Identification of drugs that enhance skin repair using dermal stem cell-based screens [Mouse]

Here, we asked whether we could identify pharmacological agents that enhance endogenous stem cell function to promote skin repair, focusing on SKPs (skin-derived precursors) 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 5 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 SKPs 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. We obtained three independent isolates of SKPs from 9 month old CD57/Bl6 mice which were either uninjured and treated with vehicle, injured and treated with vehicle, trimebutine maleate, or alprostadil. RNA samples deriving from these cells were analyzed on the Affymetrix GeneChip Mouse Gene 2.0 ST Array.

本研究旨在探究能否筛选出可增强内源性干细胞功能以促进皮肤修复的药理学制剂，研究重点聚焦于皮肤源性前体细胞（skin-derived precursors，SKPs）——一类真皮前体细胞群。我们针对已获批用于人体的化合物库，筛选其增强人类及啮齿类动物SKPs自我更新能力的活性。本研究筛选并验证了5种符合要求的化合物，其中两种——前列地尔（alprostadil）与马来酸曲美布汀（trimebutine maleate）——可促进中年小鼠全层皮肤伤口的修复。此外，从给药处理皮肤中分离得到的SKPs，即便在不含药物的基础生长培养基中培养，其自我更新能力也能长期维持提升状态。前列地尔与马来酸曲美布汀均可能通过适度过度激活MEK-ERK通路，介导SKPs自我更新能力的提升。本研究结果不仅筛选出可潜在用于人类皮肤修复的临床候选制剂，同时也支持了“通过药理学手段激活内源性组织前体细胞是一种可行的治疗策略”这一观点。我们从9月龄CD57/Bl6小鼠中分离得到3组独立的SKPs样本，这些小鼠分别接受以下处理：未受伤且给予赋形剂、受伤且给予赋形剂、受伤且给予马来酸曲美布汀、受伤且给予前列地尔。我们通过Affymetrix GeneChip Mouse Gene 2.0 ST芯片对这些细胞的RNA样本进行了基因表达谱分析。