title: Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.
abstract: Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Foreman
authors.forename: Judith
authors.initials: J
authors.lastname: Staerk
authors.forename: Michael
authors.initials: M
authors.lastname: Garcia
authors.forename: Divya
authors.initials: D
authors.lastname: Mathur
authors.forename: Styliani
authors.initials: S
authors.lastname: Markoulaki
authors.forename: Jacob
authors.initials: J
authors.lastname: Hanna
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Charette
authors.forename: Laure C
authors.initials: LC
authors.lastname: Bouchez
authors.forename: Michael
authors.initials: M
authors.lastname: Bollong
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.forename: Achim
authors.initials: A
authors.lastname: Brinker
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002454:Cell Differentiation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics; D007211:Indoles / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D018398:Homeodomain Proteins; D007211:Indoles; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D054852:Small Molecule Libraries; C119620:kenpaullone; D008156:Luciferases