Regulation of Boundary Cap Neural Crest Stem Cell Differentiation After Transplantation
Regulation of Boundary Cap Neural Crest Stem Cell Differentiation After Transplantation
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DOI：
10.1002/stem.77
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Kozlova, Elena N.
中科院分区：
文献类型：
--
作者：
Aldskogius, Hakan;Berens, Christian;Kozlova, Elena N.
神经系统疾病细胞替代疗法的成功将在很大程度上取决于优化策略，以提高干细胞移植后的生存能力和控制干细胞的发育命运。一旦移植，干细胞/祖细胞表现出维持未分化表型或分化为不适当细胞类型的倾向。功能增益和功能损失实验揭示了驱动未成熟干细胞/祖细胞向更成熟阶段分化并最终完全分化的关键转录因子。因此，促进移植干细胞存活并引导其向特定细胞类型分化的一个有吸引力的行动过程是，使用可从外部控制的诱导基因表达系统，在已经移植的干细胞中强制表达调节分化分子。在这里，我们通过四环素基因调节系统（Tet-On）来驱动边界帽神经嵴干细胞（bNCSCs）在移植后向感觉神经元的分化来探索这一假设。我们在表达sox10的bscs中诱导关键转录因子Runx1的表达。在背根神经节腔丰富的神经营养环境中，Runx1的强制表达强烈地提高了移植存活率，并足以在移植后的体外和体内引导bNCSCs向非肽能性伤害感觉神经元表型分化。这些发现表明，干细胞/祖细胞移植后转录因子表达的外源激活可能是控制其存活以及向所需细胞类型分化的建设性方法，而tet系统是实现这一目标的有用工具。干细胞2009；27日:1592 - 1603
Success of cell replacement therapies for neurological disorders will depend largely on the optimization of strategies to enhance viability and control the developmental fate of stem cells after transplantation. Once transplanted, stem/progenitor cells display a tendency to maintain an undifferentiated phenotype or differentiate into inappropriate cell types. Gain and loss of function experiments have revealed key transcription factors which drive differentiation of immature stem/progenitor cells toward more mature stages and eventually to full differentiation. An attractive course of action to promote survival and direct the differentiation of transplanted stem cells to a specific cell type would therefore be to force expression of regulatory differentiation molecules in already transplanted stem cells, using inducible gene expression systems which can be controlled from the outside. Here, we explore this hypothesis by employing a tetracycline gene regulating system (Tet-On) to drive the differentiation of boundary cap neural crest stem cells (bNCSCs) toward a sensory neuron fate after transplantation. We induced the expression of the key transcription factor Runx1 in Sox10-expressing bNCSCs. Forced expression of Runx1 strongly increased transplant survival in the enriched neurotrophic environment of the dorsal root ganglion cavity, and was sufficient to guide differentiation of bNCSCs toward a nonpeptidergic nociceptive sensory neuron phenotype both in vitro and in vivo after transplantation. These findings suggest that exogenous activation of transcription factors expression after transplantation in stem/progenitor cell grafts can be a constructive approach to control their survival as well as their differentiation to the desired type of cell and that the Tet-system is a useful tool to achieve this. STEM CELLS 2009; 27: 1592-1603