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
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
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DOI：
10.1002/jnr.21843
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Ogawa, Daisuke;Okada, Yohei;Okano, Hideyuki
预计人类神经干/祖细胞 (hNS/PC) 有一天将用于细胞替代疗法。然而，由于伦理问题，它们的可用性受到限制，因此必须扩大它们以获得足够的临床应用量。此外，体外维持的 hNS/PC 可能具有潜在的致瘤性，这种致瘤性可能在体内移植后表现出来。在本研究中，我们展示了长期扩增的 hNS/PC 的体外和体内特性，包括对其体内致瘤性进行的为期 6 个月的生物发光成像 (BLI) 研究。体外培养约 250 天的 hNS/PCs (hNS/PCs-250) 比体外培养约 500 天的 hNS/PCs (hNS/PCs-500) 表现出更高的生长速率和更大的神经生成潜力，后者表现出更大的神经胶质生成潜力。在体内，hNS/PCs-250和-500在移植到免疫缺陷小鼠纹状体中4周后均分化为神经元和星形胶质细胞，并且hNS/PCs-250在该时间点表现出比hNS/PCs-500更好的存活率。我们还发现，移植的 hNS/PCs-250 在术后 6 个月仍能稳定存活并正确分化为神经元和星形胶质细胞。此外，在BLI的6个月观察期内，我们没有检测到移植的hNS/PC快速致瘤生长的任何证据，组织学上也没有检测到PCNA/Ki67阳性增殖细胞或显着的恶性侵袭特征。这些发现支持这样的观点，即 hNS/PC 可能代表一种非致瘤性、安全且合适的细胞来源，用于神经系统疾病的再生治疗。 (c) 2008 年 Wiley-Liss, Inc.
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. (c) 2008 Wiley-Liss, Inc.