Tamoxifen treatment ameliorates contractile dysfunction of Duchenne muscular dystrophy stem cell-derived cardiomyocytes on bioengineered substrates

Foster Birnbaum; Asuka Eguchi; Gaspard Pardon; Alex C Y Chang; Helen M Blau

doi:10.1038/s41536-022-00214-x

Tamoxifen treatment ameliorates contractile dysfunction of Duchenne muscular dystrophy stem cell-derived cardiomyocytes on bioengineered substrates

NPJ Regen Med. 2022 Mar 18;7(1):19. doi: 10.1038/s41536-022-00214-x.

Authors

Foster Birnbaum^#¹, Asuka Eguchi^#^{1

2}, Gaspard Pardon^#^{1

2}, Alex C Y Chang^{3

4

5}, Helen M Blau^{6

7}

Affiliations

¹ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
² Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
³ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA. alexchang@shsmu.edu.cn.
⁴ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. alexchang@shsmu.edu.cn.
⁵ Department of Cardiology and Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. alexchang@shsmu.edu.cn.
⁶ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA. hblau@stanford.edu.
⁷ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. hblau@stanford.edu.

^# Contributed equally.

Abstract

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.

Abstract

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