Transplantation of Neural Crest-Like Cells Derived From Induced Pluripotent Stem Cells Improves Diabetic Polyneuropathy in Mice
Transplantation of Neural Crest-Like Cells Derived From Induced Pluripotent Stem Cells Improves Diabetic Polyneuropathy in Mice
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DOI：
10.3727/096368912x657710
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Isobe, Ken-Ichi
中科院分区：
文献类型：
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作者：
Okawa, Tetsuji;Kamiya, Hideki;Isobe, Ken-Ichi
血管受损和神经变性是糖尿病性多发性神经病（DPN）最重要的病理生理异常。因此，血管和神经系统的再生是治疗DPN所必需的。神经嵴（NC）是脊椎动物中的一种短暂的胚胎结构，其分化为广泛的细胞，包括外周神经元、许旺细胞和血管平滑肌细胞。在这项研究中，我们研究了来自老年小鼠诱导多能干细胞（iPS）的NC样（NCL）细胞移植治疗DPN的能力。通过基质细胞衍生的诱导活性（SDIA）诱导iPS细胞向神经细胞分化，随后补充骨形态发生蛋白4以促进NC谱系的分化。诱导后，p75神经营养因子受体阳性的NCL细胞使用磁激活细胞分选纯化。通过额外的SDIA，分选的NCL细胞分化为外周神经元、神经胶质细胞和平滑肌细胞。将NCL细胞移植到16周链脲佐菌素糖尿病小鼠的后肢骨骼肌中。评价神经传导速度、电流感知阈值、表皮内神经纤维密度、对热刺激的敏感性、坐骨神经血流量、足底皮肤血流量和毛细血管数与肌纤维的比率。移植后四周，移植的细胞产生生长因子：神经生长因子，神经营养因子3，血管内皮生长因子和碱性成纤维细胞生长因子。还证实了一些移植的细胞在每个内在位点分化为血管平滑肌细胞或许旺细胞样细胞。移植改善了受损的神经和血管功能。这些结果表明，移植来自iPS细胞的NCL细胞可以通过生长因子的旁分泌作用和向雪旺细胞样细胞和血管平滑肌细胞的分化对DPN具有治疗作用。
Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both the vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells, and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC-like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote differentiation of NC lineage. After the induction, p75 neurotrophin receptor-positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells, and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow, and capillary number-to-muscle fiber ratio were evaluated. Four weeks after transplantation, the engrafted cells produced growth factors: nerve growth factor, neurotrophin 3, vascular endothelial growth factor, and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell-like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell-like cells and vascular smooth muscle cells.