Richardson R Mark, Nguyen Binh, Holt Shawn E, Broaddus William C, Fillmore Helen L
Department of Neurosurgery, Medical College of Virginia, Hospitals, Virginia Commonwealth University, VA, USA.
Neurosci Lett. 2007 Jun 27;421(2):168-72. doi: 10.1016/j.neulet.2007.03.079. Epub 2007 Jun 2.
There is significant interest in the potential use of telomerase-immortalized cells in transplantation to replace neurons lost to neurodegenerative diseases and other central nervous system injuries. Neural progenitor cells (NPCs) transduced with human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, have the potential both to proliferate indefinitely in vitro and to respond to differentiation signals necessary for generating appropriate cells for transplantation. The purpose of this study was to evaluate the differentiation of neurons from NT2 cells, a model NPC cell line, following hTERT transduction. RT-PCR and telomerase activity data demonstrated that persistent exogenous hTERT expression significantly inhibited the differentiation of neurons from NT2 cells. Following retinoic acid induced differentiation, hTERT-NT2 cells produced only one fourth of the neurons generated by parental and vector-control cells. A differentiation-inhibiting effect of constitutive telomerase activity has not been reported previously in other hTERT-transduced progenitor cell lines, implying a unique role for telomerase in the proliferation and differentiation of NPCs that have tumorigenic potential. Elucidating the mechanism responsible for this effect may aid in understanding the potential role of telomerase activity in the tumorigenicity of NPCs, as well as in optimizing the production of safe, telomerase-engineered, transplantable neurons.
人们对端粒酶永生化细胞在移植中的潜在用途有着浓厚兴趣，以替代因神经退行性疾病和其他中枢神经系统损伤而丧失的神经元。用端粒酶的催化成分人端粒酶逆转录酶（hTERT）转导的神经祖细胞（NPCs），既有在体外无限增殖的潜力，又能对生成适合移植的细胞所需的分化信号作出反应。本研究的目的是评估hTERT转导后，模型NPC细胞系NT2细胞向神经元的分化情况。逆转录聚合酶链反应（RT-PCR）和端粒酶活性数据表明，持续的外源性hTERT表达显著抑制了NT2细胞向神经元的分化。在视黄酸诱导分化后，hTERT-NT2细胞产生的神经元仅为亲本细胞和载体对照细胞产生的神经元的四分之一。组成型端粒酶活性的分化抑制作用此前在其他hTERT转导的祖细胞系中尚未见报道，这意味着端粒酶在具有致瘤潜力的NPCs的增殖和分化中具有独特作用。阐明造成这种效应的机制可能有助于理解端粒酶活性在NPCs致瘤性中的潜在作用，以及优化安全的、经端粒酶工程改造的可移植神经元的生产。
