium indicator, to measure the cellular calcium transient at the single cell level. For functional validation, we investigated the response of the surface marker-sorted CMs to vernakalant, an atrial-selective anti-arrhythmic agent.
    Results: In this study, while JAK2 and CD200 were identified as potential surface markers for the purification of ventricular-like CMs, the SIRPA+/JAK2+ population showed a higher percentage of MLC2V-expressing cells (~ 90%) compared to SIRPA+/CD200+ population (~ 75%). SIRPA+/JAK2+ sorted CMs exhibited ventricular-like electrophysiological properties, including slower beating rate, slower calcium depolarization and longer calcium repolarization duration. Importantly, vernakalant had limited to no significant effect on the calcium repolarization duration of SIRPA+/JAK2+ population, indicating their enrichment for ventricular-like CMs.
    Conclusion: Our study lays the groundwork for the identification of cardiac subtype surface markers that allow purification of cardiomyocyte sub-populations. Our findings suggest that JAK2 can be employed as a cell surface marker for enrichment of hPSC-derived ventricular-like CMs.
    MeSH term(s) Humans ; Myocytes, Cardiac/metabolism ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism ; Janus Kinase 2/pharmacology ; Calcium/metabolism ; Pluripotent Stem Cells ; Cell Differentiation ; Induced Pluripotent Stem Cells/metabolism
    Chemical Substances vernakalant (9G468C8B13) ; Janus Kinase 2 (EC 2.7.10.2) ; Calcium (SY7Q814VUP) ; JAK2 protein, human (EC 2.7.10.2)
    Language English
    Publishing date 2023-12-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2548671-8
    ISSN 1757-6512 ; 1757-6512
    ISSN (online) 1757-6512
    ISSN 1757-6512
    DOI 10.1186/s13287-023-03610-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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