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Enhanced ASC-mediated Cell Therapies via Klotho

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Review of “The Antiaging Gene Klotho Regulates Proliferation and Differentiation of Adipose-Derived Stem Cells” from Stem Cells by Stuart P. Atkinson

Adipose stem cells (ASCs) are an abundant and therapeutically useful cell type with regards to their multi-lineage differentiation potential. A deeper understanding of the mechanisms which mediate ASC stemness and differentiation may help to build more effective therapies. 

With this in mind, researchers from the laboratory of Zhongjie Sun (University of Oklahoma Health Sciences Center (OUHSC), USA) have been studying the role of Klotho (or SKL) gene, an aging-suppressor gene linked to lifespan extension in mice [1], in the proliferation and adipogenic differentiation of ASCs. The authors hope that their findings may be useful in the development of enhanced ASC-mediated cell therapies [2].

The study employed a Klotho knockout mouse [3] which, compared to wild type control, contained significantly less adipose tissue. Isolated ASCs had a senescent morphology, decreased proliferative rate, and expressed lower levels of stem cell factors (including Nanog, Sox-2, and Oct-4) as compared to wild-type ASCs which expressed Klotho mRNA and protein. Additionally, the authors found a decrease in the adipogenic (as well as osteogenic and myofibroblastic) differentiation potential of Klotho KO ASCs (See attached figure). Further studies suggested that SKL loss mediates an increase in TGF-β1 expression and phosphorylated-Smad2/3 levels, which may promote the loss of the stem cell-characteristics of ASCs, as descried in other studies [4, 5], and a loss of PPAR activity, which mediates adipocyte differentiation.

This study, for the first time, correlates Klotho gene expression to the normal proliferation and differentiation capacity of ASCs. This finding could contribute to strategies to enhance the long-term in vitro cultivation of ASCs without cell senescence [6] and thereby enhanced ASC-mediated cell therapies for multiple diseases/disorders.

References

  1. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-1833.
  2. Fan J and Sun Z The Antiaging Gene Klotho Regulates Proliferation and Differentiation of Adipose-Derived Stem Cells. STEM CELLS 2016;34:1615-1625.
  3. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51.
  4. Kim YJ, Hwang SJ, Bae YC, et al. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue. Stem Cells 2009;27:3093-3102.
  5. Park JG, Lee DH, Moon YS, et al. Reversine increases the plasticity of lineage-committed preadipocytes to osteogenesis by inhibiting adipogenesis through induction of TGF-beta pathway in vitro. Biochem Biophys Res Commun 2014;446:30-36.
  6. Mantovani C, Terenghi G, and Magnaghi V Senescence in adipose-derived stem cells and its implications in nerve regeneration. Neural Regen Res 2014;9:10-15.