研究生: |
翁琬婷 Weng, Wan-Ting. |
---|---|
論文名稱: |
促發炎細胞激素藉由細胞自噬作用調節人類骨髓間質幹細胞之黏附因子表現量 Pro-inflammatory Cytokines Regulate Adhesion Molecules of Human Bone Marrow-derived Mesenchymal Stem Cells via Autophagic Degradation |
指導教授: |
伍焜玉
Wu, Kenneth K. |
口試委員: |
郭呈欽
Kuo, Cheng-Chin 劉俊揚 Liou, Jun-Yang |
學位類別: |
碩士 Master |
系所名稱: |
生命科學暨醫學院 - 生物科技研究所 Biotechnology |
論文出版年: | 2018 |
畢業學年度: | 106 |
語文別: | 中文 |
論文頁數: | 31 |
中文關鍵詞: | 人類骨髓間質幹細胞 、促發炎細胞激素 、細胞間隙黏附因子 、血管細胞黏附因子 、細胞自噬作用 |
外文關鍵詞: | BM-MSCs, pro-inflammatory cytokines, ICAM-1, VCAM-1, autophagy |
相關次數: | 點閱:2 下載:0 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
促發炎細胞激素(Pro-inflammatory cytokines)能夠透過活化細胞自噬作用(autophagy),促使人類骨髓間質幹細胞(human bone marrow-derived mesenchymal stem cells, BM-MSCs)的表面黏附因子(adhesion molecules)、細胞間隙黏附因子(intercellular adhesion molecule-1, ICAM-1)與血管細胞黏附因子(vascular cell adhesion molecule-1, VCAM-1)之蛋白質表現量上升。為了驗證促發炎細胞激素白介素-1β(interleukin-1β, IL-1β)與腫瘤壞死因子(tumor necrosis factor-α, TNFα)能否透過調控細胞自噬作用進而誘導BM-MSCs的ICAM-1與VCAM-1表現量上升,因此使用了具有降低溶酶體水解酶(lysosomal acid hydrolases)活性的巴佛洛黴素(bafilomycin A, Baf)以及能夠抑制自噬體(autophagosomes)形成的3-MA (3-methyladenine)進行實驗。實驗結果顯示Baf可促進由IL-1β與TNFα所引發的ICAM-1與VCAM-1表現量,使得ICAM-1與VCAM-1的總體表現量趨升;而3-MA則具有相反的作用,使得ICAM-1與VCAM-1的總體表現量下降。由以上實驗結果可得知,BM-MSCs能夠藉由活化細胞自噬作用以調節促發炎細胞激素所引發的ICAM-1和VCAM-1蛋白質表現量。
Pro-inflammatory cytokines induce expression of surface adhesion molecules ICAM-1 and VCAM-1 of human bone marrow-derived mesenchymal stem cells (BM-MSCs). To determine whether autophagy plays a role in regulating interleukin-1β (IL-1β)- or tumor necrosis factor-α (TNFα)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), I treated BM-MSCs with bafilomycin A (Baf) which inhibits lysosomal acid hydrolases or with 3-methyladenine (3-MA) which inhibits autophagosome formation. The results reveal that Baf enhanced the expression of ICAM-1 and VCAM-1, while 3-MA inhibited IL-1β- or TNFα-induced expression of ICAM-1 and VCAM-1. These findings suggest that pro-inflammatory cytokine-induced ICAM-1 and VCAM-1 expression in BM-MSCs is regulated by autophagic activation.
1. Gardner OF, Alini M, Stoddart MJ. Mesenchymal Stem Cells Derived from Human Bone Marrow. Methods Mol Biol. 2015; 1340: 41-52.
2. Bernardo ME, Locatelli F, Fibbe WE. Mesenchymal stromal cells. Ann N Y Acad Sci. 2009; 1176: 101-17.
3. Rasini V, Dominici M, Kluba T, Siegel G, Lusenti G et al. Mesenchymal stromal/stem cells markers in the human bone marrow. Cytotherapy. 2013; 15: 292-306.
4. S Ma, N Xie, W Li, B Yuan, Y Shi, and Y Wang. Immunobiology of mesenchymal stem cells. Cell Death and Differentiation. 2014; 21: 216-25.
5. Park JS, Yang HN, Woo DG, Jeon SY, Park KH. The promotion of chondrogenesis, osteogenesis, and adipogenesis of human mesenchymal stem cells by multiple growth factors incorporated into nanosphere-coated microspheres. Biomaterials. 2011; 32: 28-38.
6. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013; 13: 392-402.
7. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012; 33: 136-43.
8. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006; 107: 367-72.
9. Xu G, Zhang L, Ren G, Yuan Z, Zhang Y, Zhao RC, Shi Y. Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res. 2007; 17: 240-8.
10. Shi Y, Hu G, Su J, Li W, Chen Q et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010; 20: 510-8.
11. Nasef A, Mazurier C, Bouchet S, François S, Chapel A et al. Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008; 253: 16-22.
12. English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2013; 91: 19-26.
13. Ponte AL, Marais E, Gallay N, Langonné A, Delorme B et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007; 25: 1737-45.
14. Steingen C, Brenig F, Baumgartner L, Schmidt J, Schmidt A, Bloch W. Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. J Mol Cell Cardiol. 2008; 44: 1072-84.
15. Chamberlain G, Smith H, Rainger GE, Middleton J. Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: effects of chemokines and shear. PLoS One. 2011; 6: e25663.
16. Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol. 2010; 184: 2321-8
17. Fu X, Han B, Cai S, Lei Y, Sun T, Sheng Z. Migration of bone marrow-derived mesenchymal stem cells induced by tumor necrosis factor-alpha and its possible role in wound healing. Wound Repair Regen. 2009; 17: 185-91.
18. Moynagh PN, Williams DC, O'Neill LA. Activation of NF-kappa B and induction of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression in human glial cells by IL-1. Modulation by antioxidants. J Immunol. 1994; 153: 2681-90.
19. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J. 1995; 9: 899-909.
20. Manning AM, Bell FP, Rosenbloom CL, Chosay JG, Simmons CA et al. NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J Inflamm. 1995; 45: 283-96.
21. Jing SH, Gao X, Yu B1, Qiao H. Raf Kinase Inhibitor Protein (RKIP) Inhibits Tumor Necrosis Factor-α (TNF-α) Induced Adhesion Molecules Expression in Vascular Smooth Muscle Bells by Suppressing (Nuclear Transcription Factor-κB (NF-kappaB) Pathway. Med Sci Monit. 2017; 23: 4789-4797.
22. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011; 469: 323-35.
23. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2011; 146: 682-95.
24. Capasso S, Alessio N, Squillaro T, Di Bernardo G, Melone MA et al. Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells. Oncotarget. 2015; 6: 39457-68.
25. Alessio N, Del Gaudio S, Capasso S, Di Bernardo G, Cappabianca S et al. Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process. Oncotarget. 2015; 6: 8155-66.
26. Chang TC, Hsu MF, Wu KK. High glucose induces bone marrow-derived mesenchymal stem cell senescence by upregulating autophagy. PLoS One. 2015; 10: e0126537.
27. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007; 8: 931-7.
28. Deretic V, Klionsky DJ. Autophagy and inflammation: A special review issue. Autophagy. 2018; 14: 179-180.
29. Zhang H, Baehrecke EH. Eaten alive: novel insights into autophagy from multicellular model systems. Trends Cell Biol. 2015; 25: 376-87.
30. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010; 90: 1383-435.
31. Mintern JD, Harris J. Autophagy and immunity. Immunol Cell Biol. 2015; 93:1-2.
32. Dang S, Xu H, Xu C, Cai W, Li Q et al. Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis. Autophagy. 2014; 10: 1301-15.
33. Pan H, Cai N, Li M, Liu GH, Izpisua Belmonte JC. Autophagic control of cell 'stemness'. EMBO Mol Med. 2013; 5: 327-31.
34. Harris J, Hartman M, Roche C, Zeng SG, O'Shea A et al. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 2011; 286: 9587-97.
35. Harris J. Autophagy and IL-1 Family Cytokines. Front Immunol. 2013; 4: 83.
36. Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem. 1991; 266: 17707-12.
37. You-Tong Wu, Hui-Ling Tan, Guanghou Shui, Chantal Bauvy, Qing Huang et al. Dual Role of 3-Methyladenine in Modulation of Autophagy via Different Temporal Patterns of Inhibition on Class I and III Phosphoinositide 3-Kinase. J Biol Chem. 2010; 285: 10850-61.
38. Burman C, Ktistakis NT. Regulation of autophagy by phosphatidylinositol 3-phosphate. FEBS Lett. 2010; 584: 1302-12.
39. Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005; 1: 84-91
40. Tanida I, Ueno T, Kominami E. LC3 and Autophagy. Methods Mol Biol. 2008; 445:77-88.
41. Bjørkøy G, Lamark T, Pankiv S, Øvervatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009; 452:181-97.
42. Sun Q, Fan W, Zhong Q. Regulation of Beclin 1 in autophagy. Autophagy. 2009; 5:713-6.
43. Mello AS, Goldim MP, Mezzalira J, Garcia CS, Daitx VV et al. LAMP2 as a marker of EBV-mediated B lymphocyte transformation in the study of lysosomal storage diseases. Mol Cell Biochem. 2014; 385: 1-6.
44. Appelqvist H, Wäster P, Kågedal K, Öllinger K. The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol. 2013; 5: 214-26.
45. Napetschnig J, Wu H. Molecular basis of NF-κB signaling. Annu Rev Biophys. 2013; 42: 443-68.
46. Hinz M, Scheidereit C. The IκB kinase complex in NF-κB regulation and beyond. EMBO Rep. 2014; 15: 46-61.
47. Zhong L, Simard MJ, Huot J. Endothelial microRNAs regulating the NF-κB pathway and cell adhesion molecules during inflammation. FASEB J. 2018: fj201701536R.
48. Chu LY, Hsueh YC, Cheng HL, Wu KK. Cytokine-induced autophagy promotes long-term VCAM-1 but not ICAM-1 expression by degrading late-phase IκBα. Sci Rep. 2017; 7: 12472.