Presenting Author: Evan F. Cromwell
Co-Authors: Oksana Sirenko, Pierre Turpin, Jayne Hesley, H. Roger Tang
Molecular Devices, Sunnyvale, CA
The biopharma industry is continuing to adapt more cell-based assays for primary and secondary screening because of higher biological relevance and increased value of information. As part of this evolution, there is a desire to move from immortalized, stable cell lines to primary cells and stem cells. Stem cells offer the advantages of providing better clinical relevance of information compared to cell lines, being available in larger quantities, and having higher assay reproducibility than primary cells. Accordingly, there is a great interest in automated stem cell assays to use as screening tools in early drug development, and to evaluate potential toxic effects of new compounds. We have developed high content imaging methods based upon automated image acquisition and multiplexed analysis to perform assays on three types of stem cells: hematopoietic, neuronal, and induced pluripotent stem cell (iPS) derived cardiomyocytes. Various image processing modules including neurite outgrowth and cell scoring provide multiple parameters to allow efficient characterization of cell phenotypes. Tools for cluster and principal component analysis provide additional insights into assay results. Further studies have been done with cardiomyocytes using automated electrophysiology systems. These methods in combination with optimized cell culture protocols will allow efficient screening and validation of drug candidates in three key areas of drug development: neurogenesis, hematopoiesis, or cardioprotection. We show use of these methods for evaluation of proliferation and differentiation of neuronal progenitors and demonstrate the effects of positive and negative factors on development and survival of neurons. Furthermore, we validated a homogeneous protocol for determination of the effects of anti-cancer compounds on hematopoiesis by simultaneous monitoring the expression of lineage specific (erythroid and myeloid), stem cell, and toxicity markers. Finally, we have developed methods for monitoring differentiation of iPS cells into cardiomyocytes, and validated the use of stem cell derived cardiomyocytes for cardioprotection and cardiotoxicity screening.
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