Journal
NPJ REGENERATIVE MEDICINE
Volume 7, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41536-022-00214-x
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Funding
- Stanford Bio-X Summer Undergraduate Research Program
- Stanford University Vice Provost for Undergraduate Education
- American Heart Association (AHA) [18POST34080160, 13POST14480004, 18CDA34110411, 18POST33960526, 17CSA33590101]
- Swiss National Science Foundation (SNSF) Early Postdoc Mobility Fellowship [P2SKP2_164954]
- Stanford School of Medicine Dean's Postdoctoral Fellowship
- Stanford TRAM Pilot Grant
- Keck Foundation
- Baxter Foundation
- Li Ka Shing Foundation
- Swiss National Science Foundation (SNF) [P2SKP2_164954] Funding Source: Swiss National Science Foundation (SNF)
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This study utilized iPSC-CMs and a bioengineered platform to model DMD, and found that 4-hydroxytamoxifen could ameliorate cardiomyocyte function deficits and prolong cell viability in DMD iPSC-CMs.
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.
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