Peripheral nerve injury (PNI) refers to varying degrees of trauma to peripheral nerve stems or branches. PNI
accounts for 1.5–4.0% of global trauma cases annually and is one of the most challenging health issues at present.

Nerve regeneration is a complicated cellular process involving infammation, neurotrophic factors, neurotransmitters, adhesion, the formation of axons and growth cones, and the survival of neurons.

PNI triggers a series of immunoregulatory reactions in the cellular microenvironment, involving changes of immune cells and related immunoregulatory factors. Immunomodulatory factors currently known include interleukin-1 (IL-1α, IL-1β), IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-6, tumor necrosis factor-a (TNF-α), indoleamine-2, 3-dioxygenase (IDO), interferon-γ (IFN-γ), transforming growth factor-beta1 (TGF-β1), heme oxygenase-1 (HO-1), hepatocyte growth factor (HGF), nitricoxide (NO), human leucocyte antigen-G5 (HLA-G5) and prostaglandin E2 (PGE2).

Amongst other techniques, autologous nerve grafting, nerve conduit synthesis, stem cell transplantation, and exosome extraction are currently more popular treatments for PNI. For peripheral nerve damage of more than 3 cm in length, autologous nerve grafting is considered the gold standard treatment. Stem cell transplantation is a novel method capable of regulating the infammatory response which may accelerate the transition from destructive to restorative infammatory microenvironment and has been confirmed to promote the regeneration of peripheral and central
nerves.

Mesenchymal stem cells (MSCs) can produce a variety of immunoregulatory factors modulating the immune function of autologous and allogeneic immune cells as well as innate (including natural killer (NK) cells, neutrophils, macrophages, mast cells, and dendritic cells (DCs)) and acquired immune cells (including T cells and B cells). MSCs exert their immunomodulatory role via two distinct mechanisms: secretion of cytokines, including IDO (human) or NO (mouse), PGE2, IL-4, IL-10, IL-12, and IFN-γ, and TNF-α, in a paracrine manner, and direct contact between cells.

The most important role of human MSCs (hMSCs) following injury is their secretion of bioactive molecules such as cytokines, chemokines, and growth factors, rather than their diferentiation ability and there are now several studies that have shown that many of the benefcial efects attributed to stem cell therapy may be mediated via paracrine mechanisms. However, the immunomodulatory effects exerted by MSCs after PNI are not entirely clear.

In this review, are discussed the changes occurring in the inflammatory microenvironment after treatment of PNI with
MSCs and MSC-derived exosomes (exos), as well as the immunomodulatory effects exerted by different immune cells and inflammatory factors.

In conclusion, MSCs are multipotent stem cells with multiple biological potentials and may represent an ideal option for cell therapy applications due to their regenerative and immunoregulatory functions. The use of MSCs with innate mechanistic features to mediate the local infammatory response following PNI would both reduce loss of muscle mass and shift the microenvironment towards a pro-regenerative rather than profibrotic phenotype. Animal studies with intravenous reinfusion transplantation or local tissue injection of MSCs have found that these cells can quickly migrate to injury sites and localize to sites of information where they promote antiinflammatory and immune regulatory effects.

There is a correlation between higher MSCs survival and reduced levels of pro-infammatory cytokines as well as a transformation in macrophages from M1 to M2. However, current studies investigating the immunoregulatory mechanisms of MSCs for the treatment of PNI are not comprehensive enough, and the functions played by different immune cells and cytokines remain to be studied. Moreover, the various pathways involved in the mediation of MSC-derived benefts remain to be explored.

Stem cell transplantation studies are at this point predominantly in pre-clinical stages, with several issues needing to be addressed. Although the effectiveness of MSCs/MSCs-EVs for the treatment of PNI has been demonstrated many times in animal studies, there are still few studies highlighting the exact therapeutic mechanisms, in particular relating to the immunoregulatory mechanisms exerted by MSCs/MSCs-EVs. Further studies investigating the molecular mechanism underlying the benefcial efects of MSCs in the treatment of PNI will provide new strategies for disease therapy.