Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes
| Autor: | Kristy Red-Horse, William R. Goodyer, Lei Tian, James B Hu, Michael Hesse, Haodi Wu, Paul J. M. Wijnker, Jan W. Buikema, Sean M. Wu, Daniel Lee, Yi Miao, K. Christopher Garcia, Joost P.G. Sluijter, Joy Y. Wu, David T. Paik, Aimee Beck, Larissa M. Dorsch, Srilatha Swami, Jolanda van der Velden, Pieter A. Doevendans, Benjamin Beyersdorf, Caroline Geisen, Guang Li, Sharon L. Paige, Alain van Mil, Renee G.C. Maas, Soah Lee, Nazan Puluca, Siyeon Rhee, Orlando Chirikian, Joseph C. Wu, Francisco X Galdos, Bernd K. Fleischmann, Stefan Jovinge, Maike Schuldt, Sneha Venkamatran, Vahid Serpooshan |
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| Přispěvatelé: | Physiology, ACS - Heart failure & arrhythmias |
| Rok vydání: | 2020 |
| Předmět: |
Induced Pluripotent Stem Cells
Biology Article 03 medical and health sciences 0302 clinical medicine health services administration Genetics Humans Myocytes Cardiac Induced pluripotent stem cell Cardiomyocyte proliferation Cells Cultured health care economics and organizations 030304 developmental biology 0303 health sciences Glycogen Synthase Kinase 3 beta Cell cell contact fungi Wnt signaling pathway food and beverages Cell Differentiation Cell Biology Cell biology Molecular Medicine Signal transduction 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell Buikema, J W, Lee, S, Goodyer, W R, Maas, R G, Chirikian, O, Li, G, Miao, Y, Paige, S L, Lee, D, Wu, H, Paik, D T, Rhee, S, Tian, L, Galdos, F X, Puluca, N, Beyersdorf, B, Hu, J, Beck, A, Venkamatran, S, Swami, S, Wijnker, P, Schuldt, M, Dorsch, L M, van Mil, A, Red-Horse, K, Wu, J Y, Geisen, C, Hesse, M, Serpooshan, V, Jovinge, S, Fleischmann, B K, Doevendans, P A, van der Velden, J, Garcia, K C, Wu, J C, Sluijter, J P G & Wu, S M 2020, ' Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes ', Cell Stem Cell, vol. 27, no. 1, pp. 50-63 . https://doi.org/10.1016/j.stem.2020.06.001 Cell Stem Cell, 27(1), 50-63. Cell Press |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2020.06.001 |
| Popis: | Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e., 100- to 250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show that GSK-3β inhibition suppresses CM maturation, while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10 to 25 times greater expansion beyond GSK-3β inhibition alone. Mechanistically, persistent CM proliferation required both LEF/TCF activity and AKT phosphorylation but was independent from yes-associated protein (YAP) signaling. Engineered heart tissues from expanded hiPSC-CMs showed comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In summary, we uncovered a molecular interplay that enables massive hiPSC-CM expansion for large-scale drug screening and tissue engineering applications. |
| Databáze: | OpenAIRE |
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