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Transdifferentiation of bovine epithelial cells towards adipocytes in the presence of myoepithelium

  • Sugathan, Subi (Department of Animal Biotechnology, College of Animal Life Sciences, Kangwon National University) ;
  • Lee, Sung-Jin (Department of Animal Biotechnology, College of Animal Life Sciences, Kangwon National University) ;
  • Shiwani, Supriya (Department of Animal Biotechnology, College of Animal Life Sciences, Kangwon National University) ;
  • Singh, Naresh Kumar (Department of Veterinary Surgery and Radiology, Faculty of Veterinary and Animal Sciences, Institute of Agricultural Sciences, Banaras Hindu University)
  • Received : 2018.10.25
  • Accepted : 2019.03.18
  • Published : 2020.02.01

Abstract

Objective: Orchastric changes in the mammary glands are vital, especially during lactation. The secretary epithelial cells together with the supporting myoepithelial and stromal cells function cordially to secrete milk. Increase in the number of luminal epithelial cells and a decrease in adipocytes are visible during lactation, whereas the reverse happens in the involution. However, an early involution occurs if the epithelial cells transdifferentiate towards adipocytes during the lactation period. We aimed to inhibit the adipocyte transdifferentiation of luminal cells by restraining the peroxisomal proliferator-activated receptor γ (PPARγ) pathway. Methods: Linolenic acid (LA) and thiazolidinediones (TZDs) induced adipogenesis in mammary epithelial cells were conducted in monolayer, mixed culture as well as in transwell plate co-culture with mammary myoepithelial cells. Results: Co-culture with myoepithelial cells showed higher adipogenic gene expression in epithelial cells under LA+TZDs treatment. Increase in the expressions of PPARγ, CCAAT/enhancer-binding protein α and vimentin in both mRNA as well as protein levels were observed. Whereas, bisphenol A diglycidyl ether treatment blocked LA+TZDs induced adipogenesis, as it could not show a significant rise in adipose related markers. Although comparative results were found in both mixed culture and monolayer conditions, co-culture technic was found to work better than the others. Conclusion: Antagonizing PPARγ pathway in the presence of myoepithelial cells can significantly reduce the adipogenisis in epithelial cells, suggesting therapeutic inhibition of PPARγ can be considered to counter early involution or excessive adipogenesis in mammary epithelium in animals.

Acknowledgement

Supported by : National Research Foundation of Korea

References

  1. Hovey RC, Mcfadden TB, Akers RM. Regulation of mammary gland growth and morphogenesis by the mammary fat pad: a species comparison. J Mammary Gland Biol Neoplasia 1999; 4:53-68. https://doi.org/10.1023/A:1018704603426 https://doi.org/10.1023/A:1018704603426
  2. Couldrey C, Moitra J, Vinson C, Anver M, Nagashima K, Green J. Adipose tissue: a vital in vivo role in mammary gland development but not differentiation. Dev Dyn 2002;223:459-68. https://doi.org/10.1002/dvdy.10065 https://doi.org/10.1002/dvdy.10065
  3. Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res 2004;6:1-11. https://doi.org/10.1186/bcr634 https://doi.org/10.1186/bcr820
  4. Hovey RC, Aimo L. Diverse and active roles for adipocytes during mammary gland growth and function. J Mammary Gland Biol Neoplasia 2010;15:279-90. https://doi.org/10.1007/s10911-010-9187-8 https://doi.org/10.1007/s10911-010-9187-8
  5. Wang YY, Lehuede C, Laurent V, et al. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer Lett 2012;324:142-51. https://doi.org/10.1016/j.canlet.2012.05.019 https://doi.org/10.1016/j.canlet.2012.05.019
  6. Hennighausen L, Robinson GW. Singnaling pathways in mammary gland development. Dev Cell 2001;1:467-75. https://doi.org/10.1016/S1534-5807(01)00064-8 https://doi.org/10.1016/S1534-5807(01)00064-8
  7. Rucker EB 3rd, Hale AN, Durtschi DC, Sakamoto K, Wagner KU. Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein bax. Genesis 2011;49:24-35. https://doi.org/10.1002/dvg.20691 https://doi.org/10.1002/dvg.20691
  8. Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science 2002;296:1046-9. https://doi.org/10.1126/science.1067431 https://doi.org/10.1126/science.1067431
  9. Watson CJ, Khaled WT. Mammary development in the embryo and adult: a journey of morphogenesis and commitment. Development 2008;135:995-1003. https://doi.org/10.1242/dev.005439 https://doi.org/10.1242/dev.005439
  10. Duss S, Brinkhaus H, Britschgi A, et al. Mesenchymal precursor cells maintain the differentiation and proliferation potentials of breast epithelial cells. Breast Cancer Res 2014;16:R60. https://doi.org/10.1186/bcr3673 https://doi.org/10.1186/bcr3673
  11. Cunha GR. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Cancer 1994;74:1030-44. https://doi.org/10.1002/1097-0142(19940801)74:3+<1030::AID-CNCR2820741510>3.0.CO;2-Q
  12. Walden PD, Ruan W, Feldman M, Kleinberg DL. Evidence that the mammary fat pad mediates the action of growth hormone in mammary gland development. Endocrinology 1998;139:659-62. https://doi.org/10.1210/endo.139.2.5718 https://doi.org/10.1210/endo.139.2.5718
  13. Morroni M, Giordano A, Zingaretti MC, et al. Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland. Proc Natl Acad Sci USA 2004;101:16801-6. https://doi.org/10.1073/pnas.0407647101 https://doi.org/10.1073/pnas.0407647101
  14. Ohyama M, Matsuda K, Torii S, et al. The interaction between vitamin A and thiazolidinedione on bovine adipocyte differentiation in primary culture. J Anim Sci 1998;76:61-5. https://doi.org/10.2527/1998.76161x https://doi.org/10.2527/1998.76161x
  15. Shin S, Ajuwon KM. Divergent response of murine and porcine adipocytes to stimulation of browning genes by 18-carbon polyunsaturated fatty acids and beta-receptor agonists. Lipids 2018;53:65-75. https://doi.org/10.1002/lipd.12010 https://doi.org/10.1002/lipd.12010
  16. Tamori Y, Masugi J, Nishino N, Kasuga M. Role of peroxisome proliferator-activated receptor-$\gamma$ in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes 2002;51:2045-55. https://doi.org/10.2337/diabetes.51.7.2045 https://doi.org/10.2337/diabetes.51.7.2045
  17. Valet P, Tavernier G, Castan-Laurell I, Saulnier-Blache JS, Langin D. Understanding adipose tissue development from transgenic animal models. J Lipid Res 2002;43:835-60.
  18. Farmer SR. Transcriptional control of adipocyte formation. Cell Metab 2006;4:263-73. https://doi.org/10.1016/j.cmet.2006.07.001 https://doi.org/10.1016/j.cmet.2006.07.001
  19. Kokubun K, Pankajakshan D, Kim MJ, Agrawal DK. Differentiation of porcine mesenchymal stem cells into epithelial cells as a potential therapeutic application to facilitate epithelial regeneration. J Tissue Eng Regen Med 2016;10:E73-83. https://doi.org/10.1002/term.1758 https://doi.org/10.1002/term.1758
  20. Marin F, Luquet G, Marie B, Medakovic D. Molluscan shell proteins: primary structure, origin, and evolution. Curr Top Dev Biol 2007;80:209-76. https://doi.org/10.1016/S0070-2153(07)80006-8
  21. Buhler H, Schaller G. Transfection of Keratin 18 gene in human breast cancer cells causes induction of adhesion proteins and dramatic regression of malignancy in vitro and in vivo. Mol Cancer Res 2005;3:365-71. https://doi.org/10.1158/1541-7786.MCR-04-0117 https://doi.org/10.1158/1541-7786.MCR-04-0117
  22. Stingl J, Raouf A, Emerman JT, Eaves CJ. Epithelial progenitors in the normal human mammary gland. J Mammarry Gland Biol Neoplasia 2005;10:49-59. https://doi.org/10.1007/s10911-005-2540-7 https://doi.org/10.1007/s10911-005-2540-7
  23. Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M. Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs 2007;185:191-203. https://doi.org/10.1159/ 000101320 https://doi.org/10.1159/000101320
  24. Ackland ML, Newgreen DF, Fridman M, et al. Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest 2003;83:435-48. https://doi.org/10.1097/01.LAB.0000059927.97515.FD
  25. Farmer SR. Regulation of $PPAR{\gamma}$ activity during adipogenesis. Int J Obes 2005;29(Suppl 1):S13-6. https://doi.org/10.1038/sj.ijo.0802907
  26. Ahmed M1, Gaffen SL. IL-17 inhibits adipogenesis in part via $C/EBP{\alpha}$, $PPAR{\gamma}$ and Kruppel-like factors. Cytokine 2013;61: 898-905. https://doi.org/10.1016/j.cyto.2012.12.007 https://doi.org/10.1016/j.cyto.2012.12.007
  27. Rosen ED. The transcriptional basis of adipocyte development. Prostaglandins Leukot Essent Fatty Acids 2005;73:31-4. https://doi.org/10.1016/j.plefa.2005.04.004 https://doi.org/10.1016/j.plefa.2005.04.004
  28. Salmeron C, Riera-Heredia N, Gutierrez J, Navarro I, Capilla E. Adipogenic gene expression in gilthead sea bream mesenchymal stem cells from different origin. Front Endocrinol (Lausanne) 2016;7:113. https://doi.org/10.3389/fendo.2016.00113
  29. Kolehmainen M, Vidal H, Ohisalo JJ, Pirinen E, Alhava E, Uusitupa MI. Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss. Int J Obes Relat Metab Disord 2002;26:6-16. https://doi.org/10.1038/sj.ijo.0801858 https://doi.org/10.1038/sj.ijo.0801858
  30. Fu Y, Luo N, Klein RL, Garvey WT. Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J Lipid Res 2005;46:1369-79. https://doi.org/10.1194/jlr.M400373-JLR200 https://doi.org/10.1194/jlr.M400373-JLR200
  31. Polyak K, Hu M. Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol Neoplasia 2005; 10:231-47. https://doi.org/10.1007/s10911-005-9584-6 https://doi.org/10.1007/s10911-005-9584-6
  32. Lee YJ, Choi HS, Seo MJ, Jeon HJ, Kim KJ, Lee BY. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish. Food Funct 2015;6:2824-33. https://doi.org/10.1039/c5fo00481k https://doi.org/10.1039/C5FO00481K
  33. Pechoux C, Gudjonsson T, Ronnov-Jessen L, Bissell MJ, Petersen OW. Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. Dev Biol 1999;206:88-99. https://doi.org/10.1006/dbio.1998.9133 https://doi.org/10.1006/dbio.1998.9133
  34. Wright HM, Clish CB, Mikami T, et al. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem 2000;275:1873-7. https://doi.org/10.1074/jbc.275.3.1873 https://doi.org/10.1074/jbc.275.3.1873
  35. McManaman JL, Palmer CA, Anderson S, Schwertfeger K, Neville MC. Regulation of milk lipid formation and secretion in the mouse mammary gland. In: Pickering LK, Morrow AL, Ruiz-Palacios GM, Schanler RJ, editors. Protecting infants through human milk. Advances in experimental medicine and biology. Boston, MA, USA: Springer; 2004. vol 554. pp. 263-79. https://doi.org/10.1007/978-1-4757-4242-8_22