Human Bone Marrow-Derived Mesenchymal Stem Cells Home via the PI3K-Akt, MAPK, and Jak/Stat Signaling Pathways in Response to Platelet-Derived Growth Factor.

Abstract

Mesenchymal stem cells (MSCs) have great potential to improve clinical outcomes for many inflammatory and degenerative diseases either through intravenously delivered MSCs or through mobilization and migration of endogenous MSCs to injury sites, termed "stem cell homing." Stem cell homing involves the processes of attachment to and transmigration through endothelial cells lining the vasculature and migration through the tissue stroma to a site of injury or inflammation. Although the process of leukocyte transendothelial migration (TEM) is well understood, far less is known about stem cell homing. In this study, a transwell-based model was developed to monitor adherence and TEM of human MSCs in response to chemokine exposure. Specifically, transwell membranes lined with human synovial microvascular endothelial cells were partitioned from the tissue injury-mimetic site containing chemokine stromal cell-derived factor-1 (SDF-1). Two population subsets of MSCs were studied: migratory cells that initiated transmigration on the endothelial lining and nonmigratory cells. We hypothesized that cells would adhere to and migrate through the endothelial lining in response to SDF-1 exposure and that gene and protein expression changes would be observed between migratory and nonmigratory cells. We validated a vasculature model for MSC transmigration that showed increased expression of several genes and activation of proteins of the PI3K-Akt, MAPK, and Jak/Stat signaling pathways. These findings showed that MSC homing may be driven by activation of PDGFRA/PI3K/Akt, PDGFRA/MAPK/Grb2, and PDGFRA/Jak2/Stat signaling, as a result of SDF-1-stimulated endothelial cell production of platelet-derived growth factor. This model can be used to further investigate these key regulatory molecules toward the development of targeted therapies.