A new technique for increasing the survival rates of human embryonic stem cells promises to revolutionize their use in drug discovery and therapy.
Human embryonic stem cells often die during the process of isolation using enzymatic disaggregation or low-density plating, which limits their usefulness in drug discovery and basic research. Similarly, the low rate of attachment of implanted cells hinders cell therapy.
Now, researchers from the Universities of Dundee, Glasgow and Heriot-Watt University, Edinburgh, have produced a high-content assay for human embryonic stem cell survival and used this to screen a range of libraries of 'lead-like' small molecules and known bioactives.
In their paper published in the ChemBio Knowledge Environment of the Biochemical Journal, Paul Andrew and colleagues describe how they managed to find some compounds, protein kinases, which worked by targeting the ROCK2/PRK2 kinases. They also found that pinacidil, a K+-ATP channel opener, often used for preconditioning in organ transplantation, has hES cell pro-survival effects through a mechanism unrelated to its effects on ion channel pharmacology; again this compound inhibits ROCK2/PRK2 kinases in vitro.
The researchers say that their lead molecule is effective in promoting survival in three different hES cell lines and that their findings emphasize the critical importance of the ROCK2/PRK2 signalling pathway in human embryonic cell survival.
Bart Vanhaesebroeck, Deputy Chair for the BJ ChemBio Knowledge Environment, said: "These findings bring us one step closer to realizing the immense potential of human stem cells for therapeutic benefit."
- Paul Andrews, Melissa Becroft, Anders Aspegren, Jane Gilmour, Martyn James, Scott McRae, Robert Kime, Robert Allcock, Achamma Abraham, Zhong Jiang, Raimund Strehl, Joanne Mountford, Graeme Milligan, Miles Houslay, David Adams, Julie Frearson. High content screening of feeder-free human embryonic stem cells to identify pro-survival small molecules. Biochemical Journal, 2010; DOI: 10.1042/BJ20101022
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