Upregulation of the JAK-STAT pathway promotes maturation of human embryonic stem cell-derived cardiomyocytes
| العنوان: | Upregulation of the JAK-STAT pathway promotes maturation of human embryonic stem cell-derived cardiomyocytes |
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| المؤلفون: | Shi-Yan Ng, Jin-Hui Hor, Colin L. Stewart, Omer An, Lee Chuen Liew, Beatrice Xuan Ho, Hongbing Yu, Boon Seng Soh, Henry He Yang, Jeremy Kah Sheng Pang, Woon-Khiong Chan, Piotr Szyniarowski, Christina Ying Yan Lim |
| المصدر: | Stem Cell Reports |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cellular differentiation, Green Fluorescent Proteins, Human Embryonic Stem Cells, Biology, Biochemistry, Article, Cell Line, JAK-STAT pathway, Interferon-gamma, Calcium imaging, Downregulation and upregulation, Genes, Reporter, Genetics, Humans, Myocytes, Cardiac, Glycolysis, stem cell differentiation, health care economics and organizations, Janus Kinases, JAK-STAT signaling pathway, Cell Differentiation, RNA sequencing, Cell Biology, electrophysiology, Embryonic stem cell, Electrophysiological Phenomena, Up-Regulation, cardiomyocyte maturation, Cell biology, STAT Transcription Factors, Cell culture, MYH6, CRISPR-Cas Systems, Signal Transduction, Developmental Biology |
| الوصف: | Summary The immature characteristics and metabolic phenotypes of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) restrict their applications for disease modeling, drug discovery, and cell-based therapy. Leveraging on the metabolic shifts from glycolysis to fatty acid oxidation as CMs mature, a human hexokinase1-GFP metabolic reporter cell line (H7 HK1-GFP) was generated to facilitate the isolation of fetal or more matured hPSC-CMs. RNA sequencing of fetal versus more matured CMs uncovered a potential role of interferon-signaling pathway in regulating CM maturation. Indeed, IFN-γ-treated CMs resulted in an upregulation of the JAK-STAT pathway, which was found to be associated with increased expression of CM maturation genes, shift from MYH6 to MYH7 expression, and improved sarcomeric structure. Functionally, IFN-γ-treated CMs exhibited a more matured electrophysiological profile, such as increased calcium dynamics and action potential upstroke velocity, demonstrated through calcium imaging and MEA. Expectedly, the functional improvements were nullified with a JAK-STAT inhibitor, ruxolitinib. Highlights • RNA-seq revealed upregulation of IFN-signaling pathways during CM maturation • IFN-γ-treated PSC-derived fetal CMs display increased MYH7:MYH6 ratio • IFN-γ-treated PSC-derived fetal CMs exhibited improved electrophysiological profile In this article, Soh and colleagues utilize a metabolic reporter to identify a novel role of JAK-STAT signaling in hPSC-CM maturation. IFN-γ treatment activates the JAK-STAT pathway and upregulates STAT1 expression in hPSC-derived fetal CMs, thereby enhancing the expression of CM maturation genes including MYH7, which subsequently resulted in improved sarcomeric structure, and a relatively more matured electrophysiological profile in vitro. |
| تدمد: | 2213-6711 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b5e4ca1b9fbf90e416441129c44caf7Test https://doi.org/10.1016/j.stemcr.2021.10.009Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0b5e4ca1b9fbf90e416441129c44caf7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22136711 |
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