Tbx18 Orchestrates Cytostructural Transdifferentiation of Cardiomyocytes to Pacemaker Cells by Recruiting the Epithelial–Mesenchymal Transition Program
العنوان: | Tbx18 Orchestrates Cytostructural Transdifferentiation of Cardiomyocytes to Pacemaker Cells by Recruiting the Epithelial–Mesenchymal Transition Program |
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المؤلفون: | D. Brian Foster, Jin-mo Gu, Elizabeth H. Kim, David W. Wolfson, Robert O’Meally, Robert N. Cole, Hee Cheol Cho |
المصدر: | Journal of Proteome Research. 21:2277-2292 |
بيانات النشر: | American Chemical Society (ACS), 2022. |
سنة النشر: | 2022 |
مصطلحات موضوعية: | Proteomics, Epithelial-Mesenchymal Transition, Proteome, Cell Transdifferentiation, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Animals, TRPM Cation Channels, Myocytes, Cardiac, General Chemistry, T-Box Domain Proteins, Biochemistry, Rats, Transcription Factors |
الوصف: | Previously, we reported that heterologous expression of an embryonic transcription factor, Tbx18, reprograms ventricular cardiomyocytes into induced pacemaker cells (Tbx18-iPMs), though the key pathways are unknown. Here, we have used a tandem mass tag proteomic approach to characterize the impact of Tbx18 on neonatal rat ventricular myocytes. Tbx18 expression triggered vast proteome remodeling. Tbx18-iPMs exhibited increased expression of known pacemaker ion channels, including Hcn4 and Cx45 as well as upregulation of the mechanosensitive ion channels Piezo1, Trpp2 (PKD2), and TrpM7. Metabolic pathways were broadly downregulated, as were ion channels associated with ventricular excitation-contraction coupling. Tbx18-iPMs also exhibited extensive intracellular cytoskeletal and extracellular matrix remodeling, including 96 differentially expressed proteins associated with the epithelial-to-mesenchymal transition (EMT). RNAseq extended coverage of low abundance transcription factors, revealing upregulation of EMT-inducing Snai1, Snai2, Twist1, Twist2, and Zeb2. Finally, network diffusion mapping ofgt;200 transcriptional regulators indicates EMT and heart development factors occupy adjacent network neighborhoods downstream of Tbx18 but upstream of metabolic control factors. In conclusion, transdifferentiation of cardiac myocytes into pacemaker cells entails massive electrogenic, metabolic, and cytostructural remodeling. Structural changes exhibit hallmarks of the EMT. The results aid ongoing efforts to maximize the yield and phenotypic stability of engineered biological pacemakers. |
تدمد: | 1535-3907 1535-3893 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::638d4d095a879972dbf30a3d1b792a1c https://doi.org/10.1021/acs.jproteome.2c00133 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....638d4d095a879972dbf30a3d1b792a1c |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15353907 15353893 |
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