Alternative splicing dynamics during human cardiac development in vivo and in vitro
Summary
Cardiomyocytes differentiated in vitro from human induced pluripotent stem cells (iPSC-CMs) are increasingly used in studies of disease mechanisms, drug development, toxicity testing, and regenerative medicine. Alternative splicing (AS) plays a pivotal role in cardiac development. However, the extent to which iPSC-CMs recapitulate native cardiac splicing patterns remains poorly understood. Here, we provide a comprehensive temporal map of AS regulation during human cardiac development. iPSC-derived cardiomyocytes globally recapitulate the transcriptome of prenatal cardiomyocytes, yet their splicing profiles remain heterogeneous, with certain events reflecting early embryonic patterns and others resembling those of later-stage fetal hearts. Moreover, we uncover altered splicing events in iPSC-CMs, including mis-splicing of splicing factors. In conclusion, we present a resource of AS dynamics throughout human cardiac development and a catalog of splicing markers to assess cardiomyocyte maturation in vitro. Our findings provide critical insights into the limitations of iPSC-CM models and their utility in cardiovascular research. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
| Authors | Gomes-Silva B, Furtado M, Ribeiro M, Martins S, Carvalho T, Ventura-Gomes A, Maatz H, Parakkat P, Crocini C, Gotthardt M, Savisaar R, Carmo-Fonseca M |
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| Journal | Stem cell reports |
| Publication Date | 2026 Jan 13;21(1):102757 |
| PubMed | 41483812 |
| PubMed Central | PMC12925949 |
| DOI | 10.1016/j.stemcr.2025.102757 |