Cho et al., Nature Biomedical Engineering, 2021
Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts
Jaeyeaon Cho 1 2, Sangsung Kim 2, Hyein Lee 2, Woongchan Rah 2, Hee Cheol Cho 3, Nam Kyun Kim 3, Seongho Bae 1, Dong Hoon Shin 2, Min Goo Lee 4, In-Hyun Park 5, Yoshiaki Tanaka 6, Eric Shin 1, Hong Yi 7, Ji Woong Han 1, Patrick Tae Joon Hwang 8, Ho-Wook Jun 8, Hun-Jun Park 9, Kyuwon Cho 1, Sang Wook Lee 1, Jae Kyung Jung 1, Rebecca D Levit 1, Mark A Sussman 10 11, Richard P Harvey 12, Young-Sup Yoon 13 14
Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.