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Title: | Monoamine oxidase A-dependent ROS formation modulates human cardiomyocyte differentiation through AKT and WNT activation | Authors: | Di Sante, Moises Antonucci, Salvatore Pontarollo, Laura Cappellaro, Ilaria Segat, Francesca Deshwal, Soni Greotti, Elisa Grilo, Luís F. Menabò, Roberta Di Lisa, Fabio Kaludercic, Nina |
Keywords: | Reactive oxygen species; hiPSCs; Cardiomyocyte differentiation; Development; Cell fate | Issue Date: | 20-Jan-2023 | Publisher: | Dietrich Steinkopff Verlag | Project: | Open access funding provided by Università degli Studi di Padova within the CRUI-CARE Agreement Leducq Transatlantic Network of Excellence 16CVD04 COST Action EU-CARDIOPROTECTION CA16225 |
Serial title, monograph or event: | Basic Research in Cardiology | Volume: | 118 | Issue: | 1 | Abstract: | During embryonic development, cardiomyocytes undergo differentiation and maturation, processes that are tightly regulated by tissue-specific signaling cascades. Although redox signaling pathways involved in cardiomyogenesis are established, the exact sources responsible for reactive oxygen species (ROS) formation remain elusive. The present study investigates whether ROS produced by the mitochondrial flavoenzyme monoamine oxidase A (MAO-A) play a role in cardiomyocyte differentiation from human induced pluripotent stem cells (hiPSCs). Wild type (WT) and MAO-A knock out (KO) hiPSCs were generated by CRISPR/Cas9 genome editing and subjected to cardiomyocyte differentiation. Mitochondrial ROS levels were lower in MAO-A KO compared to the WT cells throughout the differentiation process. MAO-A KO hiPSC-derived cardiomyocytes (hiPSC-CMs) displayed sarcomere disarray, reduced α- to β-myosin heavy chain ratio, GATA4 upregulation and lower macroautophagy levels. Functionally, genetic ablation of MAO-A negatively affected intracellular Ca2+ homeostasis in hiPSC-CMs. Mechanistically, MAO-A generated ROS contributed to the activation of AKT signaling that was considerably attenuated in KO cells. In addition, MAO-A ablation caused a reduction in WNT pathway gene expression consistent with its reported stimulation by ROS. As a result of WNT downregulation, expression of MESP1 and NKX2.5 was significantly decreased in MAO-A KO cells. Finally, MAO-A re-expression during differentiation rescued expression levels of cardiac transcription factors, contractile structure, and intracellular Ca2+ homeostasis. Taken together, these results suggest that MAO-A mediated ROS generation is necessary for the activation of AKT and WNT signaling pathways during cardiac lineage commitment and for the differentiation of fully functional human cardiomyocytes. | URI: | https://hdl.handle.net/10316/110981 | ISSN: | 1435-1803 | DOI: | 10.1007/s00395-023-00977-4 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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Monoamine-oxidase-Adependent-ROS-formation-modulates-human-cardiomyocyte-differentiation-through-AKT-and-WNT-activationBasic-Research-in-Cardiology.pdf | 4.17 MB | Adobe PDF | View/Open |
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