Martewicz, S;
Serena, E;
Zatti, S;
Keller, G;
Elvassore, N;
(2017)
Substrate and mechanotransduction influence SERCA2a localization in human pluripotent stem cell-derived cardiomyocytes affecting functional performance.
Stem Cell Research
, 25
pp. 107-114.
10.1016/j.scr.2017.10.011.
Preview |
Text
1-s2.0-S1873506117302143-main.pdf - Published Version Download (1MB) | Preview |
Abstract
Physical cues are major determinants of cellular phenotype and evoke physiological and pathological responses on cell structure and function. Cellular models aim to recapitulate basic functional features of their in vivo counterparts or tissues in order to be of use in in vitro disease modeling or drug screening and testing. Understanding how culture systems affect in vitro development of human pluripotent stem cell (hPSC)-derivatives allows optimization of cellular human models and gives insight in the processes involved in their structural organization and function. In this work, we show involvement of the mechanotransduction pathway RhoA/ROCK in the structural reorganization of hPSC-derived cardiomyocytes after adhesion plating. These structural changes have a major impact on the intracellular localization of SERCA2 pumps and concurrent improvement in calcium cycling. The process is triggered by cell interaction with the culture substrate, which mechanical cues drive sarcomeric alignment and SERCA2a spreading and relocalization from a perinuclear to a whole-cell distribution. This structural reorganization is mediated by the mechanical properties of the substrate, as shown by the process failure in hPSC-CMs cultured on soft 4 kPa hydrogels as opposed to physiologically stiff 16 kPa hydrogels and glass. Finally, pharmacological inhibition of Rho-associated protein kinase (ROCK) by different compounds identifies this specific signaling pathway as a major player in SERCA2 localization and the associated improvement in hPSC-CMs calcium handling ability in vitro.
| Type: | Article |
|---|---|
| Title: | Substrate and mechanotransduction influence SERCA2a localization in human pluripotent stem cell-derived cardiomyocytes affecting functional performance |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.scr.2017.10.011 |
| Publisher version: | http://dx.doi.org/10.1016/j.scr.2017.10.011 |
| Language: | English |
| Additional information: | © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Biotechnology & Applied Microbiology, Cell Biology, Human cardiomyocytes, Hydrogel, Mechanotransduction, Rock, SERCA2, Structural organization, ATOMIC-FORCE MICROSCOPY, RHO-KINASE INHIBITORS, CONTRACTION FORCE, MYOCYTE SHAPE, IN-VITRO, MATURATION, HEART, DIFFERENTIATION, ELASTICITY, MATRIX |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10051071 |
Archive Staff Only
 |
View Item |
