Tissue-embedded stretchable nanoelectronics reveal endothelial cell-mediated electrical maturation of human 3D cardiac microtissues.
Zuwan Lin, Jessica C Garbern, Ren Liu, Qiang Li, Estela Mancheño Juncosa, Hannah L T Elwell, Morgan Sokol, Junya Aoyama, Undine-Sophie Deumer, Emma Hsiao, Hao Sheng, Richard T Lee, Jia Liu
Author Information
Zuwan Lin: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. ORCID
Jessica C Garbern: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Ren Liu: School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA.
Qiang Li: School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA. ORCID
Estela Mancheño Juncosa: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Hannah L T Elwell: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Morgan Sokol: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Junya Aoyama: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Undine-Sophie Deumer: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Emma Hsiao: School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA.
Hao Sheng: School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA. ORCID
Richard T Lee: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ORCID
Jia Liu: School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA. ORCID
Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning-based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.
References
BMC Genomics. 2018 Jun 19;19(1):477
[PMID: 29914354]
