Human embryonic stem cell-derived neural precursors as a continuous, stable, and on-demand source for human dopamine neurons.
Human embryonic stem (hES) cells can be guided to differentiate into ventral midbrain-type neural precursor (NP) cells that proliferate in vitro by specific mitogens. We investigated the potential of these NP cells derived from hES cells (hES-NP) for the large-scale generation of human dopamine (DA) neurons for functional analyses and therapeutic applications. To address this, hES-NP cells were expanded in vitro for 1.5 months with six passages, and their proliferation and differentiation properties determined over the NP passages. Interestingly, the total hES-NP cell number was increased by > 2 x 10(4)-folds over the in vitro period without alteration of phenotypic gene expression. They also sustained their differentiation capacity toward neuronal cells, exhibiting in vitro pre-synaptic DA neuronal functionality. Furthermore, the hES-NP cells can be cryopreserved without losing their proliferative and developmental potential. Upon transplantation into a Parkinson's disease rat model, the multi-passaged hES-NP cells survived, integrated into the host striatum, and differentiated toward the neuronal cells expressing DA phenotypes. A significant reduction in the amphetamine-induced rotation score of Parkinson's disease rats was observed by the cell transplantation. Taken together, these findings indicate that hES-NP cell expansion is exploitable for a large-scale generation of experimental and transplantable DA neurons of human-origin.
Ko
Ji-Yun
JY
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, South Korea.
Park
Chang-Hwan
CH
Koh
Hyun-Chul
HC
Cho
Youl-Hee
YH
Kyhm
Jee-Hong
JH
Kim
Young-Soo
YS
Lee
Inchul
I
Lee
Yong-Sung
YS
Lee
Sang-Hun
SH
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004298:Dopamine