Recruitment of mesenchymal stem cells to injury sites

Abstract

Systemic administration of mesenchymal stem cells (MSC) has been shown to be efficacious in ameliorating disease conditions in animal models and clinical trials. However the mechanism underlying MSC homing to injury sites has not been fully elucidated. This study aims to investigate the factors which may play a role in MSC homing and migration to injury sites. The homing mechanism of MSC is hypothesized to be similar to that of leukocyte recruitment, a multi-step process involving a number of factors. Our study showed that MSC responded positively in an in vitro transwell assay to platelet-derived growth factor AB (PDGF-AB), a growth factor secreted by activated platelets found in injury sites. However, in the presence of TNFa, the response of MSC to PDGF-AB was inhibited. Pre-treating MSC with TNFa for 24 hours not only rescues this inhibition but also enhanced both MSC basal migratory capabilities and their response towards PDGF-AB. Next, we showed that VLA4 (a4?1 integrin) expressed on MSC mediates interaction with endothelial cells under defined flow conditions. However, TNFa pre-treatment of MSC inhibited the MSC-endothelial interactions unlike the enhancement seen in migration. This was inconsistent with published studies showing that TNFa pre-treated MSC had increased homing capacity in animal models. However, FACS analysis of TNFa treated MSC did not reveal any change in expression of surface adhesion molecules with the exception of ICAM-1 and VCAM-1. Hence, we asked if the presence of immune cells that were recruited to injury sites could an explanation to the findings in the literature. We manage to rescue this inhibition by introducing fresh monocytes but not neutrophils v into the flow chamber together with the TNFa pre-treated MSC. During the assay, MSC were observed to interact physically with the monocytes. Unlike monocytes, matured neutrophils lack VLA4 expression. Therefore, these MSC-monocyte interactions were likely to be between VLA4 expressed on monocytes and VCAM-1 expressed on TNFa pre-treated MSC. These data collectively suggest the involvement of PDGF-AB, monocytes in MSC recruitment and the potential role of TNFa in mediating the cross-talk between various cell-types and soluble mediators present within injury sites.