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Fungal Metabolite Boosts ASC Osteogenesis and Skeletal Regenerative Strategies

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Review of “Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Their relative abundance, ease of collection, and mesenchymal characteristics make adipose-derived stem cells (ASCs) an attractive cell type for incorporation into a wide range of regenerative strategies. However, while bone-marrow mesenchymal stem cells (BM-MSCs) can readily differentiate into skeletal tissues such as bone and cartilage [1, 2], ASCs exhibit a more muted osteogenic capacity.

This lack of activity prompted researchers from the laboratory of Andre van Wijnen (Mayo Clinic, Rochester, Minnesota, USA) to search for strategies to elevate levels of osteogenesis in ASCs. In their new STEM CELLS Translational Medicine article, Samsonraj et al. demonstrate that the actin-cytoskeleton modifying fungal metabolite cytochalasin D (CytoD) [3] efficiently promotes the osteogenic potential of ASCs, thereby boosting the potential of ASC-mediated skeletal regenerative strategies [4].

Initial assessments suggested that CytoD promoted the osteogenic differentiation of ASCs by redistributing the intracellular location of β-actin and blocking cytoplasmic actin polymerization, as indicated by significant increases in alkaline phosphatase activity, extracellular matrix mineralization, and osteoblast-related gene expression. Interestingly, the authors also discovered that early changes in ASCs exposed to CytoD included not only alterations to osteogenic biomarkers but also significant changes in the levels of epigenetic regulators. 

At the epigenetic level, CytoD treatment led to a decrease in repressive H3K27me3 histone modification levels due to the reduced expression of the Polycomb chromatin regulator Enhancer of Zeste Homolog 2 (EZH2), suggesting that the osteogenesis of ASCs requires a more permissive chromatin environment on a genome-wide scale. Indeed, the authors discovered that the CytoD-mediated reduction in H3K27me3 levels led to an increase in the expression of the architectural bone-specific transcription factor RUNX2 and likely permitted the expression of a wide-range of osteogenic genes.

Overall, this exciting new study suggests that pretreatment of ASCs with the fungal metabolite CytoD may represent an efficient means to elevate the naturally low levels of ASC osteogenesis to a therapeutically relevant level, thereby boosting the potential of ASC-mediated skeletal regenerative strategies

For more on ASCs, osteogenesis, and epigenetics, stay tuned to the Stem Cells Portal!

References

  1. Marmotti A, de Girolamo L, Bonasia DE, et al., Bone marrow derived stem cells in joint and bone diseases: a concise review. Int Orthop 2014;38:1787-801.
  2. Hermida-Gomez T, Fuentes-Boquete I, Gimeno-Longas MJ, et al., Bone marrow cells immunomagnetically selected for CD271+ antigen promote in vitro the repair of articular cartilage defects. Tissue Eng Part A 2011;17:1169-79.
  3. Sen B, Xie Z, Uzer G, et al., Intranuclear Actin Regulates Osteogenesis. STEM CELLS 2015;33:3065-3076.
  4. Samsonraj RM, Dudakovic A, Manzar B, et al., Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2. STEM CELLS Translational Medicine 2018;7:197-209.