A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson's Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity
A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson's Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity
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DOI：
10.1007/s12015-019-09906-2
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发表时间：
2019-10-01
影响因子：
4.8
通讯作者：
Borlongan, Cesario V.
中科院分区：
文献类型：
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作者：
Lee, Jea-Young;Tuazon, Julian P.;Borlongan, Cesario V.
帕金森病 (PD) 的药物和细胞再生医学可以提供姑息治疗，但不能阻止疾病的进展。细胞疗法已成为一种实验性治疗方法，但目前的细胞来源，例如人脐带血 (hUCB) 干细胞，仅表现出成熟多巴胺能神经元表型和功能的部分重现。尽管如此，干细胞移植物可能通过干细胞移植物分泌的治疗物质改善与帕金森病相关的组织学和行为缺陷。我们最近在 PD 的 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 啮齿动物模型中证明了 hUCB 衍生血浆在增强运动能力和胃肠功能以及防止多巴胺能神经元细胞损失方面的潜力。认识到需要在另一种 PD 模型中进行测试，我们现在检查了静脉内移植 hUCB 和血浆组合到 6-羟基多巴胺 (6-OHDA) 损伤的成年大鼠中的效果。动物在立体定位 6-OHDA 损伤后 7 天开始接受三份单独剂量的 4x10(6) hUCB 细胞和血浆，然后在损伤后 56 天进行行为和免疫组织化学评估。媒介物处理的病变动物表现出典型的 6-OHDA 神经行为症状，而 hUCB 和血浆处理的病变动物表现出运动功能、肠道运动和黑质多巴胺能神经元存活的显着减弱，同时黑质和肠道中促炎微生物组的减少。总而言之，这些数据支持通过纠正肠道菌群失调来隔离炎症和神经毒性来治疗帕金森病的再生医学方法。
Pharmaceuticals and cell-based regenerative medicine for Parkinson's disease (PD) offer palliative relief but do not arrest the disease progression. Cell therapy has emerged as an experimental treatment, but current cell sources such as human umbilical cord blood (hUCB) stem cells display only partial recapitulation of mature dopaminergic neuron phenotype and function. Nonetheless, stem cell grafts ameliorate PD-associated histological and behavioral deficits likely through stem cell graft-secreted therapeutic substances. We recently demonstrated the potential of hUCB-derived plasma in enhancing motor capabilities and gastrointestinal function, as well as preventing dopaminergic neuronal cell loss, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) rodent model of PD. Recognizing the translational need to test in another PD model, we now examined here the effects of an intravenously transplanted combination of hUCB and plasma into the 6-hydroxydopamine (6-OHDA) lesioned adult rats. Animals received three separate doses of 4x10(6) hUCB cells with plasma beginning at 7 days after stereotaxic 6-OHDA lesion, then behaviorally and immunohistochemically evaluated over 56 days post-lesion. Whereas vehicle-treated lesioned animals exhibited the typical 6-OHDA neurobehavioral symptoms, hUCB and plasma-treated lesioned animals showed significant attenuation of motor function, gut motility, and nigral dopaminergic neuronal survival, combined with diminished pro-inflammatory microbiomes not only in the nigra, but also in the gut. Altogether these data support a regenerative medicine approach for PD by sequestering inflammation and neurotoxicity through correction of gut dysbiosis.