Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery.
Original language | English (US) |
---|---|
Pages (from-to) | 2005-2022 |
Number of pages | 18 |
Journal | Stem Cell Reports |
Volume | 17 |
Issue number | 9 |
DOIs | |
State | Published - Sep 13 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Author(s)
Keywords
- MAPK
- PI3K-AKT
- calcium handling
- cardiomyocyte
- electrophysiology
- inhibitors
- maturation
- multinucleation
- pluripotent stem cells