TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma
Résumé
Bone marrow-derived human mesenchymal stem cells (hMSCs) have become valuable candidates for cell-based therapeutical applications including neuroregenerative and anti-tumor strategies. Yet, the molecular mechanisms that control hMSC transdifferentiation to neural cells and hMSC tropism toward glioma remain unclear. Here, we demonstrate that hMSCs incubated with 50 ng/ml TNF-α acquired astroglial cell morphology without affecting proliferation which was increased at 5 ng/ml. TNF-α (50 ng/ml) upregulated expression of numerous genes important for neural cell growth and function including LIF, BMP2, SOX2, and GFAP, whereas NES transcription ceased suggesting a premature neural phenotype in TNF-α-differentiated hMSCs. Studies on intracellular MAPK signaling revealed that inhibition of ERK1/2 activity abolished the TNF-α-mediated regulation of neural genes in hMSCs. In addition, TNF-α significantly enhanced expression of the chemokine receptor CXCR4 which facilitated the chemotactic invasiveness of hMSCs toward SDF-1alpha. TNF-α-pretreated hMSCs not only exhibited an increased ability to infiltrate glioma cell spheroids dependent on matrix metalloproteinase activity in vitro, but they also showed a potentiated tropism toward intracranial malignant gliomas in an in vivo mouse model. Taken together, our results provide evidence that culture-expansion of hMSCs in the presence of TNF-α triggers neural gene expression and functional capacities which could improve the use of hMSCs in the treatment of neurological disorders including malignant gliomas.
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