Trichostatin A Induces Both Cell Division Arrest and Neural-linage Differentiation of the Mesenchymal Stem Cells Possibly by Triggering Wnt/β-Catenin Signaling

Ntroduction: The bone marrow-derived mesenchymal stem cells (BM-MSC), with active proliferation and pluripotent differentiation abilities, present an ideal source of cell transplant therapy. It remains obscure, but, how to promote their neural-linage differentiation efficiently and controlling moderate proliferation for clinical application in neurological diseases. Methods: By in vitro culture of rat BM-MSC, regulation of a histone deacetylase inhibitor trichostatin A (TSA) in both cell proliferation and neural-linage cell commitment, and possible involvement of Wnt/β-catenin signaling pathway in TSA-inducing biological effect were examined in this study. Results: By cell count and flowcytometry, TSA exhibited cell division or cycle arrest of BM-MSC at doses above 10ng/ml by increased percentage of G1/S phase and apoptotic cells. Immunocytochemistry and immunoblot revealed promotion effect of TSA on neuronal cell differentiation with appearance of neuron-like ones and increased nestin and Tuj-1 expression in BM-MSC treated with TSA at dose of 100 and 500ng/ml. Enhanced glial cell differentiation was also observed by upregulation of NG2, glial fibrillary acidic protein and CNPase expression in BM-MSC with TSA treatment dose-dependently. Furthermore, significant activation of Wnt/β-catenin signaling was detected in TSA-treated BM-MSC, while Wnt signaling inhibitor IWR1 impeded above TSA-induced effects on BM-MSC. Conclusion: This study has provided new evidence that TSA could induce neural-linage differentiation and cell division arrest of BM-MSC dose-dependently by triggering Wnt/β-catenin signaling activation, suggesting that TSA may be applied as a candidate drug in manipulation of MSC therapy for the treatment of various neurological disorders.