Abstract
Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. However, due to the challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of the mature phenotype remains poorly understood. Here we implement large-particle sorting and analyze single myocytes from neonatal to adult hearts. Early myocytes exhibit wide-ranging transcriptomic and size heterogeneity that is maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and identifies a multifaceted regulator controlling cardiomyocyte maturation.
Highlights
Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body
By combining gene regulatory network analysis with mosaic gene deletion and pluripotent stem cells (PSCs)-CM assays at the single-cell level, we identify peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC1) signaling as a multi-faceted regulator coordinating CM maturation via its targets Yap[1] and SF3B2
Since PGC1 is required for CM hypertrophy and contractility, and its levels and activity remain low in PSC-CMs6, we further investigated if increased levels of PGC1 can promote the maturation of PSC-derived CMs (PSC-CMs)
Summary
Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. The myocytes become tightly connected via intercalated discs to allow simultaneous contraction These events are accompanied with functional and metabolic changes including mature calcium handling, increased contractile force, and mitochondrial maturation and oxidative phosphorylation[8]. By combining gene regulatory network analysis with mosaic gene deletion and PSC-CM assays at the single-cell level, we identify peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC1) signaling as a multi-faceted regulator coordinating CM maturation via its targets Yap[1] and SF3B2
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