Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors.
Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors.
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DOI：
10.1371/journal.pone.0042838
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zambidis ET
中科院分区：
文献类型：
--
作者：
Park TS;Huo JS;Peters A;Talbot CC Jr;Verma K;Zimmerlin L;Kaplan IM;Zambidis ET
皮肤或血细胞向临床有用的人诱导多能干细胞（hiPSC）的非病毒转化仅发生在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。发育不成熟干祖细胞的多能性诱导通常比分化的体细胞靶更有效。然而，增强的祖细胞重编程的性质仍然不清楚，其潜力尚未得到充分探索，以改善非整合重编程的极其缓慢的步伐。在这里，我们报告了高度优化的四因子重编程谱系承诺的脐带血（CB）髓系祖细胞的批量效率为50%以上的纯化的附加体表达细胞。谱系定向的CD 33 + CD 45 + CD 34 −髓样细胞而不是原始造血干祖细胞是快速且几乎完全的非整合重编程的主要目标。成熟骨髓群体向NANOG+TRA-1-81+ hiPSC的有效转化由造血生长因子（GF）、基质活化信号和附加型Yamanaka因子表达之间的协同作用介导。使用模块化生物信息学方法，我们证明了有效的骨髓重编程与增殖或内源性核心因子表达增加无关，但与GF激活的转录回路的平衡表达相关，该转录回路通常调节造血祖细胞和胚胎干细胞（ESC）的可塑性。可溶性和接触依赖性基质信号进一步加速了因子驱动的骨髓祖细胞向高保真多能状态的转化，其中包括Toll受体-NF κB信号传导的隐含和意外作用。这些数据提供了一个范例，了解增强的重编程能力的体细胞祖细胞，并揭示，有效的诱导多能性在其他细胞类型也可能需要外源性激活的分子框架，通常调节自我更新和分化的造血祖细胞和ESC。
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.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
重编程因子表达引发了广泛的靶向染色质重塑。
影响因子：
23.9
作者：
Koche RP;Smith ZD;Adli M;Gu H;Ku M;Gnirke A;Bernstein BE;Meissner A
通讯作者：
Meissner A
影响因子：
64.8
作者：
Gaspar-Maia A;Alajem A;Polesso F;Sridharan R;Mason MJ;Heidersbach A;Ramalho-Santos J;McManus MT;Plath K;Meshorer E;Ramalho-Santos M
通讯作者：
Ramalho-Santos M
影响因子：
5.2
作者：
Hayashi, Yohei;Furue, Miho Kusuda;Asashima, Makoto
通讯作者：
Asashima, Makoto
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.