Mesenchymal stem cells (MSCs) can be differentiated into cell types derived from all three germ layers by manipulating culture conditions in vitro. A multitude of growth and differentiation factors have been employed for driving MSCs towards a neuronal phenotype In the present Study, we investigated the potential of extracellular matrix (ECM) proteins-fibronectin. collagen-1. collagen-IV, laminin-1, and laminin-10/11. to induce a neuronal phenotype in bone marrow derived human MSCs in the absence of growth factors/differentiating agents. All of the ECM proteins tested were found to support adhesion of MSCs to different extents However. direct interaction only with laminin-1 triggered sprouting of neurite-like processes. Cells plated on laminin-1 exhibited neurite Out growth as early as 3 h, and by 24 h, the cells developed elaborate neurites with contracted cell bodies and neuronal-like morphology Function-blocking antibodies directed against alpha 6 and beta 1 integrin subunits inhibited neurite formation on laminin-1 which confirmed the involvement of integrin alpha 6 beta 1 in neurite outgrowth Mechanistic studies revealed that cell adhesion to laminin-1 activated focal adhesion kinase (FAK), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways Abrogation of FAK phosphorylation by herbimycin-A inhibited neurite formation and also decreased activities of MEK and ERK. Pharmacological inhibitors of MEK (U0126) and ERK (PD98059) also blocked neurite Outgrowth in cells plated on laminin-1. Our study demonstrates the involvement of integrin alpha 6 beta 1 and FAK-MEK/ERK signaling pathways in laminin-1-induced neurite outgrowth in MSCs in the absence of serum and differentiation factors (C) 2009 Elsevier Inc All rights reserved