Edited by Ned Mantei
Keywords:Mesenchymal stem cell Laminin-1 Neurite outgrowth MAPK PI3K/Akt c-Jun/AP-1 a b s t r a c tIn this study, we demonstrated that laminin-1 (LM-1) induces neurite outgrowth and enhances the expression of neurofilament-L and MAP2 in human bone marrow mesenchymal stem cells (MSCs). The c-Jun transcription factor was strongly activated by LM-1 during neurite induction. Suppression of c-Jun inhibited the expression of the c-Jun target genes a6 integrin and neurofilament-L, resulting in the loss of neurite outgrowth. Additionally, we found that the LM-1-a6 integrin interaction stimulated phosphorylation of FAK, leading to the activation of JNK and Akt. Pharmacological inhibition of these pathways blocked c-Jun activation and neurite outgrowth. Collectively, our findings suggest that c-Jun/AP-1 activity mediated by JNK, PI3K/Akt and ERK pathways is required for LM-1-induced neurite outgrowth in human bone marrow MSCs.
The mechanisms underlying the differentiation of Mesenchymal stem cells (MSCs) toward neuronal cell type are not clearly understood. Earlier, we reported that laminin-1 induces neurite outgrowth in human MSCs via c-Jun/AP-1 activation through ERK, JNK, and Akt pathways. In this study, we demonstrate that laminin-1 increases the expression of proneural gene, neuroD1 and induces the expression of immediate-early biomarkers of neuronal cell-programming-Egr1, Egr3, PC3, and PC4. Gene expression profiling of MSCs cultured on laminin-1 and Poly-l-lysine for 12 h revealed differential regulation of 267 genes (>1.5 fold, p < 0.05), predominantly in the category of nervous system development and affected the pathways involved in TGF-β/TNF-α signaling, regulation of MAPK and JNK cascade. Data for 11 selected genes related to nervous system development was validated by real time PCR. Transcriptional regulatory network analysis revealed c-Jun as the key transcription factor regulating majority of differentially expressed genes and identified Disrupted in schizophrenia 1, as a novel target of c-Jun. Modeling and analysis of biological network showed selective induction of Growth Arrest and DNA damage 45 (GADD45B) and repression of NF-κB inhibitor A (NFκBIA). Collectively, our findings provide the basis for understanding the molecular mechanisms associated with laminin-1-induced neurogenic expression in MSCs.
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