Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (44), p.15804-15809
• Main Authors: Kang, Xinjiang, Xu, Huadong, Teng, Sasa, Zhang, Xiaoyu, Deng, Zijun, Zhou, Li, Zuo, Panli, Liu, Bing, Liu, Bin, Wu, Qihui, Wang, Li, Hu, Meiqin, Dou, Haiqiang, Liu, Wei, Zhu, Feipeng, Li, Qing, Guo, Shu, Gu, Jingli, Lei, Qian, Lü, Jing, Mu, Yu, Jin, Mu, Wang, Shirong, Jiang, Wei, Liu, Kun, Wang, Changhe, Li, Wenlin, Zhang, Kang, Zhou, Zhuan
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cell Differentiation; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Electrodes; Embryonic stem cells; Heterografts; Humans; Lamps; Male; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - transplantation; Neurons; Parkinson disease; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - therapy; Parkinson's disease; Pluripotent stem cells; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Stem cells; Tissue grafting; Tissue therapy; Transplantation; Transplants & implants; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1408484111

Significance With a combination of HPLC and carbon fiber electrodes, we demonstrate that grafted neural stem cells directly release dopamine in the damaged striatum in vivo and partially rescue a Parkinson’s disease (PD) model. ( i ) Primitive neural stem cell–dopamine-like neuron (pNSC–DAn) retained tyrosine hydroxylase expression and reduced the PD-like asymmetric rotation; ( ii ) depolarization-evoked dopamine release and reuptake were significantly rescued in striatum in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical micro-carbon fiber electrodes; and ( iii ) the rescued dopamine was released directly from the grafted pNSC–DAn (not from the injured original cells). Thus, pNSC–DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation. Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson’s disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopamine-like neurons (pNSC–DAn) in culture. Here, we showed that after the striatal transplantation of pNSC–DAn, ( i ) pNSC–DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; ( ii ) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and ( iii ) the rescued dopamine was released directly from the grafted pNSC–DAn (and not from injured original cells). Thus, pNSC–DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proof-of-concept for human clinical translation.