Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

Yijie Wang; Qihao Li; Bo Tao; Marina Angelini; Sivakumar Ramadoss; Baiming Sun; Ping Wang; Yuliya Krokhaleva; Feiyang Ma; Yiqian Gu; Alejandro Espinoza; Ken Yamauchi; Matteo Pellegrini; Bennett Novitch; Riccardo Olcese; Zhilin Qu; Zhen Song; Arjun Deb

doi:10.1126/science.adh9925

Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

Science. 2023 Sep 29;381(6665):1480-1487. doi: 10.1126/science.adh9925. Epub 2023 Sep 28.

Authors

Yijie Wang^{1

2

3

4

5

6}, Qihao Li⁷, Bo Tao^{1

2

3

4

5

6}, Marina Angelini⁸, Sivakumar Ramadoss^{1

2

3

4

5

6}, Baiming Sun^{1

2

3

4

5

6}, Ping Wang^{1

2

3

4

5

6}, Yuliya Krokhaleva⁹, Feiyang Ma¹⁰, Yiqian Gu^{3

11}, Alejandro Espinoza^{3

11}, Ken Yamauchi^{4

12}, Matteo Pellegrini^{3

11}, Bennett Novitch^{4

12}, Riccardo Olcese^{8

13}, Zhilin Qu¹, Zhen Song⁷, Arjun Deb^{1

2

3

4

5

6}

Affiliations

¹ Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Cardiovascular Theme, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁶ California Nanosystems Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁷ Peng Cheng Laboratory, Shenzhen, Guangdong 518000, China.
⁸ Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁹ UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹¹ Institute for Quantitative and Computational Biosciences-The Collaboratory, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹² Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹³ Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Abstract

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.

MeSH terms

Animals
Arrhythmias, Cardiac* / genetics
Arrhythmias, Cardiac* / physiopathology
Channelrhodopsins* / genetics
Channelrhodopsins* / physiology
Cicatrix* / pathology
Cicatrix* / physiopathology
Connexin 43 / genetics
Connexin 43 / physiology
Fibroblasts* / physiology
Gene Knockout Techniques
Mice
Myocytes, Cardiac* / physiology
Optogenetics

Substances

Channelrhodopsins
Connexin 43

Abstract

MeSH terms

Substances

Grants and funding