Evaluation of human fetal neural stem/progenitor cells as a source for cell replacement therapy for neurological disorders: properties and tumorigenicity after long-term in vitro maintenance.
It is expected that human neural stem/progenitor cells (hNS/PCs) will some day be used in cell replacement therapies. However, their availability is limited because of ethical issues, so they have to be expanded to obtain sufficient amounts for clinical application. Moreover, in-vitro-maintained hNS/PCs may have a potential for tumorigenicity that could be manifested after transplantation in vivo. In the present study, we demonstrate the in vitro and in vivo properties of long-term-expanded hNS/PCs, including a 6-month bioluminescence imaging (BLI) study of their in vivo tumorigenicity. hNS/PCs cultured for approximately 250 days in vitro (hNS/PCs-250) exhibited a higher growth rate and greater neurogenic potential than those cultured for approximately 500 days in vitro (hNS/PCs-500), which showed greater gliogenic potential. In vivo, both hNS/PCs-250 and -500 differentiated into neurons and astrocytes 4 weeks after being transplanted into the striatum of immunodeficient mice, and hNS/PCs-250 exhibited better survival than hNS/PCs-500 at this time point. We also found that the grafted hNS/PCs-250 survived stably and differentiated properly into neurons and astrocytes even 6 months after the surgery. Moreover, during the 6-month observation period by BLI, we did not detect any evidence of rapid tumorigenic growth of the grafted hNS/PCs, and neither PCNA/Ki67-positive proliferating cells nor significant malignant invasive features were detected histologically. These findings support the idea that hNS/PCs may represent a nontumorigenic, safe, and appropriate cell source for regenerative therapies for neurological disorders.
Ogawa
Daisuke
D
Department of Physiology, School of Medicine, Keio University, Tokyo, Japan.
Okada
Yohei
Y
Nakamura
Masaya
M
Kanemura
Yonehiro
Y
Okano
Hirotaka James
HJ
Matsuzaki
Yumi
Y
Shimazaki
Takuya
T
Ito
Mamoru
M
Ikeda
Eiji
E
Tamiya
Takashi
T
Nagao
Seigo
S
Okano
Hideyuki
H
D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005333:Fetus; D005434:Flow Cytometry; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009422:Nervous System Diseases / Q000628:therapy; D009474:Neurons / Q000166:cytology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000473:pathology*