Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors
Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors
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DOI：
10.1186/s13287-020-01758-9
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发表时间：
2020-06-16
影响因子：
7.5
通讯作者：
Naruse, Keiko
中科院分区：
文献类型：
--
作者：
Hata, Masaki;Omi, Maiko;Naruse, Keiko
背景牙髓干细胞（DPSC）具有高度增殖和多向分化能力，冻存后仍能保持其功能。在我们之前的研究中，我们证明了冷冻保存的大鼠DPSC改善糖尿病多发性神经病，并且冷冻保存的大鼠DPSC的功效与新鲜分离的大鼠DPSC的功效相当。本研究旨在评估冻存人DPSC（hDPSC）移植是否也能有效治疗糖尿病性多发性神经病。方法从因正畸原因拔除的人阻生第三磨牙中分离hDPSCs。在裸鼠中诱导糖尿病后8周，将hDPSC（1 × 105/肢）单侧移植到后肢骨骼肌中，并将载体（盐水）注射到对侧作为对照。在移植后4周分析hDPSC的效果。结果hDPSC移植后4周，糖尿病小鼠感觉阈值降低，神经传导速度减慢，坐骨神经血流量减少，hDPSC移植组明显改善。培养的hDPSC分泌血管内皮生长因子（VEGF）和神经生长因子（NGF）蛋白。移植的hDPSC的一个子集位于肌束周围，并在移植部位表达人VEGF和NGF基因。糖尿病小鼠腓肠肌hDPSC移植侧的毛细血管/肌束比显著增加。抗VEGF和NGF的中和抗体可阻断hDPSC移植对糖尿病小鼠神经传导速度的影响，提示VEGF和NGF可能在hDPSC移植治疗糖尿病多发性神经病中发挥作用。结论干细胞移植联合hDPSC治疗糖尿病周围神经病变可能是通过hDPSC分泌的血管生成和神经营养因子发挥作用。
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 x 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 post-transplantation. 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. Conclusions These results suggest that stem cell transplantation with hDPSCs may be efficacious in treating diabetic polyneuropathy via the angiogenic and neurotrophic mechanisms of hDPSC-secreted factors.