Migration of Bone Marrow and Cord Blood Mesenchymal Stem Cells In Vitro Is Regulated by Stromal‐Derived Factor‐1‐CXCR4 and Hepatocyte Growth Factor‐c‐met Axes and Involves Matrix Metalloproteinases

TLDR

Human mesenchymal stem cells are increasingly explored for regenerative therapies, yet the signals that guide their homing to injured tissues remain incompletely defined. The study aimed to determine whether the injury‑upregulated factors stromal‑derived factor‑1 (SDF‑1) and hepatocyte growth factor (HGF) can chemoattract bone marrow‑ and cord blood‑derived MSCs expanded ex vivo. To this end, the authors examined CXCR4 and c‑met receptor expression and function, monitored matrix metalloproteinase (MMP) production, and tracked tissue‑specific marker expression in MSCs over 15–18 passages. They found that expanded MSCs retained tissue markers, expressed functional CXCR4 and c‑met, were strongly attracted to SDF‑1 and HGF gradients, expressed MMP‑2 and MT1‑MMP, and invaded Matrigel, supporting a role for the SDF‑1/CXCR4 and HGF/c‑met axes plus MMPs in MSC recruitment.

Abstract

Human mesenchymal stem cells (MSCs) are increasingly being considered in cell-based therapeutic strategies for regeneration of various organs/tissues. However, the signals required for their homing and recruitment to injured sites are not yet fully understood. Because stromal-derived factor (SDF)-1 and hepatocyte growth factor (HGF) become up-regulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSCs derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSCs of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSCs. We also determined whether MSCs express matrix metalloproteinases (MMPs), including membrane type 1 (MT1)-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSCs for up to 15-18 passages with monitoring of the expression of 1) various tissue markers (cardiac and skeletal muscle, neural, liver, and endothelial cells), 2) functional CXCR4 and c-met, and 3) MMPs. We found that for up to 15-18 passages, both BM- and CB-derived MSCs 1) express mRNA for cardiac, muscle, neural, and liver markers, as well as the vascular endothelial (VE) marker VE-cadherin; 2) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients; 3) express MMP-2 and MT1-MMP transcripts and proteins; and 4) are chemo-invasive across the reconstituted basement membrane Matrigel. These in vitro results suggest that the SDF-1-CXCR4 and HGF-c-met axes, along with MMPs, may be involved in recruitment of expanded MSCs to damaged tissues.