Cardiogenic small molecules that enhance myocardial repair by stem cells
Cardiogenic small molecules that enhance myocardial repair by stem cells
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DOI：
10.1073/pnas.0711507105
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发表时间：
2008-04-22
影响因子：
11.1
通讯作者：
Schneider, Jay W.
中科院分区：
文献类型：
--
作者：
Sadek, Hesham;Hannack, Britta;Schneider, Jay W.
干细胞治疗心肌修复的临床成功取决于对心脏命运机制的更好理解。我们在小鼠 P19CL6 多能干细胞中使用荧光素酶敲入细菌人工染色体 (BAC)，筛选特征基因 NkK2.5 激活剂的化学文库，从而鉴定出参与心脏命运的小分子。我们描述了磺酰腙 (Shz) 小分子家族，它们可以触发各种胚胎和成体干/祖细胞（包括人动员外周血单核细胞 (M-PBMC)）中的心脏 mRNA 和蛋白质表达。将小分子增强的 M-PBMC 移植到实验损伤附近的大鼠心脏中，比对照细胞更好地改善了心脏功能。心脏功能的恢复与表达人类特异性心脏 mRNA 和蛋白质的存活人类细胞的持续存在相关。 Shz 小分子是通过激活 M-PBMC 心脏分化来促进心肌修复/再生的药物的有前途的起点。
The clinical success of stem cell therapy for myocardial repair hinges on a better understanding of cardiac fate mechanisms. We have identified small molecules involved in cardiac fate by screening a chemical library for activators of the signature gene NkK2.5, using a luciferase knockin bacterial artificial chromosome (BAC) in mouse P19CL6 pluripotent stem cells. We describe a family of sulfonylhydrazone (Shz) small molecules that can trigger cardiac mRNA and protein expression in a variety of embryonic and adult stem/progenitor cells, including human mobilized peripheral blood mononuclear cells (M-PBMCs). Small-molecule-enhanced M-PBMCs engrafted into the rat heart in proximity to an experimental injury improved cardiac function better than control cells. Recovery of cardiac function correlated with persistence of viable human cells, expressing humanspecific cardiac mRNAs and proteins. Shz small molecules are promising starting points for drugs to promote myocardial repair/regeneration by activating cardiac differentiation in M-PBMCs.