Identification of Drugs that Regulate Dermal Stem Cells and Enhance Skin Repair

• Published in: Stem cell reports Vol. 6; no. 1; pp. 74 - 84
• Main Authors: Naska, Sibel, Yuzwa, Scott A., Johnston, Adam P.W., Paul, Smitha, Smith, Kristen M., Paris, Maryline, Sefton, Michael V., Datti, Alessandro, Miller, Freda D., Kaplan, David R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-01-2016; Elsevier
• Subjects: Alprostadil - administration & dosage; Alprostadil - pharmacology; Animals; Animals, Newborn; Blotting, Western; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Self Renewal - drug effects; Cell Self Renewal - genetics; Cells, Cultured; Culture Media - chemistry; Culture Media - pharmacology; Gene Expression Profiling - methods; Gene Ontology; Humans; MAP Kinase Signaling System - drug effects; Mice; NIH 3T3 Cells; Oligonucleotide Array Sequence Analysis; Pharmaceutical Preparations - administration & dosage; Rats; Skin - drug effects; Skin - metabolism; Skin - physiopathology; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - physiology; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - physiology; Trimebutine - administration & dosage; Trimebutine - pharmacology; Wound Healing - drug effects; Wound Healing - genetics
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2015.12.002

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.
[Display omitted]
•Small-molecule screens identify compounds that enhance SKP self-renewal•Alprostadil and trimebutine maleate both increase SKP self-renewal•Both compounds likely act by promoting activation of the MEK-ERK pathway•Both compounds activated dermal precursors in vivo to enhance wound healing
In this article, Kaplan, Miller, and colleagues performed screens to identify drugs already used in humans that enhance proliferation of skin-derived precursor (SKP) cells. They show that two of the compounds they identified, alprostadil and trimebutine maleate, promoted murine skin wound healing, likely by enhancing self-renewal of endogenous dermal precursors via activation of the MEK-ERK signaling pathway.