Stem cells display a fundamentally different mechanism of proliferation control when compared to somatic cells. Uncovering these mechanisms would maximize the impact in drug discovery with a higher translational applicability. The unbiased approach used in phenotype-based drug discovery (PDD) programs can offer a unique opportunity to identify such novel biological phenomenon. Here, we describe an integrated phenotypic screening approach, employing a combination of in vitro and in vivo PDD models to identify a small molecule increasing stem cell proliferation. We demonstrate that a combination of both in vitro and in vivo screening models improves hit identification and reproducibility of effects across various PDD models. Using cell viability and colony size phenotype measurement we characterize the structure activity relationship of the lead molecule, and identify that the small molecule inhibits phosphorylation of ERK2 and promotes stem cell proliferation. This study demonstrates a PDD approach that employs combinatorial models to identify compounds promoting stem cell proliferation.
Journal Article Reduced β2-microglobulin mRNA levels in transgenic mice expressing a designed hammerhead ribozyme Get access Sten Larsson, Sten Larsson Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Graham Hotchkiss, Graham Hotchkiss Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Andäng, Michael Andäng Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Tommy Nyholm, Tommy Nyholm Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar José Inzunza, José Inzunza Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Irma Jansson, Irma Jansson Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Lars Ährlund-Richter Lars Ährlund-Richter * Unit for Molecular Genetics, Center for Biotechnology, Karolinska InstituteNovum, 141 57 Huddinge, Sweden * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 22, Issue 12, 25 June 1994, Pages 2242–2248, https://doi.org/10.1093/nar/22.12.2242 Published: 25 June 1994 Article history Received: 08 April 1994 Revision received: 25 May 1994 Accepted: 25 May 1994 Published: 25 June 1994
