| Title: |
Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells |
| Authors: |
Dark, N; Cosson, M-V; Tsansizi, LI; Owen, TJ; Ferraro, E; Francis, AJ; Tsai, S; Bouissou, C; Weston, A; Collinson, L; Abi-Gerges, N; Miller, PE; MacLeod, KT; Ehler, E; Mitter, R; Harding, SE; Smith, JC; Bernardo, AS |
| Publisher Information: |
Elsevier |
| Publication Year: |
2023 |
| Collection: |
Imperial College London: Spiral |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Cell Reports: Methods; http://hdl.handle.net/10044/1/107369 |
| DOI: |
10.1016/j.crmeth.2023.100456 |
| Availability: |
http://hdl.handle.net/10044/1/107369; https://doi.org/10.1016/j.crmeth.2023.100456 |
| Rights: |
Crown Copyright © 2023 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.36EFD109 |
| Database: |
BASE |