GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice.
GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice.
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DOI：
10.1038/s41598-018-23795-4
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发表时间：
2018-04-03
影响因子：
4.6
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Chen C;Li X;Ge G;Liu J;Biju KC;Laing SD;Qian Y;Ballard C;He Z;Masliah E;Clark RA;O'Connor JC;Li S
胶质细胞源性神经营养因子 (GDNF) 是在帕金森病 (PD) 细胞和动物模型中测试的最有效的神经保护剂。然而，中枢神经系统输送 GDNF 受到血脑屏障 (BBB) 的限制。我们之前报道，使用全身照射作为移植预处理，基于造血干细胞（HSC）移植（HSCT）的巨噬细胞介导的基因治疗可以将GDNF递送至大脑，以防止急性小鼠神经毒性模型中黑质纹状体多巴胺（DA）神经元的变性。在这里，我们在慢性进行性 PD 模型（MitoPark 小鼠）中验证了这种治疗方法，该模型采用头部屏蔽以避免诱发神经炎症和损害 BBB 完整性。用表达巨噬细胞启动子驱动的 GDNF 的慢病毒载体离体转导骨髓 HSC，并将其移植到表现出发育良好的 PD 样损伤的 MitoPark 小鼠中。表达转基因的巨噬细胞渗入 MitoPark 小鼠的中脑，但不渗入正常同窝小鼠的中脑，并在局部递送 GDNF。巨噬细胞 GDNF 的递送显着改善了运动和非运动症状，并显着减轻了黑质中 DA 神经元和纹状体中酪氨酸羟化酶阳性轴突末端的损失。我们的数据支持进一步开发这种基于 HSCT 的巨噬细胞介导的 GDNF 递送方法，以解决 PD 疾病缓解疗法的未满足需求。
Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson’s disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model – the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD.
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DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
影响因子：
17.1
作者：
Chhabra A;Ring AM;Weiskopf K;Schnorr PJ;Gordon S;Le AC;Kwon HS;Ring NG;Volkmer J;Ho PY;Tseng S;Weissman IL;Shizuru JA
通讯作者：
Shizuru JA
影响因子：
2.5
作者：
Biju KC;Santacruz RA;Chen C;Zhou Q;Yao J;Rohrabaugh SL;Clark RA;Roberts JL;Phillips KA;Imam SZ;Li S
通讯作者：
Li S
影响因子：
64.8
作者：
Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
82.9
作者：
Baruch, Kuti;Deczkowska, Aleksandra;Schwartz, Michal
通讯作者：
Schwartz, Michal