Secreted factors from cultured dental pulp stem cells promoted neurite outgrowth of dorsal root ganglion neurons and ameliorated neural functions in streptozotocin‐induced diabetic mice

Abstract

Aims/IntroductionTransplantation of stem cells promotes axonal regeneration and angiogenesis in a paracrine manner. In the present study, we examined whether the secreted factors in conditioned medium of stem cells from human exfoliated deciduous teeth (SHED‐CM) had beneficial effects on diabetic polyneuropathy in mice.Materials and MethodsConditioned medium of stem cells from human exfoliated deciduous teeth was collected 48 h after culturing in serum‐free Dulbecco's modified Eagle's medium (DMEM), and separated into four fractions according to molecular weight. Dorsal root ganglion neurons from C57BL/6J mice were cultured with SHED‐CM or DMEM to evaluate the effect on neurite outgrowth. Streptozotocin‐induced diabetic mice were injected with 100 μL of SHED‐CM or DMEM into the unilateral hindlimb muscles twice a week over a period of 4 weeks. Peripheral nerve functions were evaluated by the plantar test, and motor and sensory nerve conduction velocities. Intraepidermal nerve fiber densities, capillary number‐to‐muscle fiber ratio, capillary blood flow and morphometry of sural nerves were also evaluated.ResultsConditioned medium of stem cells from human exfoliated deciduous teeth significantly promoted neurite outgrowth of dorsal root ganglion neurons compared with DMEM. Among four fractions of SHED‐CM, the only fraction of <6 kDa promoted the neurite outgrowth of dorsal root ganglion neurons. In addition, SHED‐CM significantly prevented decline in sensory nerve conduction velocities compared with DMEM in diabetic mice. Although SHED‐CM did not improve intraepidermal nerve fiber densities or morphometry of sural nerves, SHED‐CM ameliorated the capillary number‐to‐muscle fiber ratio and capillary blood flow.ConclusionsThese results suggested that SHED‐CM might have a therapeutic effect on diabetic polyneuropathy through promoting neurite outgrowth, and the increase in capillaries might contribute to the improvement of neural function.

Secreted Factors from Stem Cells of Human Exfoliated Deciduous Teeth Directly Activate Endothelial Cells to Promote All Processes of Angiogenesis

“…These observations suggest that the improvement is attributable to paracrine effects and the secreted soluble factors from transplanted cells play a vital role [19]. Accordingly, our subsequent study showed that secreted factors from SHED, which can be collected as serum-free conditioned medium (CM), prevent deterioration of DPN in mice and only secreted factors of less than 6 kDa in SHED-CM promoted neurite outgrowth of mouse dorsal root ganglion (DRG) neurons [20]. Interestingly, both transplantation of stem cells and administration of SHED-CM improved blood flow in peripheral neurotrophic blood vessels and increased the capillary number to muscle fiber ratio in diabetic mice, which indicated that soluble factors from the stem cells promoted angiogenesis [20].…”

“…Accordingly, our subsequent study showed that secreted factors from SHED, which can be collected as serum-free conditioned medium (CM), prevent deterioration of DPN in mice and only secreted factors of less than 6 kDa in SHED-CM promoted neurite outgrowth of mouse dorsal root ganglion (DRG) neurons [20]. Interestingly, both transplantation of stem cells and administration of SHED-CM improved blood flow in peripheral neurotrophic blood vessels and increased the capillary number to muscle fiber ratio in diabetic mice, which indicated that soluble factors from the stem cells promoted angiogenesis [20]. Furthermore, transplantation of SHED has been reported to up-regulate the level of serum VEGF and heal hindlimb ulcers in rat diabetic models [21].…”

Dental Tissue-Derived Human Mesenchymal Stem Cells and Their Potential in Therapeutic Application

“…Furthermore, dental MSCs might be another choice for systemic lupus erythmatosus (SLE) therapy and are also effective in reducing a kidney glomerular lesion and perivascular inflammation infiltration [ 119 ]. And dental MSCs are able to treat diabetes by obtaining insulin-producing cells or improving diabetic polyneuropathy [ 119 , 120 ].…”

Advancements in transplantation therapy for diabetes: Pancreas, islet and stem cell

“…Dental pulp stem cells produce angiogenic, neurotrophic and immunomodulatory factors 16 , and injection of conditioned media after culturing rat dental pulp stem cells into the hindlimb of diabetic rats improves sciatic motor/sensory nerve conduction velocity and sciatic nerve blood flow 17 . Similar methods using dental pulp stem cells from human exfoliated deciduous teeth facilitate neurite outgrowth of dorsal root ganglion neurons of mice in vitro , and sensory nerve conduction velocity after injection of the conditioned media into the soleus of mice 18 . Regarding nephropathy, subrenal capsule transplantation of adipose‐derived mesenchymal stem cells from rats reduces albuminuria and urinary tumor necrosis factor‐alpha and interleukin‐6 levels of diabetic rats, which is presumed to be the result of renoprotective paracrine factors 19 .…”