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The article offers information on effects of dynamic shear stress on the biological properties of pericyte-like cells from human dental pulp in an inflammatory micro environment. Topics include information on low immunogenicity and immunomodulatory/anti-inflammatory properties; how they regulate numerous functions including vessel growth; and pericytes localized in the head, dental pulp, thymus and the outflow tract of the aorta.

Introduction & Aim: Mesenchymal stromal/stem cells (MSCs) have been widely characterized for their regenerative and immunomodulatory properties. Recent studies reported that MSCs can contribute to tissue regeneration by modulating inflammatory microenvironment suggesting how these properties are strictly related [1]. MSCs can be isolated from diff erent adult tissues including dental pulp. Human dental pulp stromal/stem cells (hDPSCs) are characterized by multipotency and low immunogenicity, as well as by immunomodulatory properties exerted by diff erent mechanisms (i.e., Fas/FasL pathway) after exposure to an infl ammatory microenvironment [2,3]. Among these immunoregulatory mechanisms, PD-1/PD-L1 pathway seems to be an important effector in the suppression of immune system activation and its role is not fully understood in hDPSCs [4]. Therefore, the present study aimed to 1) investigate the downstream mechanism of a new immune-regulatory pathway, i.e., PD-1/PD-L1, in hDPSCs 2) how the inflammatory microenvironment might affect hDPSCs immunomodulatory potential. Methods: Infl ammatory microenvironment was created in vitro by the activation of peripheral blood mononuclear cells (PBMCs) isolated from healthy donors and rheumatoid arthritis (RA) patients with anti-CD3 and anti-CD28 antibodies. Direct and indirect co-cultures between hDPSCs and PBMCs were carried out to evaluate the activation of immunomodulatory checkpoints in hDPSCs and the inflammatory pattern in PBMCs through Real-Time PCR, Western Blot, Immunofluorescence and Immunohistochemistry analyses. Results: Our data revealed that hDPSCs up-regulate PD-L1 and IL6 via both direct and indirect interaction-dependent mechanisms in response to exposure to CD3/CD28 co-stimulated PBMCs (aPBMCs). This ability is strictly related to hDPSCs stemness status. Moreover, as demonstrated by using a selective PD-L1 inhibitor, hDPSCs were able to activate compensatory pathways (i.e., Fas/FasL). At the same time, hDPSCs are able to control the inflammatory process by modulating pro-inflammatory cytokines expression in aPBMCs. In the second step of our study, we investigate how PD-L1, IL6 and FasL expression might be affected by different inflammatory conditions mimicked by direct and indirect hDPSCsaPBMCs co-cultures at different ratios and timepoints. Our data revealed that PD-L1 and IL6 mRNA levels show the same trend in both direct and indirect co-culture systems, regardless hDPSCs-aPBMCs ratio and timepoints. On the other hand, FasL mRNA levels were significantly up-regulated in hDPSCs only after a direct contact with aPBMCs, with an increasing trend across the different hDPSCs-aPBMCs ratios. The up-regulation of FasL mRNA levels in hDPSCs was also observed after indirect co-cultures only at later timepoints. Future studies aimed at deeply investigating the molecular mechanisms involved will corroborate these results. Conclusions: Our results pointed out that DPSCs can modulate the infl ammatory microenvironment by the activation of PD-1/PD-L1 pathway synergistically cooperating with other immune-regulatory pathways including Fas/FasL. These immunomodulatory properties are orchestrated by the infl ammatory microenvironment. Based on this evidence, these properties might be functional in controlling the inflammatory milieu typical of autoimmune diseases, such as rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The peripheral nerve injuries, representing some of the most common types of traumatic lesions affecting the nervous system, are highly invalidating for the patients besides being a huge social burden. Although peripheral nervous system owns a higher regenerative capacity than does central nervous system, mostly depending on Schwann cells intervention in injury repair, several factors determine the extent of functional outcome after healing. Based on the injury type, different therapeutic approaches have been investigated so far. Nerve grafting and Schwann cell transplantation have represented the gold standard treatment for peripheral nerve injuries, however these approaches own limitations, such as scarce donor nerve availability and donor site morbidity. Cell based therapies might provide a suitable tool for peripheral nerve regeneration, in fact, the ability of different stem cell types to differentiate towards Schwann cells in combination with the use of different scaffolds have been widely investigated in animal models of peripheral nerve injuries in the last decade. Dental pulp is a promising cell source for regenerative medicine, because of the ease of isolation procedures, stem cell proliferation and multipotency abilities, which are due to the embryological origin from neural crest. In this article we review the literature concerning the application of tooth derived stem cell populations combined with different conduits to peripheral nerve injuries animal models, highlighting their regenerative contribution exerted through either glial differentiation and neuroprotective/neurotrophic effects on the host tissue., Competing Interests: None