Serine synthesis pathway regulates cardiac differentiation from human pluripotent stem cells
Human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) differentiation can improve using chemical compounds which mimic early heart development. However, variations in hPSC-CM differentiation efficiency and its poor reproducibility have remained a challenge. Here, we report a unique metabolic method to promote hPSC-CM differentiation that involves marked suppression of the mitochondrial oxidative phosphorylation from the mesendoderm to the cardiac mesoderm, which is regulated by PHGDH, a rate-limiting enzyme in the serine synthesis pathway. Mechanistically, PHGDH inhibition impairs mitochondrial respiration by blocking the electron transport chain, resulting in elevated ROS levels and promoting the cardiomyocyte lineage specification by disrupting the cardiopharyngeal mesoderm lineage differentiation. Additionally, antioxidant supplementation can scavenge ROS and eliminate the effects of PHGDH inhibition. Collectively, our findings show that serine synthesis pathway can regulate cardiomyocyte lineage specification and have implications in providing a cellular source for transplantation and elucidating the potential mechanisms of heart development and pathogenesis of heart disease.
Authors
- Masashi Nakamura (ORCID: https://orcid.org/0000-0001-5248-5896)
- Y Soma (ORCID: https://orcid.org/0000-0003-2150-5465)
- Tomomi Matsuura
- Masaki Ieda (ORCID: https://orcid.org/0000-0003-4724-3299)
- Otoya Sekine
- Seitaro Nomura (ORCID: https://orcid.org/0000-0002-2957-2016)
- Yoshikazu Kishino (ORCID: https://orcid.org/0000-0003-3291-2795)
- Taijun Moriwaki (ORCID: https://orcid.org/0000-0002-0432-3363)
- Kotaro Haga (ORCID: https://orcid.org/0000-0003-2697-2097)
- Tomohiko Umei (ORCID: https://orcid.org/0000-0003-0294-6732)
- Keiichi Fukuda (ORCID: https://orcid.org/0000-0003-1413-0482)
- Takako Hishiki (ORCID: https://orcid.org/0000-0003-3167-6524)
- Manami Katoh (ORCID: https://orcid.org/0000-0001-5634-9170)
- Shugo Tohyama (ORCID: https://orcid.org/0000-0002-5898-3543)
- Yuika Morita-Umei
- Hidenori Tani (ORCID: https://orcid.org/0000-0002-5042-6187)
- Masatoshi Ohno
Institutions
- Fujita Health University (JP)
- Keio University (JP)
- Keio University Hospital (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- iScience
- Published
- 2025-06-07
- DOI
- https://doi.org/10.1016/j.isci.2025.112843
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Japan Agency for Medical Research and Development
- Kanagawa Institute of Industrial Science and Technology
- Keio University
- Japanese Circulation Society
- Japan Heart Foundation
- Japan Society for the Promotion of Science