Neurosciences Laboratory, Felsenstein Medical Research Center-Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel.
Oral Biology Dept., School of Dental Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
PLoS One. 2014 Jun 19;9(6):e100445. doi: 10.1371/journal.pone.0100445. eCollection 2014.
Achieving safe and readily accessible sources for cell replacement therapy in Parkinson's disease (PD) is still a challenging unresolved issue. Recently, a primitive neural crest stem cell population (hOMSC) was isolated from the adult human oral mucosa and characterized in vitro and in vivo. In this study we assessed hOMSC ability to differentiate into dopamine-secreting cells with a neuronal-dopaminergic phenotype in vitro in response to dopaminergic developmental cues and tested their therapeutic potential in the hemi-Parkinsonian rat model. We found that hOMSC express constitutively a repertoire of neuronal and dopaminergic markers and pivotal transcription factors. Soluble developmental factors induced a reproducible neuronal-like morphology in the majority of hOMSC, downregulated stem cells markers, upregulated the expression of the neuronal and dopaminergic markers that resulted in dopamine release capabilities. Transplantation of these dopaminergic-induced hOMSC into the striatum of hemi-Parkinsonian rats improved their behavioral deficits as determined by amphetamine-induced rotational behavior, motor asymmetry and motor coordination tests. Human TH expressing cells and increased levels of dopamine in the transplanted hemispheres were observed 10 weeks after transplantation. These results demonstrate for the first time that soluble factors involved in the development of DA neurons, induced a DA phenotype in hOMSC in vitro that significantly improved the motor function of hemiparkinsonian rats. Based on their neural-related origin, their niche accessibility by minimal-invasive procedures and their propensity for DA differentiation, hOMSC emerge as an attractive tool for autologous cell replacement therapy in PD.
实现帕金森病（PD）细胞替代治疗的安全和易得来源仍然是一个具有挑战性的未解决问题。最近，从成人口腔黏膜中分离出一种原始神经嵴干细胞群体（hOMSC），并在体外和体内进行了鉴定。在这项研究中，我们评估了 hOMSC 在体外对多巴胺能发育线索分化为多巴胺能分泌细胞的能力，并测试了它们在半帕金森大鼠模型中的治疗潜力。我们发现 hOMSC 持续表达一系列神经元和多巴胺能标志物和关键转录因子。可溶性发育因子诱导大多数 hOMSC 产生可重现的神经元样形态，下调干细胞标志物，上调神经元和多巴胺能标志物的表达，从而产生多巴胺释放能力。将这些诱导产生多巴胺的 hOMSC 移植到半帕金森大鼠的纹状体中，改善了它们的行为缺陷，如安非他命诱导的旋转行为、运动不对称性和运动协调测试。移植后 10 周观察到表达人类 TH 的细胞和移植半球中多巴胺水平升高。这些结果首次表明，参与 DA 神经元发育的可溶性因子在体外诱导 hOMSC 产生 DA 表型，显著改善了半帕金森大鼠的运动功能。基于其神经相关起源、通过微创程序进入其龛位的能力以及向 DA 分化的倾向，hOMSC 成为 PD 自体细胞替代治疗的一种有吸引力的工具。
