Brown-Like Adipocyte Progenitors Derived from Human iPS Cells: A New Tool for Anti-obesity Drug Discovery and Cell-Based Therapy?
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.
KeywordsAdipocyte progenitors Brown adipocytes Cell-based therapy Drug discovery Human-induced pluripotent stem cells Obesity
- 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 14:209–219CrossRefGoogle Scholar
- 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 19:635–639CrossRefGoogle Scholar
- 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 6:32490CrossRefGoogle Scholar
- 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
- 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 3:553–561CrossRefGoogle Scholar
- 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 18:62–74CrossRefGoogle Scholar
- 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 22:312–318CrossRefGoogle Scholar
- 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 32:1459–1467CrossRefGoogle Scholar
- 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 16:394–406CrossRefGoogle Scholar
- 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 19:341–354CrossRefGoogle Scholar
- 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 109:656–663CrossRefGoogle Scholar
- 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 538:388–391CrossRefGoogle Scholar
- 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 583:1029–1033CrossRefGoogle Scholar