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

Sergey Yechikov; Hillary K.J. Kao; Che-Wei Chang; Dalyir Pretto; Xiao-Dong Zhang; Yao-Hui Sun; Regan Smithers; Padmini Sirish; Jan A. Nolta; James W. Chan; Nipavan Chiamvimonvat; Deborah K. Lieu

Stem Cell Research (Dec 2020)

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

Sergey Yechikov,
Hillary K.J. Kao,
Che-Wei Chang,
Dalyir Pretto,
Xiao-Dong Zhang,
Yao-Hui Sun,
Regan Smithers,
Padmini Sirish,
Jan A. Nolta,
James W. Chan,
Nipavan Chiamvimonvat,
Deborah K. Lieu

Affiliations

Sergey Yechikov: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA
Hillary K.J. Kao: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA
Che-Wei Chang: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA
Dalyir Pretto: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA
Xiao-Dong Zhang: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA
Yao-Hui Sun: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA
Regan Smithers: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA; Bridges to Stem Cell Research Program, California State University Sacramento, Sacramento, CA 95819, USA
Padmini Sirish: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA
Jan A. Nolta: Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA; Department of Hematology and Oncology, University of California, Davis, Sacramento, CA 95817, USA
James W. Chan: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA
Nipavan Chiamvimonvat: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA
Deborah K. Lieu: Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Regenerative Cures, University of California, Davis, Sacramento, CA 95817, USA; Corresponding author at: University of California, Davis, Department of Internal Medicine, Division of Cardiovascular Medicine, Institute for Regenerative Cures 1616, 2921 Stockton Blvd., Sacramento, CA 95817, USA.

Journal volume & issue: Vol. 49
p. 102043

Abstract

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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.

Published in Stem Cell Research

ISSN: 1873-5061 (Print); 1876-7753 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: https://www.journals.elsevier.com/stem-cell-research

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