Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti‐inflammation phenotypes and ameliorated diabetic polyneuropathy

Abstract

Aims/IntroductionDental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves.Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated.ResultsDiabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells.ConclusionsThese results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti‐inflammatory, neuroprotective and angiogenic actions: Cell‐free regenerative medicine for diabetic polyneuropathy

“…We have previously reported the therapeutic effect of DPSC transplantation on diabetic polyneuropathy. However, many of the engrafted DPSCs disappeared from the transplanted site during a certain period after transplantation, which is consistent with other cell transplantation therapies for ischemic heart disease and brain infarction.…”

Mesenchymal stem cells in chemotherapy‐induced peripheral neuropathy: A new challenging approach that requires further investigations

“…In an earlier study, intramuscularly transplanted MSCs improved sciatic nerve conduction velocity, sciatic nerve blood flow, and density of small vessels in the muscle of streptozotocin‐induced diabetic rats (Shibata et al, ). This was again recapitulated in other experiments, where several studies showed that transplantation of progenitor/stem cells, such as endothelial progenitor cells and MSCs, ameliorated neuropathy in experimentally‐induced diabetes (Jeong et al, ; Kim, Jin, & Bae, ; Omi et al, ). The therapeutic effects of MSCs not only depend on their differentiation capability to repair damaged tissue but also depend on their potency to activate endogenous progenitor cells, modulate local environment, and secrete various factors such as insulin‐like growth factor‐1, vascular endothelial growth factor (VEGF), and neurotrophin‐3 (Baraniak & McDevitt, ).…”

“…Therefore, inhibition of inflammatory cytokines has been considered as a useful target for CIPN prevention (Wolf, Gabay, Tal, Yirmiya, & Shavit, ). The modulatory action of MSCs on cytokine expression in peripheral tissues was previously demonstrated (Omi et al, ; Waterman et al, ). For example, treatment with MSCs reduced the levels of inflammatory markers such as NF‐κB p65, IL‐1β, TNF‐α, and IL‐6 in the sciatic nerve and spinal cord in experimental models of neuropathic pain (Al‐Massri et al, ; Gama et al, ).…”

“…In addition, neurotrophic factors such as glial cell line–derived neurotrophic factor, produced by stem and progenitor cells, can mediate potent antioxidant effects (Klass et al, ). Furthermore, the contribution of immunosuppressive and anti‐inflammatory effects of MSC on peripheral nerves in streptozotocin‐induced diabetic neuropathy has been proposed (Omi et al, ; Waterman et al, ). A previous study also indicated that blocking the spinal neuroinflammatory cascade is a possible mechanism by which MSCs could reduce the signs of sensorial diabetic neuropathy (Evangelista et al, ).…”

Oral Mesenchymal Stem/Progenitor Cells: The Immunomodulatory Masters

“…Moreover, diabetic polyneuropathy, the most common microvascular complication of both type 1 and type 2 diabetes, involves inflammatory response during the disease development. DPSC introduction ameliorated diabetic polyneuropathy, improving the delay in sciatic nerve conduction velocities and the decreased nerve blood flow, through downregulating monocytes/macrophages, inflammatory messenger ribonucleic acid and upregulating CD206 mRNA (a M2 macrophage marker) [135].…”