Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration
Heart regeneration after myocardial infarction (MI) using human stem cell-derived cardiomyocytes (CMs) is rapidly accelerating with large animal and human clinical trials. However, vascularization methods to support the engraftment, survival, and development of implanted CMs in the ischemic environm...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/13/1698 |
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| author | Rajeev J. Kant Kiera D. Dwyer Jang-Hoon Lee Collin Polucha Momoka Kobayashi Stephen Pyon Arvin H. Soepriatna Jonghwan Lee Kareen L. K. Coulombe |
| author_facet | Rajeev J. Kant Kiera D. Dwyer Jang-Hoon Lee Collin Polucha Momoka Kobayashi Stephen Pyon Arvin H. Soepriatna Jonghwan Lee Kareen L. K. Coulombe |
| author_sort | Rajeev J. Kant |
| collection | DOAJ |
| description | Heart regeneration after myocardial infarction (MI) using human stem cell-derived cardiomyocytes (CMs) is rapidly accelerating with large animal and human clinical trials. However, vascularization methods to support the engraftment, survival, and development of implanted CMs in the ischemic environment of the infarcted heart remain a key and timely challenge. To this end, we developed a dual remuscularization-revascularization therapy that is evaluated in a rat model of ischemia-reperfusion MI. This study details the differentiation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for engineering cardiac tissue containing patterned engineered vessels 400 μm in diameter. Vascularized engineered human myocardial tissues (vEHMs) are cultured in static conditions or perfused in vitro prior to implantation and evaluated after two weeks. Immunohistochemical staining indicates improved engraftment of hiPSC-CMs in in vitro-perfused vEHMs with greater expression of SMA+ vessels and evidence of inosculation. Three-dimensional vascular reconstructions reveal less tortuous and larger intra-implant vessels, as well as an improved branching hierarchy in in vitro-perfused vEHMs relative to non-perfused controls. Exploratory RNA sequencing of explanted vEHMs supports the hypothesis that co-revascularization impacts hiPSC-CM development in vivo. Our approach provides a strong foundation to enhance vEHM integration, develop hierarchical vascular perfusion, and maximize hiPSC-CM engraftment for future regenerative therapy. |
| first_indexed | 2024-03-11T01:44:45Z |
| format | Article |
| id | doaj.art-05c0d69b5ab745648949c984eb650893 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T01:44:45Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-05c0d69b5ab745648949c984eb6508932023-11-18T16:18:45ZengMDPI AGCells2073-44092023-06-011213169810.3390/cells12131698Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart RegenerationRajeev J. Kant0Kiera D. Dwyer1Jang-Hoon Lee2Collin Polucha3Momoka Kobayashi4Stephen Pyon5Arvin H. Soepriatna6Jonghwan Lee7Kareen L. K. Coulombe8School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USASchool of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USAHeart regeneration after myocardial infarction (MI) using human stem cell-derived cardiomyocytes (CMs) is rapidly accelerating with large animal and human clinical trials. However, vascularization methods to support the engraftment, survival, and development of implanted CMs in the ischemic environment of the infarcted heart remain a key and timely challenge. To this end, we developed a dual remuscularization-revascularization therapy that is evaluated in a rat model of ischemia-reperfusion MI. This study details the differentiation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for engineering cardiac tissue containing patterned engineered vessels 400 μm in diameter. Vascularized engineered human myocardial tissues (vEHMs) are cultured in static conditions or perfused in vitro prior to implantation and evaluated after two weeks. Immunohistochemical staining indicates improved engraftment of hiPSC-CMs in in vitro-perfused vEHMs with greater expression of SMA+ vessels and evidence of inosculation. Three-dimensional vascular reconstructions reveal less tortuous and larger intra-implant vessels, as well as an improved branching hierarchy in in vitro-perfused vEHMs relative to non-perfused controls. Exploratory RNA sequencing of explanted vEHMs supports the hypothesis that co-revascularization impacts hiPSC-CM development in vivo. Our approach provides a strong foundation to enhance vEHM integration, develop hierarchical vascular perfusion, and maximize hiPSC-CM engraftment for future regenerative therapy.https://www.mdpi.com/2073-4409/12/13/1698inosculationvascularizationhiPSC-derived cardiomyocytespatterned vesselsengineered cardiac tissueheart regeneration |
| spellingShingle | Rajeev J. Kant Kiera D. Dwyer Jang-Hoon Lee Collin Polucha Momoka Kobayashi Stephen Pyon Arvin H. Soepriatna Jonghwan Lee Kareen L. K. Coulombe Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration Cells inosculation vascularization hiPSC-derived cardiomyocytes patterned vessels engineered cardiac tissue heart regeneration |
| title | Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration |
| title_full | Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration |
| title_fullStr | Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration |
| title_full_unstemmed | Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration |
| title_short | Patterned Arteriole-Scale Vessels Enhance Engraftment, Perfusion, and Vessel Branching Hierarchy of Engineered Human Myocardium for Heart Regeneration |
| title_sort | patterned arteriole scale vessels enhance engraftment perfusion and vessel branching hierarchy of engineered human myocardium for heart regeneration |
| topic | inosculation vascularization hiPSC-derived cardiomyocytes patterned vessels engineered cardiac tissue heart regeneration |
| url | https://www.mdpi.com/2073-4409/12/13/1698 |
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