title: Identification of Drugs that Regulate Dermal Stem Cells and Enhance Skin Repair.
abstract: Here, we asked whether we could identify pharmacological agents that enhance endogenous stem cell function to promote skin repair, focusing on skin-derived precursors (SKPs), a dermal precursor cell population. Libraries of compounds already used in humans were screened for their ability to enhance the self-renewal of human and rodent SKPs. We identified and validated five such compounds, and showed that two of them, alprostadil and trimebutine maleate, enhanced the repair of full thickness skin wounds in middle-aged mice. Moreover, SKPs isolated from drug-treated skin displayed long-term increases in self-renewal when cultured in basal growth medium without drugs. Both alprostadil and trimebutine maleate likely mediated increases in SKP self-renewal by moderate hyperactivation of the MEK-ERK pathway. These findings identify candidates for potential clinical use in human skin repair, and provide support for the idea that pharmacological activation of endogenous tissue precursors represents a viable therapeutic strategy.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Sibel
authors.initials: S
authors.lastname: Naska
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Adam P W
authors.initials: AP
authors.lastname: Johnston
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Smitha
authors.initials: S
authors.lastname: Paul
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Smith
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Maryline
authors.initials: M
authors.lastname: Paris
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sefton
authors.affiliation: S.M.A.R.T. Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Agricultural, Food, and Environmental Sciences, University of Perugia, 06121 Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address: dkaplan@sickkids.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000527:Alprostadil / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D000066673:Cell Self Renewal / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D063990:Gene Ontology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D051381:Rats; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014287:Trimebutine / Q000008:administration & dosage / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects* / Q000235:genetics
chemical_list: D003470:Culture Media; D004364:Pharmaceutical Preparations; D000527:Alprostadil; D014287:Trimebutine