Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease

被引：118
作者：
Chen, Yuejun [1 ]
Xiong, Man [2 ]
Dong, Yi [1 ]
Haberman, Alexander [1 ]
Cao, Jingyuan [1 ]
Liu, Huisheng [1 ]
Zhou, Wenhao [2 ]
Zhang, Su-Chun [1 ,3 ,4 ,5 ]
机构：
[1] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA
[2] Fudan Univ, Inst Pediat, Childrens Hosp, 399 Wanyuan Rd, Shanghai 201102, Peoples R China
[3] Univ Wisconsin, Neurosci Training Program, Madison, WI 53705 USA
[4] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurosci, Madison, WI 53705 USA
[5] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurol, Madison, WI 53705 USA
来源：
CELL STEM CELL | 2016年 / 18卷 / 06期
基金：
中国国家自然科学基金;
关键词：
PROTEIN-COUPLED RECEPTORS; PLURIPOTENT STEM-CELLS; DOPAMINE NEURONS; REMOTE-CONTROL; ANIMAL-MODELS; MICE; TRANSPLANTATION; MODULATION; STRIATUM; BEHAVIOR;
D O I：
10.1016/j.stem.2016.03.014
中图分类号：
Q813 [细胞工程];
学科分类号：
摘要：
Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson's disease (PD). Precise control over engrafted cell activity is highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.
引用
收藏
页码：817 / 826
页数：10
相关论文
共 33 条
[1]   Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors [J].
Alexander, Georgia M. ;
Rogan, Sarah C. ;
Abbas, Atheir I. ;
Armbruster, Blaine N. ;
Pei, Ying ;
Allen, John A. ;
Nonneman, Randal J. ;
Hartmann, John ;
Moy, Sheryl S. ;
Nicolelis, Miguel A. ;
McNamara, James O. ;
Roth, Bryan L. .
NEURON, 2009, 63 (01) :27-39
[2]   Dopamine modulation of excitatory currents in the striatum is dictated by the expression of D1 or D2 receptors and modified by endocannabinoids [J].
Andre, Veronique M. ;
Cepeda, Carlos ;
Cummings, Damian M. ;
Jocoy, Emily L. ;
Fisher, Yvette E. ;
Yang, X. William ;
Levine, Michael S. .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2010, 31 (01) :14-28
[3]   An optical neural interface:: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology [J].
Aravanis, Alexander M. ;
Wang, Li-Ping ;
Zhang, Feng ;
Meltzer, Leslie A. ;
Mogri, Murtaza Z. ;
Schneider, M. Bret ;
Deisseroth, Karl .
JOURNAL OF NEURAL ENGINEERING, 2007, 4 (03) :S143-S156
[4]   Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand [J].
Armbruster, Blaine N. ;
Li, Xiang ;
Pausch, Mark H. ;
Herlitze, Stefan ;
Roth, Bryan L. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (12) :5163-5168
[5]   Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease [J].
Barker, Roger A. ;
Barrett, Jessica ;
Mason, Sarah L. ;
Bjorklund, Anders .
LANCET NEUROLOGY, 2013, 12 (01) :84-91
[6]   L-DOPA and graft-induced dyskinesia: Different treatment, same story? [J].
Breger, Ludivine S. ;
Lane, Emma L. .
EXPERIMENTAL BIOLOGY AND MEDICINE, 2013, 238 (07) :725-732
[7]   Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9 [J].
Chen, Yuejun ;
Cao, Jingyuan ;
Xiong, Man ;
Petersen, Andrew J. ;
Dong, Yi ;
Tao, Yunlong ;
Huang, Cindy Tzu-Ling ;
Du, Zhongwei ;
Zhang, Su-Chun .
CELL STEM CELL, 2015, 17 (02) :233-244
[8]   hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice [J].
Cunningham, Miles ;
Cho, Jun-Hyeong ;
Leung, Amanda ;
Savvidis, George ;
Ahn, Sandra ;
Moon, Minho ;
Lee, Paula K. J. ;
Han, Jason J. ;
Azimi, Nima ;
Kim, Kwang-Soo ;
Bolshakov, Vadim Y. ;
Chung, Sangmi .
CELL STEM CELL, 2014, 15 (05) :559-573
[9]   Remote control of induced dopaminergic neurons in parkinsonian rats [J].
Dell'Anno, Maria Teresa ;
Caiazzo, Massimiliano ;
Leo, Damiana ;
Dvoretskova, Elena ;
Medrihan, Lucian ;
Colasante, Gala ;
Giannelli, Serena ;
Theka, Ilda ;
Russo, Giovanni ;
Mus, Liudmila ;
Pezzoli, Gianni ;
Gainetdinov, Raul R. ;
Benfenati, Fabio ;
Taverna, Stefano ;
Dityatev, Alexander ;
Broccoli, Vania .
JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (07) :3215-3229
[10]   Transplantation of embryonic dopamine neurons for severe Parkinson's disease. [J].
Freed, CR ;
Greene, PE ;
Breeze, RE ;
Tsai, WY ;
DuMouchel, W ;
Kao, R ;
Dillon, S ;
Winfield, H ;
Culver, S ;
Trojanowski, JQ ;
Eidelberg, D ;
Fahn, S .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (10) :710-719
1234