Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs

Abstract

Mesenchymal stem cells (MSCs) have been shown to be perivascular, occupying a prime location for regulating vessel stability. Here, we focused on the MSC-contribution of key regulators of the perivascular niche, the matrix metalloproteinases (MMPs) and their inhibitors, the TIMPs. Despite secretion of active forms of MMPs by MSCs, MMP enzyme activity was not detected in MSC-conditioned medium (MSC-CM) due to TIMP-mediated inhibition. By means of bifunctional-crosslinking to probe endogenous MMP:TIMP interactions, we showed MMP-2-inhibition by TIMP-2. MSCs also inhibited high levels of exogenous MMP-2 and MMP-9 through TIMP-2 and TIMP-1, respectively. Furthermore, MSC-CM protected vascular matrix molecules and endothelial cell structures from MMP-induced disruption. MSCs remained matrix-protective when exposed to pro-inflammatory cytokines and hypoxia, countering these stresses with increased TIMP-1 expression and augmented MMP-inhibition. Thus, MSCs are revealed as robust sources of TIMP-mediated MMP-inhibition, capable of protecting the perivascular niche from high levels of MMPs even under pathological conditions.