Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

BackgroundPluripotent 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.
Methodology/ Principal FindingsWe 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.
Conclusions/ SignificanceAdministration 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.

背景
多能胚胎干细胞（pluripotent embryonic stem cells, ES细胞）具备分化为体内所有组织类型的潜能，作为再生医学领域极具应用前景的多功能细胞来源，展现出广阔的转化潜力。然而，多能干细胞的谱系特化基本机制仍未完全阐明，且足量获取目标细胞类型仍是一项严峻挑战。小分子化合物，尤其是能够调控骨形态发生蛋白（bone morphogenetic protein, BMP）信号级联等关键发育通路的小分子，有望作为体外研究谱系特化、指导干细胞定向分化为特定细胞类型的工具。

方法/主要发现
本研究报道了利用多索莫芬（dorsomorphin）——一种选择性BMP信号通路小分子抑制剂——诱导小鼠ES细胞向心肌细胞分化的方案。该心脏诱导策略效果显著，可使自发搏动的心肌细胞产量提升至少20倍。与内源性BMP拮抗剂Noggin不同，仅在ES细胞分化的最初24小时施加多索莫芬，即可高效诱导心肌发生。对分化过程中ES细胞的定量PCR分析显示，在早期关键阶段通过药理学手段抑制BMP信号通路，可促进心肌细胞谱系的发育，但同时会降低内皮细胞、平滑肌细胞及造血细胞的分化效率。

结论/意义
在ES细胞分化的初始阶段施加选择性BMP小分子抑制剂，可显著促进原始多能细胞向心肌细胞谱系分化，而这似乎是以牺牲其他中胚层谱系的分化为代价的。类似多索莫芬这类能够调控发育通路的小分子调节剂，有望成为干细胞研究与再生医学领域的通用药理学工具。