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

Abstract

Aims/Introduction Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated. Results The administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells. Conclusions We showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy.

Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

“…Dental pulp MSC-CM improved neuromuscular junction innervation and motor neuron survival in treating amyotrophic lateral sclerosis through different trophic factors and cytokines [149]. Similarly, dental pulp MSC-CM exhibited neuroprotective, anti-inflammatory, and angiogenic actions when administrated into unilateral hind limb skeletal muscles of a diabetic polyneuropathy rat model [150]. Intrathecal administration of dental pulp MSC-CM in a rat aneurysmal subarachnoid hemorrhage model revealed improvement in cognitive and motor impairments, microcirculation, and reduction of neuroinflammation.…”

Insight into the Role of Dental Pulp Stem Cells in Regenerative Therapy

“…It has been shown that conditioned medium obtained from MSCs has therapeutic effects in several somatic disorders [ 140 , 141 ]. Conditioned medium from DPSCs and SHEDs have also been clarified to have regenerative potential [ 142 , 143 , 144 , 145 ]. Although the main substance contained in conditioned medium and exerting therapeutic effects has not been clarified, exosomes might play an important role in regenerative processes.…”

Direct Comparison of Therapeutic Effects on Diabetic Polyneuropathy between Transplantation of Dental Pulp Stem Cells and Administration of Dental Pulp Stem Cell-Secreted Factors

“…Currently, the therapeutic mechanism of progenitor/stem cell transplantation is considered to be mainly associated with the abundant secretomes of transplanted stem cells in the early phase of transplantation. According to the hypothesis of secretomes, we investigated the effects of DPSC-SF administration on diabetic polyneuropathy [ 19 ]. We confirmed that DPSC-SF administration ameliorates sciatic nerve conduction velocity, sciatic nerve blood flow, and intraepidermal nerve fiber density, as well as the capillary/muscle bundle ratio, in the skeletal muscles.…”

“…Rats were anesthetized with isoflurane and placed on a heated pad in a room maintained at 25 °C, and the near-nerve temperature was maintained at 37 °C using a BAT-12 multipurpose thermometer (Bioresearch Co. Nagoya, Japan). MNCV between the ankle and the sciatic notch and SNCV between the ankle and the knee were measured by a Neuropak MEB-9400 instrument (Nihon-Koden, Osaka, Japan) as described previously [ 19 ].…”

“…We already demonstrated that the administration of secreted factors from DPSCs (DPSC-SFs) could improve nerve conduction velocity and nerve blood flow in the diabetic rats [ 19 ]. However, it is not clear which is more effective for treating diabetic polyneuropathy between stem cell transplantation and the administration of secreted factors.…”