Factors secreted from dental pulp stem cells show multifaceted benefits for Synergistically Regenerate Transected Rat Peripheral Nerves by Altering Macrophage Polarity.

Abstract: Following peripheral nerve injury (PNI), Schwann cells (SCs) and macrophages cooperatively promote nerve regeneration. The dam- aged axons and myelin sheaths distal to the lesion undergo Wallerian degeneration, in which migrated macrophages remove the myelin and axonal debris from the injury site, while the mature SCs then dedifferentiate and proliferate to form the bands of Bunger, a series of tubular structure that produces trophic factors and extracellular matrix molecules that accelerate axonal regrowth toward their original targets. Recent studies have also shown that fibroblasts and endothelial cells/blood vessels in the PNI promote the sorting and directional migration of SCs, respectively. Thus, the temporal and spatial coordination of multiple cell types promotes peripheral nerve (PN) regeneration. However, while the self-reparative activities of PNs successfully repair crush or cut-induced neuronal injuries, they do not fully repair transection-induced nerve gaps, which are replaced with fibrotic scars. Stem cell transplantation-based therapy is a promising approach for patients with severe PNI. The transplantation of various types of scaffolds containing bone marrow mesenchymal stem cells, adipose-derived stem cells, umbilical cord-derived mesenchymal stem cells, or dental pulp stem cells into the transected nerves of rodents promotes substantial functional recovery. Notably, in most of these studies, neurological function is recovered primarily through paracrine/trophic mechanisms. Stem cells secrete a broad repertoire of trophic and immunomodulatory factors that can be collected as serum-free conditioned medium (CM). We previously reported that the engrafted stem cells from human exfoliated deciduous teeth (SHEDs) and SHED-CM exert similar therapeutic effects for Central Nervous System (CNS) injuries, acute liver failure, and lung injuries. However, the therapeutic mechanisms and factors in SHED-CM responsible for PN regeneration are still largely unknown. In this presentation, we report that SHED-CM regenerates PNs by inducing tissue-repairing M2 macrophages and may provide therapeutic benefits for severe peripheral nerve injuries.