Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells
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Published version
Author(s)
Type
Journal Article
Abstract
Decreased left ventricle (LV) function caused by genetic mutations or injury often leads to debilitating and fatal cardiovascular disease. LV cardiomyocytes are, therefore, a potentially valuable therapeutical target. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are neither homogeneous nor functionally mature, which reduces their utility. Here, we exploit cardiac development knowledge to instruct differentiation of hPSCs specifically toward LV cardiomyocytes. Correct mesoderm patterning and retinoic acid pathway blocking are essential to generate near-homogenous LV-specific hPSC-CMs (hPSC-LV-CMs). These cells transit via first heart field progenitors and display typical ventricular action potentials. Importantly, hPSC-LV-CMs exhibit increased metabolism, reduced proliferation, and improved cytoarchitecture and functional maturity compared with age-matched cardiomyocytes generated using the standard WNT-ON/WNT-OFF protocol. Similarly, engineered heart tissues made from hPSC-LV-CMs are better organized, produce higher force, and beat more slowly but can be paced to physiological levels. Together, we show that functionally matured hPSC-LV-CMs can be obtained rapidly without exposure to current maturation regimes.
Date Issued
2023-04-24
Date Acceptance
2023-03-25
Citation
Cell Reports: Methods, 2023, 3 (4)
ISSN
2667-2375
Publisher
Elsevier
Journal / Book Title
Cell Reports: Methods
Volume
3
Issue
4
Copyright Statement
Crown Copyright © 2023
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
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Subjects
ATRIAL
Biochemical Research Methods
Biochemistry & Molecular Biology
CARDIAC MYOCYTES
Cell Biology
CYTOARCHITECTURE
DIFFERENTIATION
GENE-EXPRESSION
HEART
Life Sciences & Biomedicine
MATURATION
MUSCLE
PLATFORM
PROTEIN
Science & Technology
Publication Status
Published
Article Number
ARTN 100456
Date Publish Online
2023-04-24