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Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats

机译：人乳牙干细胞的多巴胺能分化及其对帕金森病大鼠的治疗作用

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Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of nigrostriatal dopaminergic (DAergic) neurons and the depletion of striatal dopamine. Here we show that DAergic-neuron-like cells could be efficiently induced from stem cells derived from human exfoliated deciduous teeth (SHEDS), and that these induced cells had therapeutic benefits in a 6-OHDA-induced Parkinsonian rat model. In our protocol, EGF and bFGF signaling activated the SHED's expression of proneural genes, Ngn2 and Mash1, and subsequent treatment with brain-derived neurotrophic factor (BDNF) promoted their maturation into DAergic neuron-like SHEDs (dSHEDs). A hypoxic DAergic differentiation protocol improved cell viability and enhanced the expression of multiple neurotrophic factors, including BDNF, GDNF, NT-3, and HGF. Engrafted dSHEDs survived in the striatum of Parldnsonian rats, improved the DA level more efficiently than engrafted undifferentiated SHEDs, and promoted the recovery from neurological deficits. Our findings further suggested that paracrine effects of dSHEDs contributed to neuroprotection against 6-OHDA-induced neurodegeneration and to nigrostriatal tract restoration. In addition, we found that the conditioned medium derived from dSHEDs protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth in vitro. Thus, our data suggest that stem cells derived from dental pulp may have therapeutic benefits for PD. (C) 2015 Elsevier B.V. All rights reserved.
机译：帕金森氏病（PD）是由黑纹状体多巴胺能（DAergic）神经元的缺失和纹状体多巴胺的消耗引起的进行性神经退行性疾病。在这里，我们显示可以从人类脱落乳牙（SHEDS）衍生的干细胞中有效诱导DAergic-neuron样细胞，并且这些诱导的细胞在6-OHDA诱导的帕金森病大鼠模型中具有治疗作用。在我们的协议中，EGF和bFGF信号激活了SHED的前神经基因Ngn2和Mash1的表达，随后用脑源性神经营养因子（BDNF）的治疗促进了它们成熟为DAergic神经元样SHED（dSHED）。低氧DAergic分化方案可改善细胞活力并增强多种神经营养因子（包括BDNF，GDNF，NT-3和HGF）的表达。植入的dSHEDs在帕尔森氏大鼠的纹状体中存活，比未分化的SHEDs植入更有效地提高了DA水平，并促进了神经功能缺损的恢复。我们的发现进一步表明，dSHED的旁分泌作用有助于抗6-OHDA诱导的神经变性和黑质纹状体恢复的神经保护作用。此外，我们发现衍生自dSHED的条件培养基可保护原代神经元免受6-OHDA毒性，并在体外加速神经突生长。因此，我们的数据表明，源自牙髓的干细胞可能对PD具有治疗益处。 （C）2015 Elsevier B.V.保留所有权利。

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