Cellular and Molecular Mechanisms Mediated by recPrPC Involved in the Neuronal Differentiation Process of Mesenchymal Stem Cells

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.

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“…In fact, it has been shown that cholesterol sequestering agents selectively destroy rafts. Thus, the use of cholesterol sequestering molecules is a useful tool for identifying proteins as components of the lipid raft or simply copurified contaminants (Foster, 2009 ), as well as for determining the role of rafts in modulating cellular processes (Mattei et al, 2015 ; Martellucci et al, 2019 ).…”

A multimolecular signaling complex including PrPC and LRP1 is strictly dependent on lipid rafts and is essential for the function of tissue plasminogen activator

“…In analogy with many other GPI‐anchored proteins, the cellular prion protein (PrP C ) localizes in lipid rafts microdomains (Taylor and Hooper ; Mattei et al, ) and over the past fifteen years, evidence has accumulated that PrP C can act as a cell surface receptor, co‐receptor or ligand, able to recruit downstream signal transduction pathways (Martellucci et al, ; Martellucci et al, ). Such function is thought to be driven by the interaction of PrP C with promiscuous partners, within multimolecular complexes (Hirsch et al, ).…”

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“…Some in vitro studies have used recombinant PrP (recPrP), which, despite lacking the glycans, may be considered a suitable analog of shed PrP (sPrP). A recent study revealed that recPrP acts as a ligand on mesenchymal stem cells, inducing ERK1/2 and Akt signaling and supporting neuronal differentiation [ 206 ]. Amin et al have shown that recPrP supports neurite outgrowth as a chemotactic stimulus guiding the axonal growth cone [ 207 ].…”