Induced pluripotent stem cells (iPSCs) possess the potential to differentiate into neural lineage cells. Matrix metalloproteinase 2 (MMP2), an endopeptidase in the extracellular matrix, has been shown to protect neural cells from injury. However, the mechanisms and effects of MMP2 on neural differentiation of iPSCs remain poorly understood. Here, we demonstrated a role for MMP2 in the differentiation of iPSCs to neurons via the AKT pathway. Treatment of iPSCs with MMP2 promoted their proliferation and differentiation into neural stem cells (NSCs), and then into neurons. The transcript and protein expression of Nestin and microtubule-associated protein 2 (MAP2) increased. Moreover, MMP2 markedly induced the expression of phospho-AKT (pAKT) during these differentiation stages. Consistently, silencing MMP2 using siRNA attenuated the expression of Nestin, MAP2 and pAKT, compared with the control group. In addition, the increasing levels of Nestin, MAP2 and pAKT in the MMP2 group were declined by pretreatment with the phosphoinositide 3-kinase (PI3K)/AKT inhibitor, LY294002. Furthermore, the study detected that TrkA and TrkB were perhaps the potential receptors for these effects of MMP2 on neural differentiation through PI3K/AKT signaling pathway. Taken together, these results suggest that MMP2 induces the differentiation of iPSCs into neurons by regulating the AKT signaling pathway. (C) 2017 Elsevier B.V. All rights reserved.