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ToxSci Advance Access originally published online on December 15, 2005
Toxicological Sciences 2006 90(1):149-158; doi:10.1093/toxsci/kfj078
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Embryonic Stem Cells in Predictive Cardiotoxicity: Laser Capture Microscopy Enables Assay Development

Khuram W. Chaudhary*,1, Nestor X. Barrezueta{dagger}, Mary B. Bauchmann{dagger}, Anthony J. Milici{dagger}, Gretchen Beckius{dagger}, Donald B. Stedman{dagger}, John E. Hambor{dagger}, William L. Blake{dagger}, John D. McNeish{dagger}, Anthony Bahinski* and Gabriela Gebrin Cezar{dagger},2,3

* Pfizer Global Research and Development, Chesterfield, Missouri 63017; and {dagger} Pfizer Global Research and Development, Groton, Connecticut 06340

Received September 17, 2005; accepted November 23, 2005

Embryonic stem (ES) cells offer unprecedented opportunities for in vitro drug discovery and safety assessment of compounds. Cardiomyocytes derived from ES cells enable development of predictive cardiotoxicity models to increase the safety of novel drugs. Heterogeneity of differentiated ES cells limits the development of reliable in vitro models for compound screening. We report an innovative and robust approach to isolate ES-derived cardiomyocytes using laser microdissection and pressure catapulting (LMPC). LMPC cells were readily applied onto 96-well format in vitro pharmacology assays. The expression of developmental and functional cardiac markers, Nkx 2.5, MLC2V, GATA-4, Connexin 43, Connexin 45, Serca-2a, cardiac alpha actin, and phospholamban, among others, was confirmed in LMPC ES-derived cardiomyocytes. Functional assays exhibited cardiac-like response to increased extracellular calcium (5.4 mM extracellular Ca2+) and L-type calcium channel antagonist (1 µM nifedipine). In conclusion, laser microdissection and pressure catapulting is a robust technology to isolate homogeneous ES-derived cell types from heterogeneous populations applicable to assay development.

Key Words: embryonic stem cells; cardiomyocytes; cardiotoxicity; laser microdissection and pressure catapulting.


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