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Improving Beige Adipocyte Differentiation Potential of ASCs to Fight Metabolic Disorders

Review of "Cell immaturity and white/beige adipocyte-potential of primary human adipose-derived stromal cells are restrained by culture-medium TGFβ1" from STEM CELLS by Stuart P. Atkinson

Beige adipocytes derived from subcutaneous adipose tissue have shown great potential in the prevention of metabolic diseases such as obesity and type 2 diabetes in animal models [1, 2]; therefore, the differentiation of human adipose-derived mesenchymal stem cells (ASCs) into beige adipocytes remains of considerable clinical interest [1, 3]. The thorough optimization of culture conditions for ASC maintenance and amplification represents one of the most crucial steps towards this goal.

In their recent STEM CELLS article, researchers led by Louis Casteilla, Frédéric Deschaseaux, and Hélène Leménager (University of Toulouse, France) compared and contrasted ASC culture under standard expansion medium (containing 10% fetal bovine serum [FBS]) with endothelial cell growth medium 2 (EGM2). Importantly, EGM2-medium was previously designed for the culture of endothelial and perivascular cells, a physiological location common to ASCs [4-7], and so this media may provide optimal conditions for enhanced ASC differentiation into beige adipocytes. Fascinatingly, Leménager et al. now highlight the alternate use of EGM2 for ASC maintenance, expansion, and beige adipocyte differentiation and highlight the crucial role of transforming growth factor β1 (TGFβ1) signaling in this process [8].

A comparison of ASCs grown using both media suggested that exposure to endothelial cell medium provided ASCs with enhanced multipotentiality and an immature phenotype, as evidenced by the expression of pluripotency-associated genes, when compared to cells cultured with standard ASC culture medium. Importantly, growth in endothelial cell medium also endowed ASCs with the increased potential to differentiate into beige adipocytes. Meanwhile, standard conditions seem to prime ASCs for commitment toward osteoblast, chondroblast, and vascular smooth muscle cell lineages at the expense of their adipogenic potential and the authors link this commitment to induced TGFβ1 signaling in standard ASC culture, as evidenced by small mother of decapentaplegic homolog 3 (SMAD3) nuclear localization and phosphorylation.

With this in mind, the study next pharmacologically inhibited the TGFβ1 receptor during standard ASC culture, discovering that this strategy prompted the retention of SMAD3 in the cytoplasm, decreased the expression of osteoblast and vascular smooth muscle cell gene markers, and counteracted the priming of ASCs for osteoblast, chondroblast, and vascular smooth muscle cell lineage differentiation. Furthermore, TGFβ1 inhibition endowed ASCs with a more immature phenotype and a more robust beige adipocyte differentiation potential.

Overall, the authors find that EGM2-containing endothelial cell media may represent a more efficient culture tool for ASC expansion and highlight the importance of inhibiting TGFβ1 signaling to the maintenance of ASC immaturity and the formation of beige adipocytes. Overall, the team hopes that their new findings will help to translate the treatment of metabolic diseases with ASC-derived beige adipocytes from animal models into clinical translation.

For more on ASC culture and the therapeutic promise of beige adipocytes, stay tuned to the Stem Cells Portal!

References

  1. Min SY, Kady J, Nam M, et al., Human 'Brite/Beige' Adipocytes Develop from Capillary Networks, and their Implantation Improves Metabolic Homeostasis in Mice. Nature Medicine 2016;22:312-318.
  2. Yadav H, Quijano C, Kamaraju Anil K, et al., Protection from Obesity and Diabetes by Blockade of TGF-β/Smad3 Signaling. Cell Metabolism 2011;14:67-79.
  3. Rosenwald M, Perdikari A, Rülicke T, et al., Bi-directional Interconversion of Brite and White Adipocytes. Nature Cell Biology 2013;15:659-667.
  4. Tang W, Zeve D, Suh JM, et al., White Fat Progenitor Cells Reside in the Adipose Vasculature. Science 2008;322:583.
  5. Crisan M, Yap S, Casteilla L, et al., A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs. Cell Stem Cell 2008;3:301-313.
  6. Long Jonathan Z, Svensson Katrin J, Tsai L, et al., A Smooth Muscle-Like Origin for Beige Adipocytes. Cell Metabolism 2014;19:810-820.
  7. Tran K-V, Gealekman O, Frontini A, et al., The Vascular Endothelium of the Adipose Tissue Gives Rise to Both White and Brown Fat Cells. Cell Metabolism 2012;15:222-229.
  8. Leménager H, Fiévet LMA, Guilloton F, et al., Cell Immaturity and White/Beige Adipocyte Potential of Primary Human Adipose-derived Stromal Cells are Restrained by Culture-medium TGFβ1. STEM CELLS 2020;38:782-796.