Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores
Aim: Composite population of myofibroblasts (MFs) within myocardial tissue is known to alter impulse propagation, leading to arrhythmias. However, it remains unclear whether and how MFs alter their propagation patterns when contacting cardiomyocytes (CMs) without complex structural insertions in the...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2024.1352911/full |
| _version_ | 1797299620336893952 |
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| author | Yumika Tsuji Yumika Tsuji Takehiro Ogata Kentaro Mochizuki Shoko Tamura Yuma Morishita Tetsuro Takamatsu Tetsuro Takamatsu Satoaki Matoba Hideo Tanaka Hideo Tanaka |
| author_facet | Yumika Tsuji Yumika Tsuji Takehiro Ogata Kentaro Mochizuki Shoko Tamura Yuma Morishita Tetsuro Takamatsu Tetsuro Takamatsu Satoaki Matoba Hideo Tanaka Hideo Tanaka |
| author_sort | Yumika Tsuji |
| collection | DOAJ |
| description | Aim: Composite population of myofibroblasts (MFs) within myocardial tissue is known to alter impulse propagation, leading to arrhythmias. However, it remains unclear whether and how MFs alter their propagation patterns when contacting cardiomyocytes (CMs) without complex structural insertions in the myocardium. We attempted to unveil the effects of the one-sided, heterocellular CM-MF connection on the impulse propagation of CM monolayers without the spatial insertion of MFs as an electrical or mechanical obstacle.Methods and results: We evaluated fluo8-based spatiotemporal patterns in impulse propagation of neonatal rat CM monolayers cultured on the microporous membrane having 8-μm diameter pores with co-culture of MFs or CMs on the reverse membrane side (CM-MF model or CM-CM model, respectively). During consecutive pacing at 1 or 2 Hz, the CM monolayers exhibited forward impulse propagation from the pacing site with a slower conduction velocity (θ) and a larger coefficient of directional θ variation in the CM-MF model than that in the CM-CM model in a frequency-dependent manner (2 Hz >1 Hz). The localized placement of an MF cluster on the reverse side resulted in an abrupt segmental depression of the impulse propagation of the upper CM layer, causing a spatiotemporally non-uniform pattern. Dye transfer of the calcein loaded in the upper CM layer to the lower MF layer was attenuated by the gap-junction inhibitor heptanol. Immunocytochemistry identified definitive connexin 43 (Cx43) between the CMs and MFs in the membrane pores. MF-selective Cx43 knockdown in the MF layer improved both the velocity and uniformity of propagation in the CM monolayer.Conclusion: Heterocellular Cx43 gap junction coupling of CMs with MFs alters the spatiotemporal patterns of myocardial impulse propagation, even in the absence of spatially interjacent and mechanosensitive modulations by MFs. Moreover, MFs can promote pro-arrhythmogenic impulse propagation when in face-to-face contact with the myocardium that arises in the healing infarct border zone. |
| first_indexed | 2024-03-07T22:53:17Z |
| format | Article |
| id | doaj.art-63c67b5a6b01496f8d3c4615fd451212 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-03-07T22:53:17Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-63c67b5a6b01496f8d3c4615fd4512122024-02-23T05:01:33ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2024-02-011510.3389/fphys.2024.13529111352911Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through microporesYumika Tsuji0Yumika Tsuji1Takehiro Ogata2Kentaro Mochizuki3Shoko Tamura4Yuma Morishita5Tetsuro Takamatsu6Tetsuro Takamatsu7Satoaki Matoba8Hideo Tanaka9Hideo Tanaka10Department of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Medical Photonics, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Pathology and Cell Regulation and, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, JapanFaculty of Health and Medical Sciences, Kyoto University of Advanced Science, Kyoto, JapanAim: Composite population of myofibroblasts (MFs) within myocardial tissue is known to alter impulse propagation, leading to arrhythmias. However, it remains unclear whether and how MFs alter their propagation patterns when contacting cardiomyocytes (CMs) without complex structural insertions in the myocardium. We attempted to unveil the effects of the one-sided, heterocellular CM-MF connection on the impulse propagation of CM monolayers without the spatial insertion of MFs as an electrical or mechanical obstacle.Methods and results: We evaluated fluo8-based spatiotemporal patterns in impulse propagation of neonatal rat CM monolayers cultured on the microporous membrane having 8-μm diameter pores with co-culture of MFs or CMs on the reverse membrane side (CM-MF model or CM-CM model, respectively). During consecutive pacing at 1 or 2 Hz, the CM monolayers exhibited forward impulse propagation from the pacing site with a slower conduction velocity (θ) and a larger coefficient of directional θ variation in the CM-MF model than that in the CM-CM model in a frequency-dependent manner (2 Hz >1 Hz). The localized placement of an MF cluster on the reverse side resulted in an abrupt segmental depression of the impulse propagation of the upper CM layer, causing a spatiotemporally non-uniform pattern. Dye transfer of the calcein loaded in the upper CM layer to the lower MF layer was attenuated by the gap-junction inhibitor heptanol. Immunocytochemistry identified definitive connexin 43 (Cx43) between the CMs and MFs in the membrane pores. MF-selective Cx43 knockdown in the MF layer improved both the velocity and uniformity of propagation in the CM monolayer.Conclusion: Heterocellular Cx43 gap junction coupling of CMs with MFs alters the spatiotemporal patterns of myocardial impulse propagation, even in the absence of spatially interjacent and mechanosensitive modulations by MFs. Moreover, MFs can promote pro-arrhythmogenic impulse propagation when in face-to-face contact with the myocardium that arises in the healing infarct border zone.https://www.frontiersin.org/articles/10.3389/fphys.2024.1352911/fullmyofibroblastcardiomyocyteoptical mappingimpulse propagationelectrotonic effectconnexin 43 |
| spellingShingle | Yumika Tsuji Yumika Tsuji Takehiro Ogata Kentaro Mochizuki Shoko Tamura Yuma Morishita Tetsuro Takamatsu Tetsuro Takamatsu Satoaki Matoba Hideo Tanaka Hideo Tanaka Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores Frontiers in Physiology myofibroblast cardiomyocyte optical mapping impulse propagation electrotonic effect connexin 43 |
| title | Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores |
| title_full | Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores |
| title_fullStr | Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores |
| title_full_unstemmed | Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores |
| title_short | Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores |
| title_sort | myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap junctional coupling through micropores |
| topic | myofibroblast cardiomyocyte optical mapping impulse propagation electrotonic effect connexin 43 |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2024.1352911/full |
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