The extracellular matrix (ECM) plays many critical roles including supplying information and signals to the surrounding cells and providing structural support [1]. There are some molecules that are secreted by cells into the ECM to control different biological activities at the tissue or cellular level. Matrix metalloproteinases (MMPs) are among the key molecules that regulate different molecular and biological events in the ECM. MMPs are a family of zinc-dependent proteolytic enzymes involved in the degradation of ECM components. MMPs were firstly named based on their substrates, until it became clear that each MMP has multiple substrates. Therefore, MMPs were classified into different groups based on their domain structure, and the nomenclature was changed to a numerical system [2]. MMPs are classified into several subgroups based on their substrate preference or domain structure. Collagenases (MMP-1, MMP-8, MMP-13, and MMP-18) cleave fibrillar collagen types I, II, and III, and they can cleave other ECM proteins. Gelatinases (MMP-2 and MMP-9) have high activity against gelatin, and degrade other ECM molecules including collagens, laminin, and aggrecan. Stromelysins (MMP-3, MMP-10, and MMP-11) digest a number of noncollagen ECM molecules, and their domain arrangement is similar to that of collagenases. The membrane-type MMPs (MT-MMPs) (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25) are intracellularly activated transmembrane molecules, and their active forms are expressed on the cell surface. There are other less characterized members including MMP-7, MMP-12, MMP-19, MMP-20, MMP-22, and MMP-23 [3]. Most of the MMPs contain the single peptide, prodomain, catalytic domain, hinge domain, and hemopexin domain. The MT-MMPs have an extra domain called the transmembrane domain or GPI-anchored domain, which are integrated in the plasma membrane [2].

MMPs are important in a wide variety of developmental processes including mediation of cell–cell adhesion, tissue remodeling, cell migration, invasion, proliferation, and apoptosis [3]. MMPs can cleave growth factor binding proteins or latent growth factors which may regulate their synthesis and release from inside the cell [4, 5]. They are regulated by several MMP-specific inhibitors called tissue-specific inhibitors of metalloproteinases (TIMPs) [4, 5]. MMPs and TIMPs have a very critical role in matrix remodeling that takes place during the regeneration of any tissue [4, 5]. The activity and function of MMPs suggest their involvement in different cellular activities during cell development. This fact opens the door to investigate the involvement of these enzymes in the migration, proliferation, and differentiation of mesenchymal stem cells (MSCs).

Regenerative medicine is a promising approach that involves stem cells and microenvironmental factors to stimulate differentiation into different lineages. MSCs have great potential as a source of cells for cell-based therapy because of their ability for self-renewal and differentiation into functional cells. MSCs are adult stem cells of stromal origin that can be found in different biological sources not only in bone morrow, but also in other various tissue sources [6]. They are multipotent cells and are known to migrate from bone morrow to different tissues with different compositions of ECM, which justify the studies to examine their susceptibility to matrix variation [7]. Moreover, it has been demonstrated that MMPs have critical role in the differentiation of MSCs to adipocytes, osteocytes, and chondrocytes [4]. MSCs also interact with exogenous MMPs at their surface and activate proMMP-2 and proMMP-13, regulating the pericellular localization of MMP activities [6]. They have the capability to regulate exogenous MMP-2 and MMP-9 by the expression of TIMP-2 and TIMP-1, protecting the perivascular niche from their high levels [8].

There is increased interest in the use of MSCs as therapeutic tools to treat different diseases because of their ease of isolation, immune capability, expansion, and proliferative and differentiation potency [9]. Recently, the focus of many studies on MSCs is the connection between cells and matrix signals. However, the mechanisms that regulate the proliferation, migration, self-renewal, and differentiation of MSCs are still not fully understood [10]. Identifying the molecules that regulate the fate of MSCs is an important approach to understand how these cells can be controlled and thus used as therapeutic tools. In this study, we critically reviewed the findings on the effect of MMPs in angiogenesis, migration, and proliferation of MSCs. We also reviewed the role of MMPs on the multilineage property of multisource-derived MSCs to differentiate into adipocytes, chondrocytes, and osteocytes.