Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
Stem Cell Reports. 2020 Aug 11;15(2):498-514. doi: 10.1016/j.stemcr.2020.06.012. Epub 2020 Jul 9.
Recent studies suggest that metabolic regulation may improve differentiation of cardiomyocytes derived from induced pluripotent stem cells (iPSCs). AMP-activated protein kinase (AMPK) is a master regulator of metabolic activities. We investigated whether AMPK participates in iPSC-derived cardiomyocyte differentiation. We observed that AMPK phosphorylation at Thr172 increased at day 9 but then decreased after day 11 of differentiation to cardiomyocytes. Inhibition of AMPK with compound C significantly reduced mRNA and protein expression of cardiac troponins TNNT2 and TNNI3. Moreover, sustained AMPK activation using AICAR from days 9 to 14 of differentiation increased mRNA and protein expression of both TNNT2 and TNNI3. AICAR decreased acetylation of histone 3 at Lys9 and 56 and histone 4 at Lys16 (known target sites for nuclear-localized sirtuins [SIRT1, SIRT6]), suggesting that AMPK activation enhances sirtuin activity. Sustained AMPK activation during days 9-14 of differentiation induces sirtuin-mediated histone deacetylation and may enhance cardiomyocyte differentiation from iPSCs.
最近的研究表明，代谢调节可能改善诱导多能干细胞（iPSC）衍生的心肌细胞的分化。AMP 激活的蛋白激酶（AMPK）是代谢活动的主要调节剂。我们研究了 AMPK 是否参与 iPSC 衍生的心肌细胞分化。我们观察到，AMPK 在第 9 天向 Thr172 的磷酸化增加，但在向心肌细胞分化的第 11 天后减少。用化合物 C 抑制 AMPK 显著降低了心肌肌钙蛋白 TNNT2 和 TNNI3 的 mRNA 和蛋白表达。此外，从分化的第 9 天到第 14 天持续激活 AMPK 使用 AICAR 增加了 TNNT2 和 TNNI3 的 mRNA 和蛋白表达。AICAR 降低了组蛋白 3 在 Lys9 和 56 以及组蛋白 4 在 Lys16 的乙酰化（核定位的沉默调节蛋白 [SIRT1、SIRT6] 的已知靶位），表明 AMPK 激活增强了沉默调节蛋白的活性。在分化的第 9-14 天持续激活 AMPK 诱导沉默调节蛋白介导的组蛋白去乙酰化，并可能增强 iPSC 来源的心肌细胞分化。
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