Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue

Carolina Vasquez; Valeria Mezzano; Newman Kessler; Freja Swardh; Desiree Ernestad; Vanessa M. Mahoney; John Hanna; Gregory E. Morley

doi:10.1038/s41598-020-59449-7

Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue

Carolina Vasquez, Valeria Mezzano, Newman Kessler, Freja Swardh, Desiree Ernestad, Vanessa M. Mahoney, John Hanna, Gregory E. Morley

Research output: Contribution to journal › Article › peer-review

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Abstract

Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.

Original language	English (US)
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-59449-7
State	Published - Feb 13 2020
Externally published	Yes

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: The work was supported by grants from the National Institutes of Health (HL076751 to GEM) and the American Heart Association 12PRE11890017 to VMM. We acknowledge NYULH DART Microscopy Laboratory for assistance with EM work and NYULH DART Experimental Pathology Research Laboratory for assistance with immunophenotyping experiments. Microscopy and Experimental Pathology are partially supported by the NYU Cancer Center Support Grant NIH/NCI P30CA016087. The Gemini300SEM with 3View was purchased with support of NIH S10 ODO019974-01A1 (Microscopy). The Vectra 3.0 multispectral imaging system was purchased with support of NIH S10 OD021747 (Experimental Pathology). We wish to thank Liang Fengxia, Chris Petzhold, Kristen and Dancel-Manning from the Microscopy Laboratory for sample preparation for EM and SBF SEM, and Dr. Corrado Cali (Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia) for help with Neuromorph and Blender.

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@article{6a7725ed1e364daaae3f744303cf1ade,

title = "Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue",

abstract = "Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.",

author = "Carolina Vasquez and Valeria Mezzano and Newman Kessler and Freja Swardh and Desiree Ernestad and Mahoney, {Vanessa M.} and John Hanna and Morley, {Gregory E.}",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: The work was supported by grants from the National Institutes of Health (HL076751 to GEM) and the American Heart Association 12PRE11890017 to VMM. We acknowledge NYULH DART Microscopy Laboratory for assistance with EM work and NYULH DART Experimental Pathology Research Laboratory for assistance with immunophenotyping experiments. Microscopy and Experimental Pathology are partially supported by the NYU Cancer Center Support Grant NIH/NCI P30CA016087. The Gemini300SEM with 3View was purchased with support of NIH S10 ODO019974-01A1 (Microscopy). The Vectra 3.0 multispectral imaging system was purchased with support of NIH S10 OD021747 (Experimental Pathology). We wish to thank Liang Fengxia, Chris Petzhold, Kristen and Dancel-Manning from the Microscopy Laboratory for sample preparation for EM and SBF SEM, and Dr. Corrado Cali (Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia) for help with Neuromorph and Blender.",

year = "2020",

month = feb,

day = "13",

doi = "10.1038/s41598-020-59449-7",

language = "English (US)",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

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T1 - Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue

AU - Vasquez, Carolina

AU - Mezzano, Valeria

AU - Kessler, Newman

AU - Swardh, Freja

AU - Ernestad, Desiree

AU - Mahoney, Vanessa M.

AU - Hanna, John

AU - Morley, Gregory E.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: The work was supported by grants from the National Institutes of Health (HL076751 to GEM) and the American Heart Association 12PRE11890017 to VMM. We acknowledge NYULH DART Microscopy Laboratory for assistance with EM work and NYULH DART Experimental Pathology Research Laboratory for assistance with immunophenotyping experiments. Microscopy and Experimental Pathology are partially supported by the NYU Cancer Center Support Grant NIH/NCI P30CA016087. The Gemini300SEM with 3View was purchased with support of NIH S10 ODO019974-01A1 (Microscopy). The Vectra 3.0 multispectral imaging system was purchased with support of NIH S10 OD021747 (Experimental Pathology). We wish to thank Liang Fengxia, Chris Petzhold, Kristen and Dancel-Manning from the Microscopy Laboratory for sample preparation for EM and SBF SEM, and Dr. Corrado Cali (Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia) for help with Neuromorph and Blender.

PY - 2020/2/13

Y1 - 2020/2/13

N2 - Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.

AB - Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.

UR - http://hdl.handle.net/10754/661561

UR - http://www.nature.com/articles/s41598-020-59449-7

U2 - 10.1038/s41598-020-59449-7

DO - 10.1038/s41598-020-59449-7

M3 - Article

C2 - 32054938

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

IS - 1

ER -

Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue

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