Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 50, Issue 2, Pages 367-375Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2010.10.029
Keywords
Embryonic stem cells; Cardiomyocytes; Human; Protein kinases; Hypertrophy
Categories
Funding
- BHF
- Wellcome Trust
- Hungarian Scientific Research Fund (OTKA) [F67919, MB08A 81237]
- National Development Agency [TAMOP 4.2.2-08/1/KMR-2008-0004]
- NC3Rs
- Rosetrees Trust
- Geron Corporation (Menlo Park, CA, USA)
- BBSRC [BB/D011027/1] Funding Source: UKRI
- MRC [G0901467] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D011027/1] Funding Source: researchfish
- British Heart Foundation [RG/08/007/25296] Funding Source: researchfish
- Medical Research Council [G0901467] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0600373/1, G1000035/1] Funding Source: researchfish
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Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are being developed for tissue repair and as a model system for cardiac physiology and pathophysiology. However, the signaling requirements of their growth have not yet been fully characterized. We showed that hESC-CM retain their capacity for increase in size in long-term culture. Exposing hESC-CM to hypertrophic stimuli such as equiaxial cyclic stretch, angiotensin II, and phenylephrine (PE) increased cell size and volume, percentage of hESC-CM with organized sarcomeres, levels of ANF, and cytoskeletal assembly. PE effects on cell size were separable from those on cell cycle. Changes in cell size by PE were completely inhibited by p38-MAPK, calcineurin/FKBP, and mTOR blockers. p38-MAPK and calcineurin were also implicated in basal cell growth. Inhibitors of ERK, JNK, and CaMK II partially reduced PE effects; PKG or GSK3 beta inhibitors had no effect. The role of p38-MAPK was confirmed by an additional pharmacological inhibitor and adenoviral infection of hESC-CM with a dominant-inhibitory form of p38-MAPK. Infection of hESC-CM with constitutively active upstream MAP2K3b resulted in an increased cell size, sarcomere and cytoskeletal assembly, elongation of the cells, and induction of ANF mRNA levels. siRNA knockdown of p38-MAPK inhibited PE-induced effects on cell size. These results reveal an important role for active protein kinase signaling in hESC-CM growth and hypertrophy, with potential implications for hESC-CM as a novel in vitro test system. This article is part of a special issue entitled, Cardiovascular Stem Cells Revisited. (C) 2010 Elsevier Ltd. All rights reserved.
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