Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.
Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.
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DOI：
10.1371/journal.pone.0002904
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发表时间：
2008-08-06
期刊：
影响因子：
3.7
通讯作者：
Hong CC
中科院分区：
文献类型：
--
作者：
Hao J;Daleo MA;Murphy CK;Yu PB;Ho JN;Hu J;Peterson RT;Hatzopoulos AK;Hong CC
多能胚胎干细胞（ES）具有产生体内所有组织类型的能力，作为再生治疗的多功能细胞来源显示出巨大的前景。然而，多能干细胞谱系特化的基本机制在很大程度上是未知的，并且产生足够数量的所需细胞类型仍然是一个艰巨的挑战。小分子，特别是那些调节关键发育途径，如骨形态发生蛋白（BMP）信号级联的小分子，有望成为研究体外谱系特化和指导干细胞向特定细胞类型分化的工具。我们描述了使用dorsomorphin，BMP信号的选择性小分子抑制剂，诱导小鼠ES细胞心肌分化。心脏诱导是非常强大的，增加自发跳动的心肌细胞的产量至少20倍。与内源性BMP拮抗剂Noggin不同，当治疗仅限于ES细胞分化的最初24小时时，Dorsomorphin会强烈诱导心肌发生。分化ES细胞的定量PCR分析表明，在早期关键阶段的BMP信号的药理学抑制促进心肌细胞谱系的发展，但减少了内皮细胞，平滑肌细胞和造血细胞的分化。在ES细胞分化的初始阶段施用选择性小分子BMP抑制剂显著促进原始多能细胞向心肌细胞谱系的分化，显然是以牺牲其他中胚层谱系为代价的。像dorsomorphin这样的发育途径的小分子调节剂可以成为干细胞研究和再生医学的通用药理学工具。
Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine.
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影响因子：
15
作者：
Wu, X;Ding, S;Schultz, PG
通讯作者：
Schultz, PG
DOI：
10.1073/pnas.0605768103
发表时间：
2006-12-26
影响因子：
11.1
作者：
Naito, Atsuhiko T.;Shiojima, Ichiro;Komuro, Issei
通讯作者：
Komuro, Issei
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya
影响因子：
56.9
作者：
Yu, Junying;Vodyanik, Maxim A.;Thomson, James A.
通讯作者：
Thomson, James A.
影响因子：
14.8
作者：
Yui, Paul B.;Hong, Charles C.;Peterson, Randall T.
通讯作者：
Peterson, Randall T.