Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study
Background: Cellular transplantation has emerged as promising approach for treating cardiac diseases. However, a poor engraftment rate limits our understanding on how transplanted cardiomyocytes contribute to cardiac function in the recipient’s heart. Methods: The CRISPR/Cas9 technique was employed...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/6/951 |
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| author | Jyotsna Joshi Bing Xu Michael Rubart Yun Chang Xiaoping Bao Hari P. Chaliki Luis R. Scott Wuqiang Zhu |
| author_facet | Jyotsna Joshi Bing Xu Michael Rubart Yun Chang Xiaoping Bao Hari P. Chaliki Luis R. Scott Wuqiang Zhu |
| author_sort | Jyotsna Joshi |
| collection | DOAJ |
| description | Background: Cellular transplantation has emerged as promising approach for treating cardiac diseases. However, a poor engraftment rate limits our understanding on how transplanted cardiomyocytes contribute to cardiac function in the recipient’s heart. Methods: The CRISPR/Cas9 technique was employed for stable and constitutive gene expression in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Myocardial infarction was induced in adult immunodeficient mice, followed by intramyocardial injection of hiPSC-CMs expressing either CCND2/channelrhodopsin 2 (hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CMs) or CCND2/luciferase (hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs). Six months later, hemodynamics and intramural electrocardiogram were recorded upon blue light illuminations in anesthetized, open-chest mice. Results: Blue light resets automaticity of spontaneously beating hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CMs in culture, but not that of hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs. Response to blue light was also observed in mice carrying large (>10<sup>6</sup> cells) intracardiac grafts of hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CM but not in mice carrying hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs. The former exhibited single premature ventricular contractions upon light illumination or ventricular quadrigeminy upon second-long illuminations. At the onset of premature ventricular contractions, maximal systolic ventricular pressure decreased while ventricular volume rose concomitantly. Light-induced changes reversed upon resumption of sinus rhythm. Conclusions: We established an in vivo model for optogenetic-based modulation of the excitability of donor cardiomyocytes in a functional, reversible, and localized manner. This approach holds unique value for studying electromechanical coupling and molecular interactions between donor cardiomyocytes and recipient hearts in live animals. |
| first_indexed | 2024-03-09T20:00:48Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T20:00:48Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-44615feaa1c04c90b7d0582eb7fe49a72023-11-24T00:43:46ZengMDPI AGCells2073-44092022-03-0111695110.3390/cells11060951Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept StudyJyotsna Joshi0Bing Xu1Michael Rubart2Yun Chang3Xiaoping Bao4Hari P. Chaliki5Luis R. Scott6Wuqiang Zhu7Department of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZ 85259, USADepartment of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZ 85259, USADepartment of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USADepartment of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USADepartment of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZ 85259, USADepartment of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZ 85259, USADepartment of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZ 85259, USABackground: Cellular transplantation has emerged as promising approach for treating cardiac diseases. However, a poor engraftment rate limits our understanding on how transplanted cardiomyocytes contribute to cardiac function in the recipient’s heart. Methods: The CRISPR/Cas9 technique was employed for stable and constitutive gene expression in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Myocardial infarction was induced in adult immunodeficient mice, followed by intramyocardial injection of hiPSC-CMs expressing either CCND2/channelrhodopsin 2 (hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CMs) or CCND2/luciferase (hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs). Six months later, hemodynamics and intramural electrocardiogram were recorded upon blue light illuminations in anesthetized, open-chest mice. Results: Blue light resets automaticity of spontaneously beating hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CMs in culture, but not that of hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs. Response to blue light was also observed in mice carrying large (>10<sup>6</sup> cells) intracardiac grafts of hiPSC-CCND2<sup>OE</sup>/ChR2<sup>OE</sup>CM but not in mice carrying hiPSC-CCND2<sup>OE</sup>/Luci<sup>OE</sup>CMs. The former exhibited single premature ventricular contractions upon light illumination or ventricular quadrigeminy upon second-long illuminations. At the onset of premature ventricular contractions, maximal systolic ventricular pressure decreased while ventricular volume rose concomitantly. Light-induced changes reversed upon resumption of sinus rhythm. Conclusions: We established an in vivo model for optogenetic-based modulation of the excitability of donor cardiomyocytes in a functional, reversible, and localized manner. This approach holds unique value for studying electromechanical coupling and molecular interactions between donor cardiomyocytes and recipient hearts in live animals.https://www.mdpi.com/2073-4409/11/6/951heart failurestem cellscardiomyocytescell therapyoptogenetics |
| spellingShingle | Jyotsna Joshi Bing Xu Michael Rubart Yun Chang Xiaoping Bao Hari P. Chaliki Luis R. Scott Wuqiang Zhu Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study Cells heart failure stem cells cardiomyocytes cell therapy optogenetics |
| title | Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study |
| title_full | Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study |
| title_fullStr | Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study |
| title_full_unstemmed | Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study |
| title_short | Optogenetic Control of Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Live Mice: A Proof-of-Concept Study |
| title_sort | optogenetic control of engrafted human induced pluripotent stem cell derived cardiomyocytes in live mice a proof of concept study |
| topic | heart failure stem cells cardiomyocytes cell therapy optogenetics |
| url | https://www.mdpi.com/2073-4409/11/6/951 |
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