Abstract
Human Dental Pulp Stem Cells (hDPSCs) represent a type of adult mesenchymal stem cells that have the ability to differentiate in vitro in several lineages such as odontoblasts, osteoblasts, chondrocytes, adipocytes and neurons. In the current work, we used hDPSCs as the experimental model to study the role of recombinant prion protein 23–231 (recPrPC) in the neuronal differentiation process, and in the signal pathway activation of ERK 1/2 and Akt. We demonstrated that recPrPC was able to activate an intracellular signal pathway mediated by extracellular-signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (Akt). Moreover, in order to understand whether endogenous prion protein (PrPC) was necessary to mediate the signaling induced by recPrPC, we silenced PrPC, demonstrating that the presence of endogenous PrPC was essential for ERK 1/2 and Akt phosphorylation. Since endogenous PrPC is a well-known lipid rafts component, we evaluated the role of these structures in the signal pathway induced by recPrPC. Our results suggest that lipid rafts integrity play a key role in recPrPC activity. In fact, lipid rafts inhibitors, such as fumonisin B1 and MβCD, significantly prevented ERK 1/2 and Akt phosphorylation induced by recPrPC. In addition, we investigated the capacity of recPrPC to induce hDPSCs neuronal differentiation process after long-term stimulation through the evaluation of typical neuronal markers expression such as B3-Tubulin, neurofilament-H (NFH) and growth associated protein 43 (GAP43). Accordingly, when we silenced endogenous PrPC, we observed the inhibition of neuronal differentiation induced by recPrPC. The combined data suggest that recPrPC plays a key role in the neuronal differentiation process and in the activation of specific intracellular signal pathways in hDPSCs.
Highlights
The cellular form of prion protein (PrPC) is a cell surface glycosylphosphatidyl-inositol (GPI)-anchored glycoprotein that was first identified as a molecule that is able to bind Cu2+ in vitro [1]
Endogenous PrPC is a well-known raft component, we evaluated the role of lipid rafts in the signal pathway induced by recPrPC
In this study we have investigated the cellular and molecular mechanisms mediated by recPrPC involved in the neuronal differentiation process of mesenchymal stem cells
Summary
The cellular form of prion protein (PrPC) is a cell surface glycosylphosphatidyl-inositol (GPI)-anchored glycoprotein that was first identified as a molecule that is able to bind Cu2+ in vitro [1]. PrPC is highly conserved in mammalians and it is present in all nucleated cells, it is mainly expressed in the central and peripheral nervous system [2]. PrPC is located within lipid rafts [3,4], sphingolipid-rich membrane micro domains, and it is present in several kind of cells such as neural and lymphocytic cells [5,6,7]. Recent evidence suggests that PrPC plays a possible in the neuronal differentiation processes of stem cells [17,18,19,20,21]
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