Targeting native adult heart progenitors with cardiogenic small molecules.
Targeting native adult heart progenitors with cardiogenic small molecules.
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DOI：
10.1021/cb200525q
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发表时间：
2012-06-15
影响因子：
4
通讯作者：
Schneider, Jay W.
中科院分区：
文献类型：
--
作者：
Russell, Jamie L.;Goetsch, Sean C.;Aguilar, Hector R.;Frantz, Doug E.;Schneider, Jay W.
使用指导细胞命运决定的小分子药物靶向天然祖细胞是再生医学的一种有吸引力的方法。在这里，我们展示了最初在基于 P19 胚胎癌细胞的筛选中回收的干细胞调节剂小分子 3,5-二取代异恶唑 (Isx)，在成年转基因报告小鼠的靶组织中指导体内心肌基因表达。 Isx 还刺激成年小鼠心肌细胞周期活动。将我们的注意力集中在一个目标心脏祖细胞群上，Isx 在多能 Notch 激活的心外膜衍生细胞 (NEC) 中指导体内肌肉转录程序，产生 Notch 激活的成体心肌细胞样前体细胞。心肌梗死 (MI) 预先将 NEC 分化为成纤维细胞谱系，从而克服了 Isx 对该细胞群的心源性影响。 Isx 在体内 Notch 激活的修复成纤维细胞中基因表达失调，驱动独特的（促血管生成）基因程序，但未能减轻纤维化或避免 MI 后心室功能下降。在体外 NEC 中，Isx 指导部分肌肉分化，其中包括肌节 α-肌动蛋白前肌原纤维的生物合成和组装，这是早期发育心肌细胞特有的珠状结构。因此，尽管 Isx 小分子在天然多能祖细胞的心肌基因表达水平上具有良好的体内功效，并且在这方面是同类首创，但需要更深入地了解纤维化和心源性小分子信号之间的动态相互作用，才能在药理学上实现心脏的再生修复。
Targeting native progenitors with small-molecule pharmaceuticals that direct cell fate decisions is an attractive approach for regenerative medicine. Here, we show that 3,5-disubstituted isoxazoles (Isx), stem cell-modulator small-molecules originally recovered in a P19 embryonal carcinoma cell-based screen, directed cardiac muscle gene expression in vivo in target tissues of adult transgenic reporter mice. Isx also stimulated adult mouse myocardial cell cycle activity. Narrowing our focus onto one target cardiac-resident progenitor population, Isx directed muscle transcriptional programs in vivo in multipotent Notch-activated epicardium-derived cells (NECs), generating Notch-activated adult cardiomyocyte-like precursors. Myocardial infarction (MI) preemptively differentiated NECs towards fibroblast lineages, overriding Isx's cardiogenic influence in this cell population. Isx dysregulated gene expression in vivo in Notch-activated repair-fibroblasts, driving distinctive (pro-angiogenesis) gene programs, but failed to mitigate fibrosis or avert ventricular functional decline after MI. In NECs in vitro, Isx directed partial muscle differentiation, which included biosynthesis and assembly of sarcomeric α-actinin premyofibrils, beaded structures pathognomonic of early developing cardiomyocytes. Thus, although Isx small-molecules have promising in vivo efficacy at the level of cardiac muscle gene expression in native multipotent progenitors – and are first in class in this regard – a greater understanding of the dynamic interplay between fibrosis and cardiogenic small-molecule signals will be required to pharmacologically enable regenerative-repair of the heart.
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DOI：
10.1073/pnas.0711507105
发表时间：
2008-04-22
影响因子：
11.1
作者：
Sadek, Hesham;Hannack, Britta;Schneider, Jay W.
通讯作者：
Schneider, Jay W.
影响因子：
46.9
作者：
Adams, Gregor B.;Martin, Roderick P.;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
64.5
作者：
Daley, George Q.;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
2.9
作者：
Zhang, Ling;Li, Peng;Hsu, Tiffany;Aguilar, Hector R.;Frantz, Doug E.;Schneider, Jay W.;Bachoo, Robert M.;Hsieh, Jenny
通讯作者：
Hsieh, Jenny
影响因子：
64.8
作者：
Smart, Nicola;Bollini, Sveva;Dube, Karina N.;Vieira, Joaquim M.;Zhou, Bin;Davidson, Sean;Yellon, Derek;Riegler, Johannes;Price, Anthony N.;Lythgoe, Mark F.;Pu, William T.;Riley, Paul R.
通讯作者：
Riley, Paul R.