title: Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27(KIP¹)/p15(INK⁴b) signaling.
abstract: Multipotent skin-derived precursors (SKPs) are dermal stem cells with the capacity to reconstitute the dermis and other tissues, such as muscles and the nervous system. Thus, the easily available human SKPs (hSKPs) hold great promises in regenerative medicine. However, long-term expansion is difficult for hSKPs in vitro. We previously demonstrated that hSKPs senesced quickly under routine culture conditions. To identify the underlying mechanisms so as to find an effective way to expand hSKPs, time-dependent microarray analysis of gene expression in hSKPs during in vitro culture was performed. We found that the senescence of hSKPs had a unique gene expression pattern that differs from reported typical senescence. Subsequent investigation ruled out the role of DNA damage and classical p53 and p16(INK4a) signaling in hSKP senescence. Examination of cyclin-dependent kinase inhibitors revealed the involvement of p15(INK4b) and p27(KIP1). Further exploration about upstream signals indicated the contribution of Akt hypo-activity and FOXO3 to hSKP senescence. Forced activation of Akt and knockdown of FOXO3, p15(INK4b) and p27(KIP1) effectively inhibited hSKP senescence and promoted hSKP proliferation. The unique senescent phenotype of human dermal stem cells and the role of Akt-FOXO3-p27(KIP1)/p15(INK4b) signaling in regulating hSKP senescence provide novel insights into the senescence and self-renewal regulation of adult stem cells. The present study also points out a way to propagate hSKPs in vitro so as to fulfill their promises in regenerative medicine.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Huishan
authors.initials: H
authors.lastname: Zhang
authors.forename: Junchao
authors.initials: J
authors.lastname: Shi
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lei
authors.forename: Huashan
authors.initials: H
authors.lastname: Zhao
authors.forename: Zhili
authors.initials: Z
authors.lastname: Deng
authors.forename: Yujing
authors.initials: Y
authors.lastname: Cao
authors.forename: Lina
authors.initials: L
authors.lastname: Ning
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xia
authors.forename: Enkui
authors.initials: E
authors.lastname: Duan
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases