Nanog down-regulates the Wnt signaling pathway via β-catenin phosphorylation during epidermal stem cell proliferation and differentiation

Cell & Bioscience

Hui Huang³  Weikai Zhang³  Anmin Chen³  Fengjing Guo³  Yonghui Dong³  Liang Qin³  Kaixiang Yang³  Fei Xu³  Delong Yin²  Xuying Sun¹  Peng Cheng³ 

[1] Biological engineering and regenerative medicine center,Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China;Department of Orthopedics, The Third Hospital Affiliated to Guangzhou Medical University, Guangzhou 510150, P.R. China;Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China

关键词: Differentiation;    Proliferation;    Epidermal stem cells;    Wnt/β-catenin;    Nanog;   

Others  :  1135250
DOI  :  10.1186/2045-3701-5-5

 received in 2014-07-15, accepted in 2015-01-16,  发布年份 2015

【 摘 要 】

Background

Skin tissue homeostasis is maintained by a balance between the proliferation and differentiation of epidermal stem cells (EpSCs). EpSC proliferation and differentiation are complex processes regulated by many factors and signaling pathways. This study aimed to explore the connection between the Nanog and the Wnt/β-catenin pathway in the proliferation and differentiation of EpSCs.

Results

Our results demonstrated that during the study period, EpSC underwent differentiation when incubated in the presence neuropeptide substance P (SP), there was an opposing expression trend of Nanog and β-catenin after SP treatment, which could be antagonized by the Wnt antagonist, Dkk-1. The transduced EpSCs had a greater proliferative ability than the SP treatment group and they did not undergo differentiation upon SP treatment. More important, β-catenin expression was down-regulated but phosphorylated β-catenin expression and phosphorylated GSK-3β expression was up-regulated upon Nanog overexpression.

Conclusions

These results strongly suggest that Nanog plays an important role in maintaining the proliferation and differentiation homeostasis of EpSCs by promoting β-catenin phosphorylation via GSK-3β to inhibit the activity of the Wnt/β-catenin signaling pathway. This is important for precise regulation of proliferation and differentiation of EpSC in the application of tissue engineering.

【 授权许可】

   
2015 Cheng et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Fordham RP, Jensen KB: Reporting live from the epidermal stem cell compartment! Cell Stem Cell 2012, 11(2):141-2.
• [2]Watt FM, Jensen KB: Epidermal stem cell diversity and quiescence. EMBO Molecular Medicine 2009, 1(5):260-7.
• [3]Chai L, Cao C, Bi S, Dai X, Gan L, Guo R, et al.: Small Rho GTPase Rac1 determines human epidermal stem cell fate in vitro. Int J Mol Med 2010, 25(5):723-7.
• [4]Luo Y, Lim CL, Nichols J, Martinez-Arias A, Wernisch L: Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations. J R Soc Interface 2013, 10(78):20120525.
• [5]MacArthur BD, Sevilla A, Lenz M, Müller F, Schuldt BM, Schuppert AA, et al.: Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. Nat Cell Biol 2012, 14(11):1139-47.
• [6]Han J, Mistriotis P, Lei P, Wang D, Liu S, Andreadis ST: Nanog reverses the effects of organismal aging on mesenchymal stem cell proliferation and myogenic differentiation potential. Stem Cells 2012, 30(12):2746-59.
• [7]Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, et al.: Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003, 113(5):643-55.
• [8]Davidson KC, Adams AM, Goodson JM, McDonald CE, Potter JC, Berndt JD, et al.: Wnt/ β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proc Natl Acad Sci 2012, 109(12):4485-90.
• [9]Sokol SY: Maintaining embryonic stem cell pluripotency with Wnt signaling. Development 2011, 138(20):4341-50.
• [10]Watt FM, Collins CA: Role of beta-catenin in epidermal stem cell expansion, lineage selection, and cancer. Cold Spring Harb Symp Quant Biol 2008, 73:503-12.
• [11]Gannon HS, Donehower LA, Lyle S, Jones SN: Mdm2–p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin. Dev Biol 2011, 353(1):1-9.
• [12]Luis NM, Morey L, Mejetta S, Pascual G, Janich P, Kuebler B, et al.: Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell Stem Cell 2011, 9(3):233-46.
• [13]Berta MA, Baker CM, Cottle DL, Watt FM: Dose and context dependent effects of Myc on epidermal stem cell proliferation and differentiation. EMBO Molecular Medicine 2010, 2(1):16-25.
• [14]Flores I, Blasco MA: A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS One 2009, 4(3):e4934.
• [15]Mei G, Xia L, Zhou J, Zhang Y, Tuo Y, Fu S, et al.: Neuropeptide SP activates the WNT signal transduction pathway and enhances the proliferation of bone marrow stromal stem cells. Cell Biol Int 2013, 37(11):1225-32.
• [16]Liu Y, Zhou H, Gao F: Isolation and identification of stem cells from adult cashmere goat skin. Int J Dermatol 2008, 47(6):551-6.
• [17]Li A, Simmons PJ, Kaur P: Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A 1998, 95(7):3902-7.
• [18]Baer PC, Brzoska M, Geiger H: Epithelial differentiation of human adipose-derived stem cells. Methods Mol Biol 2011, 702:289-98.
• [19]Ruetze M, Dunckelmann K, Schade A, Reuschlein K, Mielke H, Weise JM, et al.: Damage at the root of cell renewal-UV sensitivity of human epidermal stem cells. J Dermatol Sci 2011, 64(1):16-22.
• [20]Aberdam D: Epidermal stem cell fate: what can we learn from embryonic stem cells? Cell Tissue Res 2008, 331(1):103-7.
• [21]Bourguignon LYW, Wong G, Earle C, Chen L: Hyaluronan-CD44v3 interaction with Oct4-Sox2-nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem 2012, 287(39):32800-24.
• [22]Sieber-Blum M: Epidermal stem cell dynamics. Stem cell research & therapy 2011, 2(3):29. BioMed Central Full Text
• [23]Anton R, Kestler HA, Kühl M: β-Catenin signaling contributes to stemness and regulates early differentiation in murine embryonic stem cells. Febs Lett 2007, 581(27):5247-54.
• [24]Redvers RP, Li A, Kaur P: Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci U S A 2006, 103(35):13168-73.
• [25]Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, et al.: The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003, 113(5):631-42.
• [26]Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I: MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008, 455(7216):1124-8.
• [27]Xu X, Wang HY, Zhang Y, Liu Y, Li YQ, Tao K, et al.: Adipose-derived stem cells cooperate with fractional carbon dioxide laser in antagonizing photoaging: a potential role of Wnt and beta-catenin signaling. Cell Biosci 2014, 4:24. BioMed Central Full Text
• [28]Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS: mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 2009, 5(3):279-89.
• [29]Miki T, Yasuda S, Kahn M: Wnt/β-catenin signaling in embryonic stem cell self-renewal and somatic cell reprogramming. Stem Cell Rev Rep 2011, 7(4):836-46.
• [30]Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH: Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2003, 10(1):55-63.
• [31]Haegele L, Ingold B, Naumann H, Tabatabai G, Ledermann B, Brandner S: Wnt signalling inhibits neural differentiation of embryonic stem cells by controlling bone morphogenetic protein expression. Mol Cell Neurosci 2003, 24(3):696-708.
• [32]Yin D, Tian L, Ye Y, Li K, Wang J, Cheng P, et al.: Nanog and beta-catenin: a new convergence point in EpSC proliferation and differentiation. Int J Mol Med 2012, 29(4):587-92.
• [33]Ghadially R: 25 years of epidermal stem cell research. The Journal of investigative dermatology 2012, 132(3 Pt 2):797.
• [34]Doles J, Storer M, Cozzuto L, Roma G, Keyes WM: Age-associated inflammation inhibits epidermal stem cell function. Gene Dev 2012, 26(19):2144-53.
• [35]Li J, Miao C, Guo W, Jia L, Zhou J, Ma B, et al.: Enrichment of putative human epidermal stem cells based on cell size and collagen type IV adhesiveness. Cell Res 2008, 18(3):360-71.
• [36]Brzoska M, Geiger H, Gauer S, Baer P: Epithelial differentiation of human adipose tissue-derived adult stem cells. Biochem Bioph Res Co 2005, 330(1):142-50.
• [37]Wray J, Hartmann C: WNTing embryonic stem cells. Trends Cell Biol 2012, 22(3):159-68.