Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy.
Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy.
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DOI：
10.1111/jdi.12452
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发表时间：
2016-07
影响因子：
3.2
通讯作者：
Naruse K
中科院分区：
文献类型：
--
作者：
Omi M;Hata M;Nakamura N;Miyabe M;Kobayashi Y;Kamiya H;Nakamura J;Ozawa S;Tanaka Y;Takebe J;Matsubara T;Naruse K
牙髓干细胞（DPSC）被认为是细胞治疗的一个有吸引力的候选细胞。我们最近报道了DPSCs移植增加糖尿病大鼠的神经传导速度和神经血流量。在本研究中，我们研究了DPSC移植对糖尿病周围神经的免疫调节作用。 从Sprague-Dawley大鼠的牙髓中分离DPSC并在培养物中扩增。注射链脲佐菌素8周后，将DPSCs移植到一侧后肢骨骼肌中。DPSC移植后4周，评估坐骨神经中的神经生理学测量、炎症基因表达和CD 68阳性细胞数量。为了证实DPSC的免疫调节作用，研究了DPSC条件培养基对脂多糖刺激的鼠巨噬细胞RAW 264.7细胞的作用。糖尿病大鼠坐骨神经传导速度明显延迟，坐骨神经血流量减少，DPSC移植后均得到改善。糖尿病大鼠坐骨神经中CD 68阳性单核细胞/巨噬细胞的数量和M1巨噬细胞表达的细胞因子肿瘤坏死因子α和白细胞介素1β的基因表达增加。DPSC移植显著降低了糖尿病大鼠坐骨神经中单核细胞/巨噬细胞和肿瘤坏死因子-α信使核糖核酸的表达，并增加了M2巨噬细胞标志物CD 206的基因表达。体外研究表明，DPSC条件培养基显著增加了脂多糖刺激的RAW 264.7细胞中白细胞介素-10和CD 206的基因表达。这些结果表明，DPSC移植促进巨噬细胞向抗炎M2表型极化，这可能是糖尿病多发性神经病的治疗机制之一。
Dental 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. 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. Diabetic 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. These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.