caa a22 4500 606177590 CHVBK 20210128100752.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s00018-015-1877-3 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1877-3 Senescence of human skin-derived precursors regulated by Akt-FOXO3-p27KIP1/p15INK4b signaling [Elektronische Daten] [Shuang Liu, Xinyue Wang, Qian Zhao, Shu Liu, Huishan Zhang, Junchao Shi, Na Li, Xiaohua Lei, Huashan Zhao, Zhili Deng, Yujing Cao, Lina Ning, Guoliang Xia, Enkui Duan] 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 p16INK4a signaling in hSKP senescence. Examination of cyclin-dependent kinase inhibitors revealed the involvement of p15INK4b and p27KIP1. 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, p15INK4b and p27KIP1 effectively inhibited hSKP senescence and promoted hSKP proliferation. The unique senescent phenotype of human dermal stem cells and the role of Akt-FOXO3-p27KIP1/p15INK4b 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. Springer Basel, 2015 Cellular senescence nationallicence Skin-derived precursors nationallicence Akt nationallicence p15INK4b nationallicence p27KIP1 nationallicence Adult stem cells nationallicence CDKI : Cyclin-dependent kinase inhibitor nationallicence DDR : DNA damage response nationallicence DSB : Double strand break nationallicence MAPK : Mitogen-activated protein kinase nationallicence NF-κB : Nuclear factor kappa-light-chain-enhancer of activated B cells nationallicence PCNA : Proliferating cell nuclear antigen nationallicence PI3K : Phosphatidylinositol-4,5-bisphosphate 3-kinase nationallicence RB : Retinoblastoma protein nationallicence SASP : The senescence-associated secretory phenotype nationallicence SIPS : Stress-induced premature senescence nationallicence SKPs : Skin-derived precursors nationallicence Liu Shuang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Wang Xinyue State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Zhao Qian State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan Xilu, Haidian District, 100193, Beijing, China aut Liu Shu State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Zhang Huishan State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Shi Junchao State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Li Na State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Lei Xiaohua State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Zhao Huashan State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Deng Zhili State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Cao Yujing State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Ning Lina State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Xia Guoliang State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan Xilu, Haidian District, 100193, Beijing, China aut Duan Enkui State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut Cellular and Molecular Life Sciences Springer Basel 72/15(2015-08-01), 2949-2960 1420-682X 72:15<2949 2015 72 18 https://doi.org/10.1007/s00018-015-1877-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1877-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Liu Shuang State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Wang Xinyue State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Zhao Qian State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan Xilu, Haidian District, 100193, Beijing, China aut NATIONALLICENCE 700 1- Liu Shu State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Zhang Huishan State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Shi Junchao State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Li Na State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Lei Xiaohua State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Zhao Huashan State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Deng Zhili State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Cao Yujing State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Ning Lina State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 700 1- Xia Guoliang State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan Xilu, Haidian District, 100193, Beijing, China aut NATIONALLICENCE 700 1- Duan Enkui State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101, Beijing, China aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/15(2015-08-01), 2949-2960 1420-682X 72:15<2949 2015 72 18