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首页> 美国卫生研究院文献>other >Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors
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Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors

机译：增殖物激活干细胞的电路和基质的信号协同促进加快人骨髓祖细胞的非集成的ipsC重新编程

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Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (∼0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ∼50% in purified episome-expressing cells. Lineage-committed CD33+CD45+CD34− myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG+TRA-1-81+ hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NFκB signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self-renewal and differentiation in both hematopoietic progenitors and ESC.
机译：皮肤或血细胞非病毒转化为临床上有用的人诱导多能干细胞（hiPSC）的情况仅发生于用非整合重编程因子转染的供体细胞的罕见部分（约0.001％–0.5％）中。发育不成熟的干祖细胞的多能性诱导通常比分化的体细胞靶标更有效。但是，扩增祖细胞重编程的性质仍然不清楚，并且其潜力尚未得到充分研究以改善非整合重编程的极慢速度。在这里，我们报道了高度优化的四因子重编程的谱系提交的脐带血（CB）髓系祖细胞，在纯化的附加体表达细胞中具有约50％的整体效率。沿袭定型的CD33 + CD45 + CD34 -髓样细胞而非原始造血干祖细胞是快速且几乎完全非-集成的重新编程。造血生长因子（GF），基质激活信号和游离型山梨中药之间的协同作用介导了成熟髓细胞群体向NANOG + TRA-1-81 + hiPSC的有效转化因素表达。使用模块化的生物信息学方法，我们证明了有效的髓样重编程与增殖或内源性核心因子表达的增加无关，而与通常在造血祖细胞和胚胎干细胞（ESC）中调节可塑性的GF激活的转录回路的平衡表达有关。可溶性祖先和可溶性依赖的基质信号进一步促进了髓样祖细胞向高保真多能状态的因子驱动转化，这包括Toll受体-NFκB信号的隐含和意想不到的作用。这些数据为理解体细胞祖细胞增强的重编程能力提供了范例，并揭示了在其他细胞类型中有效诱导的多能性也可能需要分子框架的外在激活，该分子框架通常调节造血祖细胞和ESC的自我更新和分化。

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