Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells.
cardiac progenitors
cardiomyocyte maturation
cardiomyocytes
differentiation
engineered heart tissues
human pluripotent stem cells
left ventricle
mesoderm
retinoic acid
ventricular
Journal
Cell reports methods
ISSN: 2667-2375
Titre abrégé: Cell Rep Methods
Pays: United States
ID NLM: 9918227360606676
Informations de publication
Date de publication:
24 04 2023
24 04 2023
Historique:
received:
25
07
2022
revised:
23
01
2023
accepted:
25
03
2023
medline:
11
5
2023
pubmed:
9
5
2023
entrez:
9
5
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37159667
doi: 10.1016/j.crmeth.2023.100456
pii: S2667-2375(23)00075-9
pmc: PMC10163040
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100456Subventions
Organisme : British Heart Foundation
ID : BHF-FS/12/37/29516
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RM/17/1/33377
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210987/Z/18/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/X50287X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R017050/01
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001157
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
Crown Copyright © 2023.
Déclaration de conflit d'intérêts
N.A.-G. is the vice president of research and development at AnaBios, San Diego. P.E.M. is a founding partner and the chief corporate development officer of AnaBios, San Diego. The Francis Crick Institute has filed a patent application related to this work (WO 2020/245612), and A.S.B. is listed as an inventor. The Francis Crick Institute has granted an exclusive license to Axol Bioscience to commercialize the protocol for the generation and sale of cardiomyocytes for R&D and the provision of contract research services. N.D., C.B., J.C.S., and A.S.B. may benefit from this license.
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