International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

FGF-17 from Hypoxic Human Wharton's Jelly-Derived Mesenchymal Stem Cells Is Responsible for Maintenance of Cell Proliferation at Late Passages

  • Han, Kyu-Hyun (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Min-Hee (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Jeong, Gun-Jae (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Ae-Kyeong (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Chang, Jong Wook (Stem Cell & Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center) ;
  • Kim, Dong-ik (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2018.05.12
  • Accepted : 2019.03.04
  • Published : 2019.07.31
⟨ Previous Next ⟩

Abstract

Background and Objectives: Although it is well known that hypoxic culture conditions enhance proliferation of human mesenchymal stem cells, the exact mechanism is not fully understood. In this study, we investigated the effect of fibroblast growth factor (FGF)-17 from hypoxic human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on cell proliferation at late passages. Methods and Results: hWJ-MSCs were cultured in α-MEM medium supplemented with 10% fetal bovine serum (FBS) in normoxic (21% O2) and hypoxic (1% O2) conditions. Protein antibody array was performed to analyze secretory proteins in conditioned medium from normoxic and hypoxic hWJ-MSCs at passage 10. Cell proliferation of hypoxic hWJ-MSCs was increased compared with normoxic hWJ-MSCs from passage 7 to 10, and expression of secretory FGF-17 was highly increased in conditioned medium from hypoxic hWJ-MSCs at passage 10. Knockdown of FGF-17 in hypoxic and normoxic hWJ-MSCs decreased cell proliferation, whereas treatment of hypoxic and normoxic hWJ-MSCs with recombinant protein FGF-17 increased their proliferation. Signal transduction of FGF-17 in hypoxic and normoxic hWJ-MSCs involved the ERK1/2 pathway. Cell phenotypes were not changed under either condition. Differentiation-related genes adiponectin, Runx2, and chondroadherin were downregulated in normoxic hWJ-MSCs treated with rFGF-17, and upregulated by siFGF-17. Expression of alkaline phosphatase (ALP), Runx2, and chondroadherin was upregulated in hypoxic hWJ-MSCs, and this effect was rescued by transfection with siFGF-17. Only chondroadherin was upregulated in hypoxic hWJ-MSCs with rFGF-17. Conclusions: In hypoxic culture conditions, FGF-17 from hypoxic hWJ-MSCs contributes to the maintenance of high proliferation at late passages through the ERK1/2 pathway.

Keywords

Acknowledgement

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Ministry of Health and Welfare, Republic of Korea (HI17C1728), and by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI14C3484).

References

  1. Liu Y, Yan W, Tohme S, Chen M, Fu Y, Tian D, Lotze M, Tang D, Tsung A. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J Hepatol 2015;63:114-121 https://doi.org/10.1016/j.jhep.2015.02.009
  2. Panigrahi GK, Praharaj PP, Peak TC, Long J, Singh R, Rhim JS, Abd Elmageed ZY, Deep G. Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Sci Rep 2018;8:3853 https://doi.org/10.1038/s41598-018-22068-4
  3. Porter KM, Kang BY, Adesina SE, Murphy TC, Hart CM, Sutliff RL. Chronic hypoxia promotes pulmonary artery endothelial cell proliferation through H2O2-induced 5-lipoxygenase. PLoS One 2014;9:e98532 https://doi.org/10.1371/journal.pone.0098532
  4. Chai X, Sun D, Han Q, Yi L, Wu Y, Liu X. Hypoxia induces pulmonary arterial fibroblast proliferation, migration, differentiation and vascular remodeling via the PI3K/Akt/p70S6K signaling pathway. Int J Mol Med 2018;41: 2461-2472
  5. Chen R, Liu Y, Su Q, Yang Y, Wang L, Ma S, Yan J, Xue F, Wang J. Hypoxia stimulates proliferation of rat neural stem/progenitor cells by regulating mir-21: an in vitro study. Neurosci Lett 2017;661:71-76 https://doi.org/10.1016/j.neulet.2017.09.037
  6. Nekanti U, Dastidar S, Venugopal P, Totey S, Ta M. Increased proliferation and analysis of differential gene expression in human Wharton's jelly-derived mesenchymal stromal cells under hypoxia. Int J Biol Sci 2010;6:499-512
  7. Tsai CC, Chen YJ, Yew TL, Chen LL, Wang JY, Chiu CH, Hung SC. Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. Blood 2011;117:459-469 https://doi.org/10.1182/blood-2010-05-287508
  8. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 2007;11:335-347 https://doi.org/10.1016/j.ccr.2007.02.006
  9. Zhang H, Nan W, Song X, Wang S, Si H, Li G. Knock-down of HIF-1α inhibits the proliferation and migration of outer root sheath cells exposed to hypoxia in vitro: an involvement of Shh pathway. Life Sci 2017;191:82-89 https://doi.org/10.1016/j.lfs.2017.10.011
  10. Bader AM, Klose K, Bieback K, Korinth D, Schneider M, Seifert M, Choi YH, Kurtz A, Falk V, Stamm C. Hypoxic preconditioning increases survival and pro-angiogenic capacity of human cord blood mesenchymal stromal cells in vitro. PLoS One 2015;10:e0138477 https://doi.org/10.1371/journal.pone.0138477
  11. Kim J, Ma T. Autocrine fibroblast growth factor 2-mediated interactions between human mesenchymal stem cells and the extracellular matrix under varying oxygen tension. J Cell Biochem 2013;114:716-727 https://doi.org/10.1002/jcb.24413
  12. Qin HH, Filippi C, Sun S, Lehec S, Dhawan A, Hughes RD. Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes. Stem Cell Res Ther 2015;6:237 https://doi.org/10.1186/s13287-015-0218-7
  13. Hoshikawa M, Ohbayashi N, Yonamine A, Konishi M, Ozaki K, Fukui S, Itoh N. Structure and expression of a novel fibroblast growth factor, FGF-17, preferentially expressed in the embryonic brain. Biochem Biophys Res Commun 1998;244:187-191 https://doi.org/10.1006/bbrc.1998.8239
  14. Granerus M, Engstrom W. Dual effects of four members of the fibroblast growth factor member family on multiplication and motility in human teratocarcinoma cells in vitro. Anticancer Res 2000;20:3527-3531
  15. Nezu M, Tomonaga T, Sakai C, Ishii A, Itoga S, Nishimura M, Matsuo Y, Tagawa M, Nomura F. Expression of the fetal-oncogenic fibroblast growth factor-8/17/18 subfamily in human hematopoietic tumors. Biochem Biophys Res Commun 2005;335:843-849 https://doi.org/10.1016/j.bbrc.2005.07.153
  16. Fortin D, Rom E, Sun H, Yayon A, Bansal R. Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage. J Neurosci 2005;25:7470-7479 https://doi.org/10.1523/JNEUROSCI.2120-05.2005
  17. Kwon S, Ki SM, Park SE, Kim MJ, Hyung B, Lee NK, Shim S, Choi BO, Na DL, Lee JE, Chang JW. Anti- apoptotic effects of human Wharton's jelly-derived mesenchymal stem cells on skeletal muscle cells mediated via secretion of XCL1. Mol Ther 2016;24:1550-1560 https://doi.org/10.1038/mt.2016.125
  18. Mammone T, Gan D, Foyouzi-Youssefi R. Apoptotic cell death increases with senescence in normal human dermal fibroblast cultures. Cell Biol Int 2006;30:903-909 https://doi.org/10.1016/j.cellbi.2006.06.010
  19. Kim M, Rhee JK, Choi H, Kwon A, Kim J, Lee GD, Jekarl DW, Lee S, Kim Y, Kim TM. Passage-dependent accumulation of somatic mutations in mesenchymal stromal cells during in vitro culture revealed by whole genome sequencing. Sci Rep 2017;7:14508 https://doi.org/10.1038/s41598-017-15155-5
  20. Crowder SW, Horton LW, Lee SH, McClain CM, Hawkins OE, Palmer AM, Bae H, Richmond A, Sung HJ. Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia. FASEB J 2013;27:2788-2798 https://doi.org/10.1096/fj.13-228288
  21. Fernandes H, Dechering K, van Someren E, Steeghs I, Apotheker M, Mentink A, van Blitterswijk C, de Boer J. Effect of chordin-like 1 on MC3T3-E1 and human mesenchymal stem cells. Cells Tissues Organs 2010;191:443-452 https://doi.org/10.1159/000281825
  22. Yun SP, Lee MY, Ryu JM, Song CH, Han HJ. Role of HIF-1alpha and VEGF in human mesenchymal stem cell proliferation by 17beta-estradiol: involvement of PKC, PI3K/Akt, and MAPKs. Am J Physiol Cell Physiol 2009; 296:C317-C326
  23. Cheng GS, Zhang YS, Zhang TT, He L, Wang XY. Bone marrow-derived mesenchymal stem cells modified with IGFBP-3 inhibit the proliferation of pulmonary artery smooth muscle cells. Int J Mol Med 2017;39:223-230 https://doi.org/10.3892/ijmm.2016.2820
  24. Hofmann Bowman M, Wilk J, Heydemann A, Kim G, Rehman J, Lodato JA, Raman J, McNally EM. S100A12 mediates aortic wall remodeling and aortic aneurysm. Circ Res 2010;106:145-154 https://doi.org/10.1161/CIRCRESAHA.109.209486
  25. Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith A. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 2007;134:2895-2902 https://doi.org/10.1242/dev.02880
  26. Conte C, Riant E, Toutain C, Pujol F, Arnal JF, Lenfant F, Prats AC. FGF2 translationally induced by hypoxia is involved in negative and positive feedback loops with HIF1-alpha. PLoS One 2008;3:e3078 https://doi.org/10.1371/journal.pone.0003078
  27. Yang J, Kim WJ, Jun HO, Lee EJ, Lee KW, Jeong JY, Lee SW. Hypoxia-induced fibroblast growth factor 11 stimulates capillary-like endothelial tube formation. Oncol Rep 2015;34:2745-2751 https://doi.org/10.3892/or.2015.4223
  28. Zhang Q, Doucet M, Tomlinson RE, Han X, Quarles LD, Collins MT, Clemens TL. The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res 2016;4:16011 https://doi.org/10.1038/boneres.2016.11