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- Title
Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation.
- Authors
Gwanghyun Jung; Fajardo, Giovanni; Ribeiro, Alexandre J. S.; Kooiker, Kristina Bezold; Coronado, Michael; Mingming Zhao; Dong-Qing Hu; Reddy, Sushma; Kodo, Kazuki; Sriram, Krishna; Insel, Paul A.; Wu, Joseph C.; Pruitt, Beth L.; Bernstein, Daniel
- Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs for efficacy/toxicity. However, the accuracy with which hiPSC-CMs recapitulate the contractile and remodeling signaling of adult cardiomyocytes is not fully known. We used β-adrenergic receptor (β-AR) signaling as a prototype to determine the evolution of signaling component expression and function during hiPSC-CM maturation. In "early" hiPSC-CMs (less than or equal to d 30), β2-ARs are a primary source of cAMP/PKA signaling. With longer culture, β1-AR signaling increases: from 0% of cAMP generation at d 30 to 56.8 ± 6.6% by d 60. PKA signaling shows a similar increase: 15.7 ± 5.2% (d 30), 49.8 ± 0.5% (d 60), and 71.0 ± 6.1% (d 90). cAMP generation increases 9-fold from d 30 to 60, with enhanced coupling to remodeling pathways (e.g., Akt and Ca2+/calmodulin-dependent protein kinase type II) and development of caveolin-mediated signaling compartmentalization. By contrast, cardiotoxicity induced by chronic β-AR stimulation, a major component of heart failure, develops much later: 5% cell death at d 30 vs. 55% at d 90. Moreover, β-AR maturation can be accelerated by biomechanical stimulation. The differential maturation of β-AR functional vs. remodeling signaling in hiPSC-CMs has important implications for their use in disease modeling and drug testing.
- Subjects
INDUCED pluripotent stem cells; HEART cells; DEVELOPMENTAL biology; ANDROGEN receptors; DRUG efficacy; ADRENERGIC receptors
- Publication
FASEB Journal, 2016, Vol 30, Issue 4, p1464
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.15-280982