Abstract

Stem cells with the ability to differentiate into a variety of cells and secrete nerve regeneration factors have become an emerging option in nerve regeneration. Dental pulp stem cells (DPSCs) appear to be a good candidate for nerve regeneration given their accessibility, neural crest origin, and neural repair qualities. We have recently demonstrated that the complement C5a system, which is an important mediator of inflammation and tissue regeneration, is activated by lipoteichoic acid-treated pulp fibroblasts, and governs the production of brain-derived nerve growth factor (BDNF). This BDNF secretion promotes neurite outgrowth towards the injury site. Here, we extend our observation to DPSCs and compare their neurogenic ability to bone marrow-derived mesenchymal stem cells (BM-MSCs) under inflammatory stimulation. Our ELISA and immunostaining data demonstrate that blocking the C5a receptor (C5aR) reduced BDNF production in DPSCs, while treatment with C5aR agonist increased the BDNF expression, which suggests that C5aR has a positive regulatory role in the BDNF modulation of DPSCs. Inflammation induced by lipopolysaccharide (LPS) treatment potentiated this effect and is C5aR dependent. Most important, DPSCs produced significantly higher levels of C5aR-mediated BDNF compared to BM-MSCs. Taken together, our data reveal novel roles for C5aR and inflammation in modulation of BDNF and NGF in DPSCs.

Highlights

  • A promising attempt to regenerate peripheral nerve involves cell-based therapies that can differentiate into neurons and/or secrete trophic factors to promote nerve r­ egeneration[1]

  • These cells have been validated in several recent ­publications[13,14,15] and our analysis confirms over 99% purity of Dental pulp stem cells (DPSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs)

  • We investigated whether DPSCs and BM-MSCs constitutively express brain-derived nerve growth factor (BDNF) and NGF

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Summary

Introduction

A promising attempt to regenerate peripheral nerve involves cell-based therapies that can differentiate into neurons and/or secrete trophic factors to promote nerve r­ egeneration[1]. DPSCs are relatively easy to obtain through a minimally invasive procedure in adults and children These characteristics make DPSCs an ideal stem cell source for neural regeneration. The recombinant protein has a very short half-life (less than 10 min), which severely limits its ­effectiveness[8] For this approach to be effective, a stable and constant BDNF production platform is crucial and stem cell engineering might fulfill this important need. Pagella et al.[9], have demonstrated the superiority of DPSCs over BM-MSCs in promoting trigeminal innervation by increased secretion of neurotropic factors (i.e., BDNF and NGF) and enhanced axonal growth. Investigate further the role of complement C5aR and inflammation in another important subset of regenerative cells in pulp—DPSCs—and compared their neurogenic ability to bone marrow-derived mesenchymal stem cells (BM-MSCs)

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