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Brown-Like Adipocyte Progenitors Derived from Human iPS Cells: A New Tool for Anti-obesity Drug Discovery and Cell-Based Therapy?

  • Xi Yao
  • Barbara Salingova
  • Christian Dani
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

Alternative strategies are urgently required to fight obesity and associated metabolic disorders including diabetes and cardiovascular diseases. Brown and brown-like adipocytes (BAs) store fat, but in contrast to white adipocytes, activated BAs are equipped to dissipate energy stored. Therefore, BAs represent promising cell targets to counteract obesity. However, the scarcity of BAs in adults is a major limitation for a BA-based therapy of obesity, and the notion to increase the BA mass by transplanting BA progenitors (BAPs) in obese patients recently emerged. The next challenge is to identify an abundant and reliable source of BAPs. In this chapter, we describe the capacity of human-induced pluripotent stem cells (hiPSCs) to generate BAPs able to differentiate at a high efficiency with no gene transfer. This cell model represents an unlimited source of human BAPs that in a near future may be a suitable tool for both therapeutic transplantation and for the discovery of novel efficient and safe anti-obesity drugs. The generation of a relevant cell model, such as hiPSC-BAs in 3D adipospheres enriched with macrophages and endothelial cells to better mimic the microenvironment within the adipose tissue, will be the next critical step.

Keywords

Adipocyte progenitors Brown adipocytes Cell-based therapy Drug discovery Human-induced pluripotent stem cells Obesity 

References

  1. Ahfeldt T, Schinzel RT, Lee YK, Hendrickson D, Kaplan A, Lum DH, Camahort R, Xia F, Shay J, Rhee EP, Clish CB, Deo RC, Shen T, Lau FH, Cowley A, Mowrer G, Al-Siddiqi H, Nahrendorf M, Musunuru K, Gerszten RE, Rinn JL, Cowan CA (2012) Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol 14:209–219Google Scholar
  2. Caspi O, Lesman A, Basevitch Y, Gepstein A, Arbel G, Habib IH, Gepstein L, Levenberg S (2007) Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ Res 100:263–272Google Scholar
  3. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH (2013) Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19:635–639Google Scholar
  4. Dani C (2013) Activins in adipogenesis and obesity. Int J Obes (Lond) 37:163–166Google Scholar
  5. Farmer SR (2009) Obesity: be cool, lose weight. Nature 458:839–840Google Scholar
  6. Giordano A, Frontini A, Cinti S (2016) Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov 15:405–424Google Scholar
  7. Gunawardana SC, Piston DW (2010) Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61:674–682Google Scholar
  8. Hafner AL, Dani C (2014) Human induced pluripotent stem cells: a new source for brown and white adipocytes. World J Stem Cells 6:467–472Google Scholar
  9. Hafner AL, Contet J, Ravaud C, Yao X, Villageois P, Suknuntha K, Annab K, Peraldi P, Binetruy B, Slukvin II, Ladoux A, Dani C (2016a) Brown-like adipose progenitors derived from human induced pluripotent stem cells: identification of critical pathways governing their adipogenic capacity. Sci Rep 6:32490Google Scholar
  10. Hafner A-L, Mohsen-Kanson T, Dani C (2016b) A protocol for the differentiation of brown adipose progenitors derived from human induced pluripotent stem cells at a high efficiency with no gene transfer. Nat Protocol Exchange. Doi:  https://doi.org/10.1038/protex.2016.067
  11. Hebert TL, Wu X, Yu G, Goh BC, Halvorsen YD, Wang Z, Moro C, Gimble JM (2009) Culture effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on cryopreserved human adipose-derived stromal/stem cell proliferation and adipogenesis. J Tissue Eng Regen Med 3:553–561Google Scholar
  12. Holmstrom TE, Mattsson CL, Falting JM, Nedergaard J (2008) Differential signalling pathways for EGF versus PDGF activation of Erk1/2 MAP kinase and cell proliferation in brown pre-adipocytes. Exp Cell Res 314:3581–3592Google Scholar
  13. Horvath P, Aulner N, Bickle M, Davies AM, Nery ED, Ebner D, Montoya MC, Ostling P, Pietiainen V, Price LS, Shorte SL, Turcatti G, von Schantz C, Carragher NO (2016) Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 15:751–769Google Scholar
  14. Kim B, Choi KM, Yim HS, Lee MG (2013) Ascorbic acid enhances adipogenesis of 3T3-L1 murine preadipocyte through differential expression of collagens. Lipids Health Dis 12:182Google Scholar
  15. Lindroos J, Husa J, Mitterer G, Haschemi A, Rauscher S, Haas R, Groger M, Loewe R, Kohrgruber N, Schrogendorfer KF, Prager G, Beck H, Pospisilik JA, Zeyda M, Stulnig TM, Patsch W, Wagner O, Esterbauer H, Bilban M (2013) Human but not mouse adipogenesis is critically dependent on LMO3. Cell Metab 18:62–74Google Scholar
  16. Liu X, Wang S, You Y, Meng M, Zheng Z, Dong M, Lin J, Zhao Q, Zhang C, Yuan X, Hu T, Liu L, Huang Y, Zhang L, Wang D, Zhan J, Jong Lee H, Speakman JR, Jin W (2015) Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 156:2461–2469Google Scholar
  17. Liu C, Huang K, Li G, Wang P, Liu C, Guo C, Sun Z, Pan J (2017) Ascorbic acid promotes 3T3-L1 cells adipogenesis by attenuating ERK signaling to upregulate the collagen VI. Nutr Metab (Lond) 14:79Google Scholar
  18. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508Google Scholar
  19. Milet C, Bleher M, Allbright K, Orgeur M, Coulpier F, Duprez D, Havis E (2017) Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice. Sci Rep 7:16153Google Scholar
  20. Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S (2016) Human “brite/beige” adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 22:312–318Google Scholar
  21. Mohsen-Kanson T, Hafner AL, Wdziekonski B, Takashima Y, Villageois P, Carriere A, Svensson M, Bagnis C, Chignon-Sicard B, Svensson PA, Casteilla L, Smith A, Dani C (2014) Differentiation of human induced pluripotent stem cells into brown and white adipocytes: role of Pax3. Stem Cells 32:1459–1467Google Scholar
  22. Nishio M, Yoneshiro T, Nakahara M, Suzuki S, Saeki K, Hasegawa M, Kawai Y, Akutsu H, Umezawa A, Yasuda K, Tobe K, Yuo A, Kubota K, Saito M, Saeki K (2012) Production of functional classical brown adipocytes from human pluripotent stem cells using specific hemopoietin cocktail without gene transfer. Cell Metab 16:394–406Google Scholar
  23. Nishizawa M, Chonabayashi K, Nomura M, Tanaka A, Nakamura M, Inagaki A, Nishikawa M, Takei I, Oishi A, Tanabe K, Ohnuki M, Yokota H, Koyanagi-Aoi M, Okita K, Watanabe A, Takaori-Kondo A, Yamanaka S, Yoshida Y (2016) Epigenetic variation between human induced pluripotent stem cell lines is an Indicator of differentiation capacity. Cell Stem Cell 19:341–354Google Scholar
  24. Orlova VV, van den Hil FE, Petrus-Reurer S, Drabsch Y, Ten Dijke P, Mummery CL (2014) Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells. Nat Protoc 9:1514–1531Google Scholar
  25. Ortmann D, Vallier L (2017) Variability of human pluripotent stem cell lines. Curr Opin Genet Dev 46:179–185Google Scholar
  26. Petrenko Y, Sykova E, Kubinova S (2017) The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids. Stem Cell Res Ther 8:94Google Scholar
  27. Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109:656–663Google Scholar
  28. Sanchez-Gurmaches J, Guertin DA (2013) Adipocyte lineages: tracing back the origins of fat. Biochim Biophys Acta 1842:340–351Google Scholar
  29. Shi Y, Inoue H, Wu JC, Yamanaka S (2016) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16:115–130Google Scholar
  30. Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T, Okada K, Shiba N, Sakamoto K, Ido D, Shiina T, Ohkura M, Nakai J, Uno N, Kazuki Y, Oshimura M, Minami I, Ikeda U (2016) Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538:388–391Google Scholar
  31. Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215–223Google Scholar
  32. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872Google Scholar
  33. Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, Zhang RR, Ueno Y, Zheng YW, Koike N, Aoyama S, Adachi Y, Taniguchi H (2013) Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499:481–484Google Scholar
  34. Taura D, Noguchi M, Sone M, Hosoda K, Mori E, Okada Y, Takahashi K, Homma K, Oyamada N, Inuzuka M, Sonoyama T, Ebihara K, Tamura N, Itoh H, Suemori H, Nakatsuji N, Okano H, Yamanaka S, Nakao K (2009) Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells. FEBS Lett 583:1029–1033Google Scholar
  35. Villarroya F, Gavalda-Navarro A, Peyrou M, Villarroya J, Giralt M (2017) The lives and times of brown adipokines. Trends Endocrinol Metab 28:855–867Google Scholar
  36. Zhang J, Zhang Y, Sun T, Guo F, Huang S, Chandalia M, Abate N, Fan D, Xin HB, Chen YE, Fu M (2013) Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2. Sci Rep 3:1476Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculté de MédecineUniversité Nice Sophia Antipolis, iBV, UMR CNRS/INSERMNiceFrance

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