دورية أكاديمية
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P53 Activation Promotes Maturational Characteristics of Pluripotent Stem Cell-Derived Cardiomyocytes in 3-Dimensional Suspension Culture Via FOXO-FOXM1 Regulation.

التفاصيل البيبلوغرافية
العنوان: P53 Activation Promotes Maturational Characteristics of Pluripotent Stem Cell-Derived Cardiomyocytes in 3-Dimensional Suspension Culture Via FOXO-FOXM1 Regulation.
المؤلفون: Velayutham N; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Garbern JC; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA.; Department of Cardiology Boston Children's Hospital Boston MA USA., Elwell HLT; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Zhuo Z; Bioinformatics Core, Department of Biostatistics Harvard T.H. Chan School of Public Health Boston MA USA., Rüland L; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Elcure Alvarez F; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Frontini S; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Rodriguez Carreras Y; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Eichholtz M; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Ricci-Blair E; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Shaw JY; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Bouffard AH; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Sokol M; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Mancheño Juncosa E; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Rhoades S; Ginkgo Bioworks Boston MA USA., van den Berg D; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Kreymerman A; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Aoyama J; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA., Höfflin J; Ginkgo Bioworks Boston MA USA., Ryan H; Ginkgo Bioworks Boston MA USA., Ho Sui S; Bioinformatics Core, Department of Biostatistics Harvard T.H. Chan School of Public Health Boston MA USA., Lee RT; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute Harvard University Cambridge MA USA.; Division of Cardiovascular Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA.
المصدر: Journal of the American Heart Association [J Am Heart Assoc] 2024 Jul 02; Vol. 13 (13), pp. e033155. Date of Electronic Publication: 2024 Jun 27.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101580524 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2047-9980 (Electronic) Linking ISSN: 20479980 NLM ISO Abbreviation: J Am Heart Assoc Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford : Wiley-Blackwell
مواضيع طبية MeSH: Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/drug effects , Forkhead Box Protein M1*/metabolism , Forkhead Box Protein M1*/genetics , Tumor Suppressor Protein p53*/metabolism , Tumor Suppressor Protein p53*/genetics , Induced Pluripotent Stem Cells*/metabolism , Induced Pluripotent Stem Cells*/drug effects , Cell Differentiation*, Humans ; Cell Culture Techniques, Three Dimensional/methods ; Cells, Cultured ; Signal Transduction ; Forkhead Box Protein O1/metabolism ; Forkhead Box Protein O1/genetics
مستخلص: Background: Current protocols generate highly pure human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro that recapitulate characteristics of mature in vivo cardiomyocytes. Yet, a risk of arrhythmias exists when hiPSC-CMs are injected into large animal models. Thus, understanding hiPSC-CM maturational mechanisms is crucial for clinical translation. Forkhead box (FOX) transcription factors regulate postnatal cardiomyocyte maturation through a balance between FOXO and FOXM1. We also previously demonstrated that p53 activation enhances hiPSC-CM maturation. Here, we investigate whether p53 activation modulates the FOXO/FOXM1 balance to promote hiPSC-CM maturation in 3-dimensional suspension culture.
Methods and Results: Three-dimensional cultures of hiPSC-CMs were treated with Nutlin-3a (p53 activator, 10 μM), LOM612 (FOXO relocator, 5 μM), AS1842856 (FOXO inhibitor, 1 μM), or RCM-1 (FOXM1 inhibitor, 1 μM), starting 2 days after onset of beating, with dimethyl sulfoxide (0.2% vehicle) as control. P53 activation promoted hiPSC-CM metabolic and electrophysiological maturation alongside FOXO upregulation and FOXM1 downregulation, in n=3 to 6 per group for all assays. FOXO inhibition significantly decreased expression of cardiac-specific markers such as TNNT2. In contrast, FOXO activation or FOXM1 inhibition promoted maturational characteristics such as increased contractility, oxygen consumption, and voltage peak maximum upstroke velocity, in n=3 to 6 per group for all assays. Further, by single-cell RNA sequencing of n=2 LOM612-treated cells compared with dimethyl sulfoxide, LOM612-mediated FOXO activation promoted expression of cardiac maturational pathways.
Conclusions: We show that p53 activation promotes FOXO and suppresses FOXM1 during 3-dimensional hiPSC-CM maturation. These results expand our understanding of hiPSC-CM maturational mechanisms in a clinically-relevant 3-dimensional culture system.
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فهرسة مساهمة: Keywords: FOXM1; FOXO; cardiomyocytes; maturation; p53; stem cells
المشرفين على المادة: 0 (Forkhead Box Protein M1)
0 (Tumor Suppressor Protein p53)
0 (FOXM1 protein, human)
0 (TP53 protein, human)
0 (FOXO1 protein, human)
0 (Forkhead Box Protein O1)
تواريخ الأحداث: Date Created: 20240627 Date Completed: 20240702 Latest Revision: 20240726
رمز التحديث: 20240726
مُعرف محوري في PubMed: PMC11255683
DOI: 10.1161/JAHA.123.033155
PMID: 38934864
قاعدة البيانات: MEDLINE
الوصف
تدمد:2047-9980
DOI:10.1161/JAHA.123.033155