TIMP-1 Modulates Chemotaxis of Human Neural Stem Cells Through CD63 and Integrin Signaling

In this study, we used microarray and proteomics analyses to identify a novel chemoattractant molecule, tissue inhibitor of metalloproteinase-1 (TIMP-1), secreted from human brain tumor tissues. We demonstrate that TIMP-1 significantly enhances hNSC adhesion and migration in a cell culture system. These effects were critically dependent on CD63, as short hairpin RNA-mediated ablation of CD63 expression attenuated the response. TIMP-1 significantly increased the number of focal adhesions (FAs) and cytoskeletal reorganization for cell migration in hNSCs, whereas knockdown of CD63 resulted in decreased hNSC spreading, FAs, and migration, even after TIMP-1 treatment. In addition, TIMP-1 binding to CD63 activated b1 integrin-mediated signaling through Akt and FAK phosphorylation, leading to pattern changes in distribution of vinculin and F-actin. Furthermore, inactivation of b1 integrin by use of a blocking antibody, or inhibition of phosphoinositide 3-kinase (PI3K) signaling impaired the migration of hNSCs toward TIMP-1. Collectively, our results underline TIMP-1 as a novel and effective key regulator of CD63 and b1 integrin-mediated signaling, which regulates hNSC adhesion and migration.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research