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NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells

Directed cardiomyogenesis from human induced pluripotent stem cells (hiPSCs) has been greatly improved in the last decade but directed differentiation to pacemaking cardiomyocytes (CMs) remains incompletely understood. In this study, we demonstrated that inhibition of NODAL signaling by a specific N...

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Autores principales: Yechikov, Sergey, Kao, Hillary K.J., Chang, Che-Wei, Pretto, Dalyir, Zhang, Xiao-Dong, Sun, Yao-Hui, Smithers, Regan, Sirish, Padmini, Nolta, Jan A., Chan, James W., Chiamvimonvat, Nipavan, Lieu, Deborah K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814970/
https://www.ncbi.nlm.nih.gov/pubmed/33128951
http://dx.doi.org/10.1016/j.scr.2020.102043
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author Yechikov, Sergey
Kao, Hillary K.J.
Chang, Che-Wei
Pretto, Dalyir
Zhang, Xiao-Dong
Sun, Yao-Hui
Smithers, Regan
Sirish, Padmini
Nolta, Jan A.
Chan, James W.
Chiamvimonvat, Nipavan
Lieu, Deborah K.
author_facet Yechikov, Sergey
Kao, Hillary K.J.
Chang, Che-Wei
Pretto, Dalyir
Zhang, Xiao-Dong
Sun, Yao-Hui
Smithers, Regan
Sirish, Padmini
Nolta, Jan A.
Chan, James W.
Chiamvimonvat, Nipavan
Lieu, Deborah K.
author_sort Yechikov, Sergey
collection PubMed
description Directed cardiomyogenesis from human induced pluripotent stem cells (hiPSCs) has been greatly improved in the last decade but directed differentiation to pacemaking cardiomyocytes (CMs) remains incompletely understood. In this study, we demonstrated that inhibition of NODAL signaling by a specific NODAL inhibitor (SB431542) in the cardiac mesoderm differentiation stage downregulated PITX2c, a transcription factor that is known to inhibit the formation of the sinoatrial node in the left atrium during cardiac development. The resulting hiPSC-CMs were smaller in cell size, expressed higher pro-pacemaking transcription factors, TBX3 and TBX18, and exhibited pacemaking-like electrophysiological characteristics compared to control hiPSC-CMs differentiated from established Wnt-based protocol. The pacemaker-like subtype increased up to 2.4-fold in hiPSC-CMs differentiated with the addition of SB431542 relative to the control. Hence, Nodal inhibition in the cardiac mesoderm stage promoted pacemaker-like CM differentiation from hiPSCs. Improving the yield of human pacemaker-like CMs is a critical first step in the development of functional human cell-based biopacemakers.
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spelling pubmed-78149702021-01-19 NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells Yechikov, Sergey Kao, Hillary K.J. Chang, Che-Wei Pretto, Dalyir Zhang, Xiao-Dong Sun, Yao-Hui Smithers, Regan Sirish, Padmini Nolta, Jan A. Chan, James W. Chiamvimonvat, Nipavan Lieu, Deborah K. Stem Cell Res Article Directed cardiomyogenesis from human induced pluripotent stem cells (hiPSCs) has been greatly improved in the last decade but directed differentiation to pacemaking cardiomyocytes (CMs) remains incompletely understood. In this study, we demonstrated that inhibition of NODAL signaling by a specific NODAL inhibitor (SB431542) in the cardiac mesoderm differentiation stage downregulated PITX2c, a transcription factor that is known to inhibit the formation of the sinoatrial node in the left atrium during cardiac development. The resulting hiPSC-CMs were smaller in cell size, expressed higher pro-pacemaking transcription factors, TBX3 and TBX18, and exhibited pacemaking-like electrophysiological characteristics compared to control hiPSC-CMs differentiated from established Wnt-based protocol. The pacemaker-like subtype increased up to 2.4-fold in hiPSC-CMs differentiated with the addition of SB431542 relative to the control. Hence, Nodal inhibition in the cardiac mesoderm stage promoted pacemaker-like CM differentiation from hiPSCs. Improving the yield of human pacemaker-like CMs is a critical first step in the development of functional human cell-based biopacemakers. 2020-10-12 2020-12 /pmc/articles/PMC7814970/ /pubmed/33128951 http://dx.doi.org/10.1016/j.scr.2020.102043 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Yechikov, Sergey
Kao, Hillary K.J.
Chang, Che-Wei
Pretto, Dalyir
Zhang, Xiao-Dong
Sun, Yao-Hui
Smithers, Regan
Sirish, Padmini
Nolta, Jan A.
Chan, James W.
Chiamvimonvat, Nipavan
Lieu, Deborah K.
NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title_full NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title_fullStr NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title_full_unstemmed NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title_short NODAL inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
title_sort nodal inhibition promotes differentiation of pacemaker-like cardiomyocytes from human induced pluripotent stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814970/
https://www.ncbi.nlm.nih.gov/pubmed/33128951
http://dx.doi.org/10.1016/j.scr.2020.102043
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