Human macrophages directly modulate iPSC-derived cardiomyocytes at healthy state and congenital arrhythmia model in vitro

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dc.authorid0000-0002-4022-1014
dc.authorid0000-0002-8647-6055
dc.authorid0000-0002-7199-583X
dc.contributor.authorKoç, Arzuhan
dc.contributor.authorAkdeniz, Celal
dc.contributor.authorÇağavi, Esra
dc.date.accessioned2022-11-23T07:51:46Z
dc.date.available2022-11-23T07:51:46Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Sağlık Bilimleri Enstitüsü, Mikrobiyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Sağlık Bilimleri Enstitüsü, Tıbbi Biyoloji ve Genetik Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.description.abstractThe electrophysiological regulation of cardiomyocytes (CMs) by the cardiac macrophages (M Phi s) has been recently described as an unconventional role of M Phi s in the murine heart. Investigating the molecular and physiological modulation of CM by M Phi is critical to understand the novel mechanisms behind cardiac disorders from the systems perspective and to develop new therapeutic approaches. Here, we developed an in vitro direct coculture system to investigate the cellular and functional interaction between human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and monocyte-derived M Phi s both in healthy-state and congenital arrhythmia disease model associated with SCN5A ion channel mutations. Congenital arrhythmia patient-derived (P) and healthy individual-derived control (C) monocytes and derived M Phi s exhibited distinct M1- and M2-like polarization-related gene expression pattern. The iPSC-CMs and M Phi s formed direct membrane contacts in cocultures demonstrated by time-lapse imaging, scanning electron microscopy, and immunolabeling. The intracellular Ca(2+ )transients were observed in iPSC-CMs and M Phi s when in contact with each other. Interestingly, the C-M Phi s in direct contact with C-CMs significantly accelerated the contraction rates, demonstrating the positive chronotropic effect of M Phi s on healthy cardiac cultures. Furthermore, the M Phi s carrying the SCN5A gene mutation significantly enhanced the arrhythmic events in both C-CMs and P-CMs, implying that the sodium channel mutation in the M Phi is important for the CM function. Importantly, when C-M Phi s were coupled to tachycardic P-CMs, the contraction frequency drastically decreased, and rhythmicity enhanced implicating the amelioration of the disease phenotype in vitro. Consequently, our results indicated the functional regulatory role of M Phi s on human iPSC-CM contractility by membrane contacts in a physiologically relevant in vitro coculture model of both steady-state and arrhythmia. Our findings could serve as a valuable source for the development of effective immunoregulatory therapies for cardiac arrhythmia in the future.
dc.identifier.citationKoç, A., Akdeniz, C. ve Çağavi, E. (2022). Human macrophages directly modulate iPSC-derived cardiomyocytes at healthy state and congenital arrhythmia model in vitro. Pflugers Archiv European Journal of Physiology, 474(12), 1295-1310. https://doi.org/10.1007/s00424-022-02743-2
dc.identifier.doi10.1007/s00424-022-02743-2
dc.identifier.endpage1310
dc.identifier.issn0031-6768
dc.identifier.issn1432-2013
dc.identifier.issue12
dc.identifier.pmid36112216
dc.identifier.scopus2-s2.0-85138192375
dc.identifier.scopusqualityQ1
dc.identifier.startpage1295
dc.identifier.urihttps://doi.org/10.1007/s00424-022-02743-2
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10013
dc.identifier.volume474
dc.identifier.wos000854395900001en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorKoç, Arzuhan
dc.institutionauthorAkdeniz, Celal
dc.institutionauthorÇağavi, Esra
dc.language.isoen
dc.publisherSpringer Heidelberg
dc.relation.ispartofPflugers Archiv European Journal of Physiologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/218S841
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectArrhythmia
dc.subjectCardiomyocytes
dc.subjectHuman-Induced Pluripotent Stem Cells
dc.subjectImmunocardiology
dc.subjectIn Vitro Disease Model
dc.subjectMacrophages
dc.titleHuman macrophages directly modulate iPSC-derived cardiomyocytes at healthy state and congenital arrhythmia model in vitro
dc.typeArticle

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