TY - JOUR
T1 - Proteomic Analysis of Human Pluripotent Stem Cell-Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation
AU - Poon, Ellen
AU - Keung, Wendy
AU - Liang, Yimin
AU - Ramalingam, Rajkumar
AU - Yan, Bin
AU - Zhang, Shaohong
AU - Chopra, Anant
AU - Moore, Jennifer
AU - Herren, Anthony
AU - Lieu, Deborah K.
AU - Wong, Hau San
AU - Weng, Zhihui
AU - Wong, On Tik
AU - Lam, Yun Wah
AU - Tomaselli, Gordon F.
AU - Chen, Christopher
AU - Boheler, Kenneth R.
AU - Li, Ronald A.
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/6/11
Y1 - 2015/6/11
N2 - Background - Differentiation of pluripotent human embryonic stem cells (hESCs) to the cardiac lineage represents a potentially unlimited source of ventricular cardiomyocytes (VCMs), but hESC-VCMs are developmentally immature. Previous attempts to profile hESC-VCMs primarily relied on transcriptomic approaches, but the global proteome has not been examined. Furthermore, most hESC-CM studies focus on pathways important for cardiac differentiation, rather than regulatory mechanisms for CM maturation. We hypothesized that gene products and pathways crucial for maturation can be identified by comparing the proteomes of hESCs, hESC-derived VCMs, human fetal and human adult ventricular and atrial CMs. Methods and Results - Using two-dimensional-differential-in-gel electrophoresis, 121 differentially expressed (>1.5-fold; P<0.05) proteins were detected. The data set implicated a role of the peroxisome proliferator-activated receptor signaling in cardiac maturation. Consistently, WY-14643, a peroxisome proliferator-activated receptor agonist, increased fatty oxidative enzyme level, hyperpolarized mitochondrial membrane potential and induced a more organized morphology. Along this line, treatment with the thyroid hormone triiodothyronine increased the dynamic tension developed in engineered human ventricular cardiac microtissue by 3-fold, signifying their maturation. Conclusions - We conclude that the peroxisome proliferator-activated receptor and thyroid hormone pathways modulate the metabolism and maturation of hESC-VCMs and their engineered tissue constructs. These results may lead to mechanism-based methods for deriving mature chamber-specific CMs.
AB - Background - Differentiation of pluripotent human embryonic stem cells (hESCs) to the cardiac lineage represents a potentially unlimited source of ventricular cardiomyocytes (VCMs), but hESC-VCMs are developmentally immature. Previous attempts to profile hESC-VCMs primarily relied on transcriptomic approaches, but the global proteome has not been examined. Furthermore, most hESC-CM studies focus on pathways important for cardiac differentiation, rather than regulatory mechanisms for CM maturation. We hypothesized that gene products and pathways crucial for maturation can be identified by comparing the proteomes of hESCs, hESC-derived VCMs, human fetal and human adult ventricular and atrial CMs. Methods and Results - Using two-dimensional-differential-in-gel electrophoresis, 121 differentially expressed (>1.5-fold; P<0.05) proteins were detected. The data set implicated a role of the peroxisome proliferator-activated receptor signaling in cardiac maturation. Consistently, WY-14643, a peroxisome proliferator-activated receptor agonist, increased fatty oxidative enzyme level, hyperpolarized mitochondrial membrane potential and induced a more organized morphology. Along this line, treatment with the thyroid hormone triiodothyronine increased the dynamic tension developed in engineered human ventricular cardiac microtissue by 3-fold, signifying their maturation. Conclusions - We conclude that the peroxisome proliferator-activated receptor and thyroid hormone pathways modulate the metabolism and maturation of hESC-VCMs and their engineered tissue constructs. These results may lead to mechanism-based methods for deriving mature chamber-specific CMs.
KW - PGC1alpha protein
KW - PPARalpha
KW - embryonic stem cells
KW - metabolism
KW - proteomics
KW - thyroid-stimulating hormone
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U2 - 10.1161/CIRCGENETICS.114.000918
DO - 10.1161/CIRCGENETICS.114.000918
M3 - Article
C2 - 25759434
AN - SCOPUS:84936948039
SN - 1942-325X
VL - 8
SP - 427
EP - 436
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 3
ER -