LAUSR

ABSTRACT Adult mesenchymal stem cells play an important role in maintaining organ homeostasis owing to their unique ability to generate more specialized cell populations in a coordinated manner. Adult mesenchymal stem cells are heterogeneous, a feature that is essential for their functions. However, studies have not elucidated how heterogeneity of mesenchymal stem cells affects their differentiation capacity. The current study thus explored the heterogeneous Dental Follicle Stem Cells (DFSCs). A previous study by our research group reported that selecting sub-clones can cause artificial damage of the heterogeneous microenvironment of DFSCs. The finds showed a decrease in differentiation capacity of the three subclones, although the underlying mechanism was not elucidated. In this study, cells were harvested and prepared for gene expression microarray analysis. Sequence data was used in gene ontology and pathway enrichment analysis. The results showed that downregulation of the TGF-β signaling pathway was the main cause of changes in differentiation of sub-clones. Additional analyses revealed that the Hippo pathway, WNT pathway and signaling pathways regulating the pluripotency of stem cells were also implicated in these changes, through a cross talk with TGF-β signaling pathway through Bmp2, Bmp4, and Bambi. In vivo implantation experiments and osteogenic induction showed that differentiation capacity of DFSCs was significantly reduced in the sub-clones. In summary, the findings of the current study show that differentiation potential of DFSCs is correlated with the heterogeneous microenvironment and TGF-β signaling pathway significantly modulates these biological processes. GRAPHICAL ABSTRACT