hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model.
hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model.
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使用可伸缩3D水凝胶产生的HPSC来源的纹状体细胞在亨廷顿病小鼠模型中促进恢复。
DOI：
10.1016/j.stemcr.2018.03.007
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发表时间：
2018-05-08
影响因子：
5.9
通讯作者：
Schaffer DV
中科院分区：
文献类型：
--
作者：
Adil MM;Gaj T;Rao AT;Kulkarni RU;Fuentes CM;Ramadoss GN;Ekman FK;Miller EW;Schaffer DV
亨廷顿病（HD）是一种遗传性、进行性神经系统疾病，其特征在于纹状体中型棘状神经元（MSN）的退化。治疗HD的一种有希望的方法是细胞替代疗法，其中丢失的细胞被来自人多能干细胞（hPSC）的MSN祖细胞替代。虽然在产生hPSC衍生的MSN方面已经取得了显着进展，但目前的生产方法依赖于二维培养系统，其可能包括定义不明确的组分，限制可扩展性，并产生不同的临床前结果。为了促进临床转化，在这里，我们在完全限定的和可扩展的PNIPAAm-PEG三维（3D）水凝胶内从hPSC产生纹状体祖细胞。将3D衍生的纹状体祖细胞移植到HD转基因小鼠模型中减缓了疾病进展，改善了运动协调性并增加了存活率。此外，移植的细胞形成了MSN样表型，并与宿主细胞形成了突触连接。我们的研究结果说明了可扩展的3D生物材料用于生成用于HD细胞治疗的纹状体祖细胞的潜力。3D生成的纹状体细胞迅速实现功能成熟移植细胞延迟疾病发作并缓解HD小鼠的症状移植纹状体细胞增加HD小鼠的寿命在移植到HD小鼠的纹状体细胞中观察到HTT聚集体Adil et al.使用3D生物材料产生hPSC衍生的MSN祖细胞，其迅速成熟为动作电位放电神经元。当纹状体移植到HD遗传模型小鼠中时，3D生成的细胞显着延迟了疾病发作，减轻了疾病症状，并延长了寿命。这种方法证明了功能MSN的可扩展生成，对HD中细胞替代疗法的临床转化具有影响。
Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results. To facilitate clinical translation, here, we generated striatal progenitors from hPSCs within a fully defined and scalable PNIPAAm-PEG three-dimensional (3D) hydrogel. Transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and increased survival. In addition, the transplanted cells developed an MSN-like phenotype and formed synaptic connections with host cells. Our results illustrate the potential of scalable 3D biomaterials for generating striatal progenitors for HD cell therapy. 3D-generated striatal cells rapidly achieve functional maturity Transplanted cells delayed disease onset and alleviated symptoms in HD mice Transplanted striatal cells increased lifespan in HD mice HTT aggregates were observed in striatal cells transplanted into HD mice Adil et al. used a 3D biomaterial to generate hPSC-derived MSN progenitors, which rapidly matured into action potential firing neurons. When striatally transplanted in HD genetic model mice, 3D-generated cells significantly delayed disease onset, alleviated disease symptoms, and increased lifespan. This approach demonstrates the scalable generation of functional MSNs, with implications for clinical translation of cell replacement therapy in HD.
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影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0808488105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Aubry, Laetitia;Bugi, Aurore;Perrier, Anselme L.
通讯作者：
Perrier, Anselme L.
DOI：
10.1523/jneurosci.0388-12.2012
发表时间：
2012-05-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cepeda-Prado E;Popp S;Khan U;Stefanov D;Rodríguez J;Menalled LB;Dow-Edwards D;Small SA;Moreno H
通讯作者：
Moreno H
影响因子：
48
作者：
Kraehenbuehl, Thomas P.;Langer, Robert;Ferreira, Lino S.
通讯作者：
Ferreira, Lino S.