A review of the literature on cardiac electrical activity between fibroblasts and myocytes

Mahoney, Vanessa M.; Mezzano, Valeria; Morley, Gregory E.

doi:10.1016/j.pbiomolbio.2015.12.006

Cited by 18 publications

(18 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that myofibroblasts coupled to cardiomyocytes show an increase in Cx43 expression and an associated increase in gap junction formation (21). Cx43-based contact between myofibroblasts and cardiomyocytes is thought to contribute to ectopic activity and arrhythmias (25,47). In the present study, we show a novel Cx43-dependent aspect of myofibroblast behavior that may contribute to heart failure pathology.…”

Section: Discussionsupporting

confidence: 61%

See 1 more Smart Citation

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

et al. 2019

View full text Add to dashboard Cite

Healthy cardiomyocytes are electrically coupled at the intercalated discs by gap junctions. In infarcted hearts, adverse gap‐junctional remodeling occurs in the border zone, where cardiomyocytes are chemically and electrically influenced by myofibroblasts. The physical movement of these contacts remains unquantified. Using scanning ion conductance microscopy, we show that intercellular contacts between cardiomyocytes and myofibroblasts are highly dynamic, mainly owing to the edge dynamics (lamellipodia) of the myofibroblasts. Decreasing the amount of functional connexin‐43 (Cx43) at the membrane through Cx43 silencing, suppression of Cx43 trafficking, or hypoxia‐induced Cx43 internalization attenuates heterocellular contact dynamism. However, we found decreased dynamism and stabilized membrane contacts when cellular coupling was strengthened using 4‐phenylbutyrate (4PB). Fluorescent‐dye transfer between cells showed that the extent of functional coupling between the 2 cell types correlated with contact dynamism. Intercellular calcein transfer from myofibroblasts to cardiomyocytes is reduced after myofibroblast‐specific Cx43 down‐regulation. Conversely, 4PB‐treated myofibroblasts increased their functional coupling to cardiomyocytes. Consistent with lamellipodia‐mediated contacts, latrunculin‐B decreases dynamism, lowers physical communication between heterocellular pairs, and reduces Cx43 intensity in contact regions. Our data show that heterocellular cardiomyocyte‐myofibroblast contacts exhibit high dynamism. Therefore, Cx43 is a potential target for prevention of aberrant cardiomyocyte coupling and myofibroblast proliferation in the infarct border zone.—Schultz, F., Swiatlowska, P., Alvarez‐Laviada, A., Sanchez‐Alonso, J. L., Song, Q., de Vries, A. A. F., Pijnappels, D. A., Ongstad, E., Braga, V. M. M., Entcheva, E., Gourdie, R. G., Miragoli, M., Gorelik, J. Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43. FASEB J. 33, 10453–10468 (2019). http://www.fasebj.org

show abstract

Section: Discussionsupporting

confidence: 61%

“…Myofibroblasts are known to promote conduction slowing and ectopic activity in cardiac tissue (25,47). As previously shown (41), these arrhythmogenic properties can be suppressed by disruption of a-SMA stress fibers using pharmacological manipulation.…”

Section: Actin Filament-based Modification Of Cx43mentioning

confidence: 90%

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Nonmyocytes, mainly interstitial and endothelial cells, represent a heterogeneous, dynamic group of nonexcitable cells that outnumber myocytes, although they occupy a smaller volume fraction (2). Whereas paracrine and structural roles of nonmyocytes are wellestablished in the mammalian heart, awareness of their potential role in electrical signal propagation has only started to emerge (3,4).…”

mentioning

confidence: 99%

Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

Quinn

Camelliti

Rog-Zielinska

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

193

177

View full text Add to dashboard Cite

Electrophysiological studies of excitable organs usually focus on action potential (AP)-generating cells, whereas nonexcitable cells are generally considered as barriers to electrical conduction. Whether nonexcitable cells may modulate excitable cell function or even contribute to AP conduction via direct electrotonic coupling to AP-generating cells is unresolved in the heart: such coupling is present in vitro, but conclusive evidence in situ is lacking. We used genetically encoded voltage-sensitive fluorescent protein 2.3 (VSFP2.3) to monitor transmembrane potential in either myocytes or nonmyocytes of murine hearts. We confirm that VSFP2.3 allows measurement of cell type-specific electrical activity. We show that VSFP2.3, expressed solely in nonmyocytes, can report cardiomyocyte AP-like signals at the border of healed cryoinjuries. Using EM-based tomographic reconstruction, we further discovered tunneling nanotube connections between myocytes and nonmyocytes in cardiac scar border tissue. Our results provide direct electrophysiological evidence of heterocellular electrotonic coupling in native myocardium and identify tunneling nanotubes as a possible substrate for electrical cell coupling that may be in addition to previously discovered connexins at sites of myocyte-nonmyocyte contact in the heart. These findings call for reevaluation of cardiac nonmyocyte roles in electrical connectivity of the heterocellular heart.

show abstract

“…The arrhythmogenic potential of scars that are highly populated with non-excitable cells is dependent on their ability to form a continuous network that is coupled to the surrounding myocardium 26,27 . However, neither the physical substrate that is responsible for coupling between scar tissue and cardiac myocytes 15,28 nor the cellular network present within this tissue have been fully described. We have characterized a non-myocyte cellular network in a 30-day old RV scar through detailed analyses at ultrastructural resolution using SBF-SEM.…”

Section: Resultsmentioning

confidence: 99%

“…We believe significant changes in these parameters are unlikely to be present in the chimeric mice, however their contribution to the changes in the passive electrical properties of the tissue cannot be discounted. In contrast to the uninjured myocardium, the cell populations in the scar have comparatively lower transmembrane conductances 28,49 , therefore a significant contribution of transmembrane conductance changes www.nature.com/scientificreports www.nature.com/scientificreports/ due to Cx43 deletion to the measured passive conduction properties is less likely. Studies have suggested that cardiac conduction may be altered as a result of enhanced mechanosensitive channel activity in response to cardiac injury 50 .…”

Section: Discussionmentioning

confidence: 99%

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

Vásquez

Mezzano

Kessler

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

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 threedimensional 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.

show abstract

A review of the literature on cardiac electrical activity between fibroblasts and myocytes

Abstract: Myocardial injuries often lead to fibrotic deposition. This review presents evidence supporting the concept that fibroblasts in the heart electrically couple to myocytes.

Cited by 18 publications

References 89 publications

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

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

Contact Info

Product

Resources

About