TISSUE-SPECIFIC STEM CELLS Inhibition of Platelet-Derived Growth Factor Receptor Signaling Regulates Oct4 and Nanog Expression, Cell Shape, and

Key Words. Adult stem cells • Multipotential differentiation • Mesenchymal stem cells • Marrow stromal stem cells Defining the signaling mechanisms that regulate the fate of adult stem cells is an essential step toward their use in re-generative medicine. Platelet-derived growth factor recep-tor (PDGFR) signaling plays a crucial role in specifying mesenchymal stem cell (MSC) commitment to mesenchy-mal lineages. Based on the hypothesis that selective inhibi-tion of signaling pathways involved in differentiation may increase stem cell potency, we examined the role of PDGFR signaling in controlling the fate of human MSCs. Using a small molecular PDGFR inhibitor that induced MSCs to-ward a more rounded shape, expression of Oct4 and Nanog were markedly upregulated. In these PDGFR inhibitor-treated MSCs, Oct4 and Nanog expression and cell shape were regulated by janus kinase (JAK), MAPK kinase (MEK), and epidermal growth factor receptor (EGFR) signaling. Under defined differentiation conditions, these PDGFR-inhibited MSCs expressed definitive endodermal, ectodermal, and mesodermal markers. We also confirmed that depletion of individual PDGF receptors upregulated expression of Oct4A and Nanog. This study identifies PDGFR signaling as a key regulator of Oct4 and Nanog expression and of MSC potency. Thus, inhibiting these specific receptor tyrosine kinases, which play essential roles in tissue formation, offers a novel approach to unlock the therapeutic capacity of MSCs. STEM CELLS 2012;30:548–560 Disclosure of potential conflicts of interest is found at the end of this article