생명과학회지 (Journal of Life Science)

  • 제23권1호
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  • Pages.137-142
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  • 2013
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
권호 표지
DOI QR코드

DOI QR Code

중간엽 줄기세포의 평활근 세포로의 분화에서 LPS에 의해 활성화된 대식세포의 역할

Role of LPS-activated Macrophages in the Differentiation of Mesenchymal Stem Cells into Smooth Muscle Cells

  • 이미정 (부산대학교 의학전문대학원 생리학교실) ;
  • 도은경 (부산대학교 의학전문대학원 생리학교실) ;
  • 김재호 (부산대학교 의학전문대학원 생리학교실)
  • Lee, Mi Jeong (Department of Physiology, School of Medicine, Pusan National University) ;
  • Do, Eun Kyoung (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Jae Ho (Department of Physiology, School of Medicine, Pusan National University)
  • 투고 : 2012.11.13
  • 심사 : 2012.12.31
  • 발행 : 2013.01.30
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초록

인체 중간엽 줄기세포는 지방세포, 골세포, 연골세포, 근육세포 등 여러 형태의 세포로의 분화되는 것이 특징이다. 특히, 최근 연구 결과를 살펴 보면, 중간엽 줄기세포는 생체 내에서 조직 특이적인 세포 형태로 분화 된다. 본 연구에서는 염증 상태에 존재하는 중간엽 줄기 세포가 혈관 형성에 관여하는지 알아보고, 염증 상태에 존재하는 줄기세포의 역할을 규명하고자 본 연구를 진행하였다. 생체 내 염증 상태와 유사한 환경을 만들고자, 강력한 염증 유발 물질인 LPS를 대식세포에 처리하여 그 배양액을 중간엽 줄기세포에 처리하여 변화를 관찰하였다. LPS 배양액을 처리한 중간엽 줄기세포는 평활근 세포로 분화가 촉진되는 것을 확인하였으며, LPS 배양액에 존재하는 분화 유도 물질이 $PGF2{\alpha}$임을 확인하였다. 이에 본 연구결과를 통해 염증 상태에서 존재하는 중간엽 줄기세포는 평활근 세포로의 분화가 촉진되는 것을 확인하였다. 본 연구는 염증성 미세환경 내에 존재하는 중간엽 줄기세포가 평활근 세포로 분화가 유도됨을 확인하였고, 혈관 형성을 촉진하는데 영향을 미칠 수 있음을 제시한다.

Human adipose-derived mesenchymal stem cells (hMSCs) are highly useful for vascular regeneration of injured or inflamed tissue. Lipopolysaccharide (LPS) is a potent activator of macrophages and stimulates macrophages to release inflammatory cytokines. In the present study, we explored the role of LPS-activated macrophages in the differentiation of hMSCs to smooth muscle cells (SMCs). We demonstrated that conditioned medium from LPS-induced macrophages (LPS CM) stimulates differentiation of hMSCs to SMCs, as evidenced by increased expression of smooth muscle-specific markers, including alpha-smooth muscle actin (${\alpha}$-SMA), smooth muscle-myosin heavy chain, and calponin. LPS induced the secretion of $PGF2{\alpha}$ from macrophages, and $PGF2{\alpha}$ treatment stimulated expression levels of SMC-specific markers in hMSCs. Furthermore, small interfering RNA-mediated silencing of the $PGF2{\alpha}$ receptor inhibited LPS CM-stimulated ${\alpha}$-SMA expression. These results suggest that LPS-activated macrophages promote differentiation of hMSCs to SMCs through a $PGF2{\alpha}$-dependent mechanism.

키워드

참고문헌

  1. Barry, F. P. and Murphy, J. M. 2004. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol 36, 568-584. https://doi.org/10.1016/j.biocel.2003.11.001
  2. Choi, K. U, Yun, J. S., Lee, I. H., Heo, S. C., Shin, S. H., Jeon, E. S., Choi, Y. J., Suh, D. S., Yoon, M. S. and Kim, J. H. 2011. Lysophosphatidic acid-induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer. Int J Cancer 128, 332-342. https://doi.org/10.1002/ijc.25341
  3. Delanty, N., Reilly, M. P., Pratico, D., Lawson, J. A., McCarthy, J. F., Wood, A. E., Ohnishi, S. T., Fitzgerald, D. J. and FitzGerald, G. A. 1997. 8-Epi $PGF2{\alpha}$ generation during coronary reperfusion: A potential quantitative marker of oxidant stress in vivo. Circulation 95, 2492-2499. https://doi.org/10.1161/01.CIR.95.11.2492
  4. Fairweather, D. and Rose, N. R. 2005. Inflammatory heart disease: a role for cytokines. Lupus 14, 646-651. https://doi.org/10.1191/0961203305lu2192oa
  5. Geng, Y., Fang, M., Wang, J., Yu, H., Hu, Z., Yew, D. T. and Chen, W. 2011. Triptolide down-regulates COX-2 expression and PGE2 release by suppressing the activity of NF-${\kappa}B$ and MAP kinases in lipopolysaccharide-treated PC12 cells. Phytother Res 26, 337-343.
  6. Hoch, A. I., Binder, B. Y., Genetos, D. C. and Leach, J. K. 2012. Differentiation-dependent secretion of proangiogenic factors by mesenchymal stem cells. PLoS ONE 7, e3557.
  7. Hong, H. S., Kim, Y. H. and Son, Y. 2012. Perspectives on mesenchymal stem cells: Tissue repair, immune modulation, and tumor homing. Arch Pharm Res 35, 201-211. https://doi.org/10.1007/s12272-012-0201-0
  8. Jeon, E. S., Heo, S. C., Lee, I. H., Choi, Y. J., Park, J. H., Choi, K. U., Park, D. Y., Suh, D. S., Yoon, M. S. and Kim, J. H. 2008. Ovarian cancer-derived lysophospahtidic acid stimulates secretion of VEGF and stromal cell-derived factor- 1 alpha from human mesenchymal stem cells. Exp Mol Med 42, 280-293.
  9. Jeon, E. S., Lee, I. H., Heo, S. C., Shin, S. H., Choi, Y. J., Park, J. H., Park, D. Y. and Kim, J. H. 2010. Mesenchymal stem cells stimulate angiogenesis in a murine xenograft model of A549 human adenocarcinoma through an LPA1 receptor-dependent mechanism. Biochim Biophys Acta 1801, 1205-1213. https://doi.org/10.1016/j.bbalip.2010.08.003
  10. Jeon, E. S., Moon, H. J., Lee, M. J., Song, H. Y., Kim, Y. M., Cho, M., Suh, D. S., Yoon, M. S., Chang, C. L., Jung, J. S. and Kim, J. H. 2008. Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells. Stem Cells 26, 789-797. https://doi.org/10.1634/stemcells.2007-0742
  11. Joh, E. H., Jeong, J. J. and Kim, D. H. 2012. Kalopanaxsaponin B inhibits LPS-induced inflammation by inhibiting IRAK1 Kinase. Cellular Immunol 279, 103-108. https://doi.org/10.1016/j.cellimm.2012.10.001
  12. Kim, M. R., Jeon, E. S., Kim, Y. M., Lee, J. S. and Kim, J. H. 2009. Thromboxane A2 induces differentiation of human mesenchymal stem cells to smooth muscle-like cells. Stem Cells 27, 191-199. https://doi.org/10.1634/stemcells.2008-0363
  13. Kotanidou, A., Xagorari, A., Bagli, E., Kitsanta, P., Fotsis, T., Papapetropoulos, A. and Roussos, C. 2002. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am J Respir Crit Care Med 165, 818-823. https://doi.org/10.1164/ajrccm.165.6.2101049
  14. Lee, M. J., Jeon, E. S., Lee, J. S., Cho, M., Suh, D. S., Chang, C. L. and Kim, J. H. 2008. Lysophosphatidic acid in malignant ascites stimulates migration of human mesenchymal stem cells. J Cell Biochem 104, 499-510. https://doi.org/10.1002/jcb.21641
  15. Lee, M. J., Kim, M. Y., Heo, S. C., Kwon, Y. W., Kim, Y. M., Do, E. K., Park, J. H., Lee, J. S., Han, J. and Kim, J. H. 2012. Macrophages regulate smooth muscle differentiation of mesenchymal stem cells via a prostaglandin $F2{\alpha}$ -mediated paracrine mechanism. Arterioscler Thromb Vasc Biol 32, 2733-2740. https://doi.org/10.1161/ATVBAHA.112.300230
  16. Li, W., Ren, G., Huang, Y., Su, J., Han, Y., Li, J., Chen, X., Cao, K., Chen, Q., Shou, P., Zhang, L., Yuan, Z. R., Roberts, A. I., Shi, S., Le, A. D. and Shi, Y. 2012. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ 19, 1505-1513. https://doi.org/10.1038/cdd.2012.26
  17. Miller, F. D. and Kaplan, D. R. 2012. Mobilizing endogenous stem cells for repair and regeneration: Are we there yet? Cell Stem Cell 10, 650-652. https://doi.org/10.1016/j.stem.2012.05.004
  18. Moncada, S. 1999. Nitric oxide: discovery and impact on clinical medicine. J R Soc Med 92, 164-169.
  19. Park, D., Spencer, J. A., Koh, B. I., Kobayashi, T., Fujisaki, J., Clemens, T. L., Lin, C. P., Kronenberg, H. M. and Scadden, D. T. 2012. Endogenous Bone Marrow MSCs Are Dynamic, Fate-Restricted Participants in Bone Maintenance and Regeneration. Cell Stem Cell 10, 259-272. https://doi.org/10.1016/j.stem.2012.02.003
  20. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S. and Marshak, D. R. 1999. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147. https://doi.org/10.1126/science.284.5411.143
  21. Prockop, D. J. 1997. Marrow stromal cells as stem cells form nonhematopoietic tissue. Science 276, 71-74. https://doi.org/10.1126/science.276.5309.71
  22. Prockop, D. J. and Oh, J. Y. 2012. Mesenchymal Stem/Stromal Cells (MSCs): Role as Guardians of Inflammation. Mol Ther 20, 14-20. https://doi.org/10.1038/mt.2011.211
  23. Short, B., Brouard, N., Occhiodoro-Scott, T., Ramakrishnan, A. and Simmons, P. J. 2003. Mesenchymal stem cells. Arch Med Res 34, 565-571. https://doi.org/10.1016/j.arcmed.2003.09.007
  24. Takahashi, K., Nammour, T. M., Fukunaga, M., Ebert, J., Morrow, J. D., Roberts, L. J. 2nd, Hoover, R. L. and Badr, K. F. 1992. Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat: Evidence for interaction with thromboxane A2 receptors. J Clin Invest 90, 136-141. https://doi.org/10.1172/JCI115826
  25. Utar, Z., Majid, M. I., Adenan, M. I., Jamil, M. F. and Lan, T. M. 2011. Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E2 production induced by lipopolysaccharide in RAW264.7 macrophage cells. J Ethnopharmacol 136, 75-82. https://doi.org/10.1016/j.jep.2011.04.011
  26. Vu, H. V., Acosta, T. J., Yoshioka, S., Abe, H. and Okuda, K. 2012. Roles of prostaglandin F2alpha and hydrogen peroxide in the regulation of Copper/Zinc superoxide dismutase in bovine corpus luteum and luteal endothelial cells. Reprod Biol Endocrinol 10, 87. https://doi.org/10.1186/1477-7827-10-87
  27. Yun, D. H., Song, H. Y., Lee, M. J., Kim, M. R., Kim, M. Y., Lee, J. S. and Kim, J. H. 2009 Thromboxane A2 modulates migration, proliferation, and differentiation of adipose tissue-derived mesenchymal stem cells. Exp Mol Med 41, 17-24. https://doi.org/10.3858/emm.2009.41.1.003
  28. Zhang, J. J., Xu, Z. M., Chang, H., Zhang, C. M., Dai, H. Y., Ji, X. Q., Li, C. and Wang, X. F. 2011. Pyrrolidine dithiocarbamate attenuates nuclear factor-${\kappa}B$ activation, cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic epithelial cells. Gynecol Obstet Invest 72, 163-168. https://doi.org/10.1159/000327934