Multiplex biomaterial matrix cues regulate redox status and stemness in human mesenchymal stem cells

Abstract

Human mesenchymal stem cells (hMSCs) offer therapeutic potential for clinical applications but exhibit a decline in overall health when isolated from aging patients or serially expanded in vitro. hMSCs have been shown to originate from pericytes, but dissection and clarification of this relationship is absent in the literature. The expression of stemness proteins declines with in vitro expansion, correlating with increasing “developmental” distance from the pericyte phenotype. Although matrix-derived physicochemical cues have been shown to regulate cell fate decisions, alterations in stemness in response to changing substrate properties remain unknown. Here, serially-expanded hMSCs were used as a model for investigating how physicochemical cues from synthetic matrices regulate intracellular functions, with an emphasis on oxidation/reduction (“redox”) status and expression of stemness markers. This work identifies one specific polymer-of-interest that stimulates an expression profile resembling that of stem cells in vivo: low intracellular reactive oxygen species (ROS) levels, reduced proliferative index, and strong expression of stemness genes. Furthermore, this material is shown to promote hMSC-mediated endothelial cell migration in vitro and improved vascularization in vivo, two reminiscent behaviors of native pericytes. Finally, a mechanism at the cell-material interface driving the observed phenotype is proposed and tested, providing new information for how cells sense and respond to their environment. The results from this study (1) identify a novel mechanism for outside-in signaling between hMSCs and their microenvironment, and (2) contribute a significant advancement to the understanding of hMSC phenotype as it relates to pericytes and the in vivo niche.