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However, the development and signal compartmentation of this crucial pathway has so far been overlooked. We studied how the three main cGMP pathways, namely, nitric oxide (NO)-cGMP, natriuretic peptide (NP)-cGMP, and \u03b23-adrenoreceptor (AR)-cGMP, mature over time in culture during cardiomyocyte differentiation from human pluripotent stem cells (hPSC-CMs). After introducing a cGMP sensor for F\u00f6rster Resonance Energy Transfer (FRET) microscopy, we used selective phosphodiesterase (PDE) inhibition to reveal cGMP signal compartmentation in hPSC-CMs at various times of culture. Methyl-\u03b2-cyclodextrin was employed to remove cholesterol and thus to destroy caveolae in these cells, where physical cGMP signaling compartmentalization is known to occur in adult cardiomyocytes. We identified PDE3 as regulator of both the NO-cGMP and NP-cGMP pathway in the early stages of culture. At the late stage, the role of the NO-cGMP pathway diminished, and it was predominantly regulated by PDE1, PDE2, and PDE5. The NP-cGMP pathway shows unrestricted locally and unregulated cGMP signaling. Lastly, we observed that maturation of the \u03b23-AR-cGMP pathway in prolonged cultures of hPSC-CMs depends on the accumulation of caveolae. Overall, this study highlighted the importance of structural development for the necessary compartmentation of the cGMP pathway in maturing hPSC-CMs.<\/jats:p>","DOI":"10.3390\/cells11203257","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T05:08:02Z","timestamp":1665983282000},"page":"3257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Compartmentation of cGMP Signaling in Induced Pluripotent Stem Cell Derived Cardiomyocytes during Prolonged Culture"],"prefix":"10.3390","volume":"11","author":[{"given":"Maria","family":"Faleeva","sequence":"first","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Diakonov","sequence":"additional","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masoud","family":"Ramuz","sequence":"additional","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0689-8387","authenticated-orcid":false,"given":"Gaia","family":"Calamera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-1501","authenticated-orcid":false,"given":"Kjetil","family":"Andressen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Bork","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Martinistrasse 52, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Tsansizi","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Victoire","family":"Cosson","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-6657","authenticated-orcid":false,"given":"Andreia","family":"Bernardo","sequence":"additional","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"},{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-5179","authenticated-orcid":false,"given":"Viacheslav","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Martinistrasse 52, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1148-9158","authenticated-orcid":false,"given":"Julia","family":"Gorelik","sequence":"additional","affiliation":[{"name":"Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,17]]},"reference":[{"key":"ref_1","first-page":"50","article-title":"cAMP signal transduction in the heart: Understanding spatial control for the development of novel therapeutic strategies","volume":"158","author":"Zaccolo","year":"2009","journal-title":"J. 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