Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease.
For the safe clinical application of embryonic stem cells (ESCs) for neurological diseases, it is critical to evaluate the tumorigenicity and function of human ESC (hESC)-derived neural cells in primates. We have herein, for the first time, compared the growth and function of hESC-derived cells with different stages of neural differentiation implanted in the brains of primate models of Parkinson's disease. We herein show that residual undifferentiated cells expressing ESC markers present in the cell preparation can induce tumor formation in the monkey brain. In contrast, a cell preparation matured by 42-day culture with brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor (BDNF/GDNF) treatment did not form tumors and survived as primarily dopaminergic (DA) neurons. In addition, the monkeys with such grafts showed behavioral improvement for at least 12 months. These results support the idea that hESCs, if appropriately matured, can serve as a source for DA neurons without forming any tumors in a primate brain.
Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Daisuke
D
Doi
Asuka
A
Morizane
Tetsuhiro
T
Kikuchi
Hirotaka
H
Onoe
Takuya
T
Hayashi
Toshiyuki
T
Kawasaki
Makoto
M
Motono
Yoshiki
Y
Sasai
Hidemoto
H
Saiki
Masanori
M
Gomi
Tatsuya
T
Yoshikawa
Hideki
H
Hayashi
Mizuya
M
Shinoyama
Mohamed M
MM
Refaat
Hirofumi
H
Suemori
Susumu
S
Miyamoto
Jun
J
Takahashi
D000818:Animals; D018929:Cell Culture Techniques; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D000882:Haplorhini; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous