Matrix metalloproteinase‐1 facilitates MSC migration via cleavage of IGF‐2/IGFBP2 complex

Abstract

The specific mechanism underlying the tumor tropism of human mesenchymal stem cells (MSCs) for cancer is not well defined. We previously showed that the migration potential of MSCs correlated with the expression and protease activity of matrix metalloproteinase (MMP)‐1. Furthermore, highly tumor‐tropic MSCs expressed higher levels of MMP‐1 and insulin‐like growth factor (IGF)‐2 than poorly migrating MSCs. In this study, we examined the functional roles of IGF‐2 and MMP‐1 in mediating the tumor tropism of MSCs. Exogenous addition of either recombinant IGF‐2 or MMP‐1 could stimulate MSC migration. The correlation between IGF‐2, MMP‐1 expression, and MSC migration suggests that MMP‐1 may play a role in regulating MSC migration via the IGF‐2 signaling cascade. High concentrations of IGF binding proteins (IGFBPs) can inhibit IGF‐stimulated functions by blocking its binding to its receptors and proteolysis of IGFBP is an important mechanism for the regulation of IGF signaling. We thus hypothesized that MMP‐1 acts as an IGFBP2 proteinase, resulting in the cleavage of IGF‐2/IGFBP2 complex and extracellular release of free IGF‐2. Indeed, our results showed that conditioned media from highly migrating MSCs, which expressed high levels of MMP‐1, cleaved the IGF‐2/IGFBP2 complex. Taken together, these results showed that the MMP‐1 secreted by highly tumor‐tropic MSCs cleaved IGF‐2/IGFBP2 complex. Free IGF‐2 released from the complex may facilitate MSC migration toward tumor.

Lineage Commitment, Signaling Pathways, and the Cytoskeleton Systems in Mesenchymal Stem Cells

“…123 To accomplish the whole process, MSCs rearrange their cytoskeleton through the activation or RhoA 124 and express different types of metalloproteinases in response to chemokine stimulation. 125,126 MSCs could also be recruited to the tumor loci, where they differentiate and support the tumor growth. 93,127 In vitro breast cancer, fibrosarcoma, and glioma cells recruit MSCs by releasing FGF.…”

Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells

“…MMPs are major regulators of cell migration that do not only act by turnover of extracellular matrix (ECM) proteins but also by affecting growth factors, cytokines, chemokines, and surface proteins [ 65 , 166 , 167 , 168 , 169 , 170 ]. Expression of MMP-1 and MMP-2 has been shown to be essential for the migration of MSCs [ 129 , 171 , 172 , 173 , 174 ]. MCP-3 and HB-EGF were identified as chemotactic factors [ 175 , 176 ], and secretion of MCP-1 by MSCs was described with regard to their enhanced migration [ 177 ].…”

Lin28B regulates the fate of grafted mesenchymal stem cells and enhances their protective effects against Alzheimer's disease by upregulating IGF‐2

“…We also found that the proliferation/promigration effects of lin28B on MSCs were mediated by the lin28B/IGF-2 signaling pathway, as these effects were abolished when IGF-2 was inhibited genetically. IGF-2, which is a member of the insulin family of polypeptide growth factors, has been shown to be relevant to the regulation of MSC proliferation, migration, and differentiation (Guan et al, 2018;Youssef, Aboalola, & Han, 2017). A previous study reported that lin28A was capable of directly binding to IGF-2 mRNA and increasing its translation efficiency in differentiating muscle cells (Polesskaya et al, 2007).…”