FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity.
FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity.
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DOI：
10.1161/circresaha.111.255950
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发表时间：
2012-02-17
影响因子：
20.1
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Zhang J;Liu J;Huang Y;Chang JY;Liu L;McKeehan WL;Martin JF;Wang F
尽管成纤维细胞生长因子（FGF）信号轴在心脏发育中起重要作用，但FGF调控心脏发生的分子机制尚不完全清楚。探讨FGF信号通路调控心脏祖细胞分化的机制。通过对小鼠心脏祖细胞中FGF受体和FGF受体底物2α (Frs2α)进行组织特异性消融，我们发现FGF信号的破坏会导致小鼠心脏祖细胞过早分化。利用胚胎体（EB）培养的小鼠胚胎干细胞（ESCs），我们发现FGF信号通路促进ESCs中胚层细胞的分化，但在后期抑制中胚层细胞的心肌细胞分化。此外，我们还报道抑制frs2 α-介导的信号增加自噬，激活自噬促进心肌分化，反之亦然。结果表明，FGF/ frs2 α-介导的信号通过抑制自噬来阻止心脏祖细胞过早分化。这一发现首次证明自噬在心脏祖细胞分化中起作用。
Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation. Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2α (Frs2α) in heart progenitor cells, we demonstrate that that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body (EB) cultures of mouse embryonic stem cells (ESCs), we reveal that FGF signaling promotes mesoderm differentiation in ESCs, but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2α-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa. The results indicate that the FGF/FRS2α-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy. The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation.