@article{6d0e1d1cd7724403ace69c16a86cac70,
title = "Stage-specific Effects of Bioactive Lipids on Human iPSC Cardiac Differentiation and Cardiomyocyte Proliferation",
abstract = "Bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) regulate diverse processes including cell proliferation, differentiation, and migration. However, their roles in cardiac differentiation and cardiomyocyte proliferation have not been explored. Using a 96-well differentiation platform for generating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) we found that S1P and LPA can independently enhance cardiomyocyte generation when administered at an early stage of differentiation. We showed that the combined S1P and LPA treatment of undifferentiated hiPSCs resulted in increased nuclear accumulation of β-catenin, the canonical Wnt signaling pathway mediator, and synergized with CHIR99021, a glycogen synthase kinase 3 beta inhibitor, to enhance mesodermal induction and subsequent cardiac differentiation. At later stages of cardiac differentiation, the addition of S1P and LPA resulted in cell cycle initiation in hiPSC-CMs, an effect mediated through increased ERK signaling. Although the addition of S1P and LPA alone was insufficient to induce cell division, it was able to enhance β-catenin-mediated hiPSC-CM proliferation. In summary, we demonstrated a developmental stage-specific effect of bioactive lipids to enhance hiPSC-CM differentiation and proliferation via modulating the effect of canonical Wnt/β-catenin and ERK signaling. These findings may improve hiPSC-CM generation for cardiac disease modeling, precision medicine, and regenerative therapies.",
author = "Arun Sharma and Yuan Zhang and Buikema, {Jan W.} and Vahid Serpooshan and Orlando Chirikian and Nina Kosaric and Churko, {Jared M.} and Elda Dzilic and Alice Shieh and Burridge, {Paul W.} and Wu, {Joseph C.} and Wu, {Sean M.}",
note = "Funding Information: We gratefully acknowledge support from the American Heart Association (AHA) Predoctoral Fellowship 13PRE15770000, National Science Foundation Graduate Research Fellowship Program DGE-114747 (AS). University Medical Center Utrecht Clinician Research Fellowship (JWB). NIH K99/R00 HL121177 and AHA Beginning Grant-in-Aid 14BGIA20480329 (PWB). NIH Director{\textquoteright}s Pioneer Award (DP1 LM012179-02), the NHLBI Progenitor Cell Biology Consortium (U01 HL099776-7), AHA Grant-in-Aid (14GRNT18630016), and the Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford (SMW). Burroughs Wellcome Foundation Innovation in Regulatory Science, AHA Established Investigator Award, NIH R01 HL113006, and NIH U01 HL099776 (JCW). We thank Francisco Galdos for his assistance with qPCR assays. Funding Information: We gratefully acknowledge support from the American Heart Association (AHA) Predoctoral Fellowship 13PRE15770000, National Science Foundation Graduate Research Fellowship Program DGE-114747 (AS). University Medical Center Utrecht Clinician Research Fellowship (JWB). NIH K99/R00 HL121177 and AHA Beginning Grant-in-Aid 14BGIA20480329 (PWB). NIH Director's Pioneer Award (DP1 LM012179-02), the NHLBI Progenitor Cell Biology Consortium (U01 HL099776-7), AHA Grant-in-Aid (14GRNT18630016), and the Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford (SMW). Burroughs Wellcome Foundation Innovation in Regulatory Science, AHA Established Investigator Award, NIH R01 HL113006, and NIH U01 HL099776 (JCW). We thank Francisco Galdos for his assistance with qPCR assays Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-24954-3",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}