Birnbaum Foster, Eguchi Asuka, Pardon Gaspard, Chang Alex C Y, Blau Helen M
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
NPJ Regen Med. 2022 Mar 18;7(1):19. doi: 10.1038/s41536-022-00214-x.
Duchenne muscular dystrophy (DMD) is a progressive genetic myopathy that leads to heart failure from dilated cardiomyopathy by early adulthood. Recent evidence suggests that tamoxifen, a selective estrogen receptor modulator widely used to treat breast cancer, ameliorates DMD cardiomyopathy. However, the mechanism of action of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on cardiomyocyte function remains unclear. To examine the effects of chronic 4-hydroxytamoxifen treatment, we used state-of-the-art human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and a bioengineered platform to model DMD. We assessed the beating rate and beating velocity of iPSC-CMs in monolayers and as single cells on micropatterns that promote a physiological cardiomyocyte morphology. We found that 4-hydroxytamoxifen treatment of DMD iPSC-CMs decreased beating rate, increased beating velocity, and ameliorated calcium-handling deficits, leading to prolonged viability. Our study highlights the utility of a bioengineered iPSC-CM platform for drug testing and underscores the potential of repurposing tamoxifen as a therapy for DMD cardiomyopathy.
杜兴氏肌肉营养不良症（DMD）是一种进行性遗传性肌病，到成年早期会因扩张型心肌病导致心力衰竭。最近的证据表明，他莫昔芬，一种广泛用于治疗乳腺癌的选择性雌激素受体调节剂，可改善DMD心肌病。然而，他莫昔芬的活性代谢物4-羟基他莫昔芬对心肌细胞功能的作用机制仍不清楚。为了研究慢性4-羟基他莫昔芬治疗的效果，我们使用了最先进的人诱导多能干细胞衍生心肌细胞（iPSC-CMs）和一个生物工程平台来模拟DMD。我们评估了单层iPSC-CMs以及在促进生理心肌细胞形态的微图案上作为单个细胞的iPSC-CMs的搏动率和搏动速度。我们发现，用4-羟基他莫昔芬治疗DMD iPSC-CMs可降低搏动率，提高搏动速度，并改善钙处理缺陷，从而延长细胞活力。我们的研究突出了生物工程iPSC-CM平台在药物测试中的实用性，并强调了将他莫昔芬重新用作DMD心肌病治疗药物的潜力。
