Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors

Abstract

Background: Dental pulp stem cells (DPSCs) have high proliferation and multi-differentiation capabilities that maintain their functionality after cryopreservation. In our previous study, we demonstrated that cryopreserved rat DPSCs improved diabetic polyneuropathy and that the efficacy of cryopreserved rat DPSCs was equivalent to that of freshly isolated rat DPSCs. The present study was conducted to evaluate whether transplantation of cryopreserved human DPSCs (hDPSCs) is also effective for the treatment of diabetic polyneuropathy. Methods: hDPSCs were isolated from human impacted third molars being extracted for orthodontic reasons. Eight weeks after the induction of diabetes in nude mice, hDPSCs (1 × 10 5 /limb) were unilaterally transplanted into the hindlimb skeletal muscle, and vehicle (saline) was injected into the opposite side as a control. The effects of hDPSCs were analyzed at 4 weeks after transplantation. Results: hDPSC transplantation significantly ameliorated reduced sensory perception thresholds, delayed nerve conduction velocity, and decreased the blood flow to the sciatic nerve in diabetic mice 4 weeks posttransplantation. Cultured hDPSCs secreted the vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) proteins. A subset of the transplanted hDPSCs was localized around the muscle bundles and expressed the human VEGF and NGF genes at the transplanted site. The capillary/muscle bundle ratio was significantly increased on the hDPSC-transplanted side of the gastrocnemius muscles in diabetic mice. Neutralizing antibodies against VEGF and NGF negated the effects of hDPSC transplantation on the nerve conduction velocity in diabetic mice, suggesting that VEGF and NGF may play roles in the effects of hDPSC transplantation on diabetic polyneuropathy.

Neural crest-like stem cells for tissue regeneration

“…Dental pulp stem cells (DPSCs) are also a source of NCLSCs that have multilineage differentiation potential, immunomodulatory properties, and high regenerative capability 126,127 . As a result, DPSCS can be utilized to treat a broad spectrum of disorders, 126,127 including PNI, 128,129 retinal injury, diabetes, cerebral ischemia, myocardial infarction, muscular dystrophy, and neurological diseases 128,130,131 . Indeed, in several case studies and preliminary clinical trials, the transplantation of DPSCs has proven to be a safe and effective therapeutic strategy, 127 indicating that DPSCs are a promising cell source for tissue regeneration and the treatment of various diseases.…”

Sustainable Effects of Human Dental Pulp Stem Cell Transplantation on Diabetic Polyneuropathy in Streptozotocine-Induced Type 1 Diabetes Model Mice

“…Studies have reported the clinical application of hDPSCs in Alzheimer’s disease, corneal reconstruction, and cerebral ischemia [ 28 , 29 , 30 ]. hDPSC transplantation into skeletal muscles ameliorates diabetic polyneuropathy at 4 weeks post-transplantation [ 22 ]. In this study, a single transplantation of hDPSCs into diabetic mice ameliorated the sciatic nerve motor nerve, sensory nerve, sciatic nerve blood flow, and CPTs, even after 16 weeks of transplantation.…”

“…hDPSC-CM promotes the neurite outgrowth of DRG neurons. The administration of VEGF- and NGF-neutralizing antibodies inhibits the effects of hDPSC transplantation on the MNCV and SNCV [ 22 ]. Our previous study revealed the critical role of the secreted factors from DPSCs [ 31 ].…”

“…Isotype-identical antibodies served as controls. The data were analyzed using MACS Quantify software Ver2.5 (Miltenyi Biotec) [ 22 ].…”

“…Transplantation of human DPSCs (hDPSCs) ameliorated DPN in a type 1 diabetes mouse model, and the effects of transplantation were related to VEGF and NGF secretion [ 22 ]. Improvements in nerve conduction velocity, nerve blood flow, and sensory thresholds were assessed 4 weeks post-transplantation.…”