Cardiogenic induction of pluripotent stem cells streamlined through a conserved SDF-1/VEGF/BMP2 integrated network.
Cardiogenic induction of pluripotent stem cells streamlined through a conserved SDF-1/VEGF/BMP2 integrated network.
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DOI：
10.1371/journal.pone.0009943
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发表时间：
2010-04-01
期刊：
影响因子：
3.7
通讯作者：
Terzic A
中科院分区：
文献类型：
--
作者：
Chiriac A;Nelson TJ;Faustino RS;Behfar A;Terzic A
多能干细胞通过程序性获取作为器官形成蓝图的顺序基因表达模式产生组织特异性谱系。由于胚胎干细胞在分化过程中同时响应多种信号通路，提取促心源网络将为简化心脏祖细胞输出提供路线图。为了解决前体转录组中的基因本体优先级，根据生长因子指导或特定阶段的生物标志物分类，在这里生成了心源亚群。先天表达谱通过无偏系统生物学作图独立描绘，并交叉参考过滤转录噪声，揭示保守的祖基序（55个上调基因和233个下调基因）。288个基因组成了一个核心生物网络，优先考虑“心血管发育”功能。心源性邻域和相关典型信号通路的递归计算机反卷积发现了集成轴CXCR4/SDF-1、Flk-1/VEGF和BMP2r/BMP2的组合，预计将同步心脏规范。在胚胎体中体外靶向解决的三联体加速了Nkx2.5， Mef2C和心脏mhc的表达，增强了跳动活性，增加了心源性产量。在转录组范围内对保守的祖基因进行解剖，从而揭示了从多能性基态协调心源性成熟的功能通路。通过对生物信息学算法的验证，建立了合理调节细胞命运、优化干细胞源性心脏发生的策略。
Pluripotent stem cells produce tissue-specific lineages through programmed acquisition of sequential gene expression patterns that function as a blueprint for organ formation. As embryonic stem cells respond concomitantly to diverse signaling pathways during differentiation, extraction of a pro-cardiogenic network would offer a roadmap to streamline cardiac progenitor output. To resolve gene ontology priorities within precursor transcriptomes, cardiogenic subpopulations were here generated according to either growth factor guidance or stage-specific biomarker sorting. Innate expression profiles were independently delineated through unbiased systems biology mapping, and cross-referenced to filter transcriptional noise unmasking a conserved progenitor motif (55 up- and 233 down-regulated genes). The streamlined pool of 288 genes organized into a core biological network that prioritized the “Cardiovascular Development” function. Recursive in silico deconvolution of the cardiogenic neighborhood and associated canonical signaling pathways identified a combination of integrated axes, CXCR4/SDF-1, Flk-1/VEGF and BMP2r/BMP2, predicted to synchronize cardiac specification. In vitro targeting of the resolved triad in embryoid bodies accelerated expression of Nkx2.5, Mef2C and cardiac-MHC, enhanced beating activity, and augmented cardiogenic yield. Transcriptome-wide dissection of a conserved progenitor profile thus revealed functional highways that coordinate cardiogenic maturation from a pluripotent ground state. Validating the bioinformatics algorithm established a strategy to rationally modulate cell fate, and optimize stem cell-derived cardiogenesis.
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DOI：
10.1084/jem.20061916
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Behfar A;Perez-Terzic C;Faustino RS;Arrell DK;Hodgson DM;Yamada S;Puceat M;Niederländer N;Alekseev AE;Zingman LV;Terzic A
通讯作者：
Terzic A
影响因子：
5.2
作者：
Arrell, D. Kent;Niederlaender, Nicolas J.;Terzic, Andre
通讯作者：
Terzic, Andre
DOI：
10.1152/ajpheart.00363.2005
发表时间：
2006-10-01
影响因子：
4.8
作者：
Chen, Yu;Amende, Ivo;Morgan, James P.
通讯作者：
Morgan, James P.
影响因子：
4.4
作者：
Arrell, D. Kent;Zlatkovic, Jelena;Kane, Garvan C.;Yamada, Satsuki;Terzic, Andre
通讯作者：
Terzic, Andre
影响因子：
3.9
作者：
Faustino, Randolph S.;Chiriac, Anca;Terzic, Andre
通讯作者：
Terzic, Andre