Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, 2213 Garland Avenue, Nashville, TN 37232-6300, USA.
Dis Model Mech. 2011 Jul;4(4):469-83. doi: 10.1242/dmm.006510. Epub 2011 Feb 14.
Despite available therapies, myocardial infarction (MI) remains a leading cause of death worldwide. Better understanding of the molecular and cellular mechanisms that regulate cardiac repair should help to improve the clinical outcome of MI patients. Using the reporter mouse line TOPGAL, we show that canonical (β-catenin-dependent) Wnt signaling is induced 4 days after experimental MI in subepicardial endothelial cells and perivascular smooth muscle actin (SMA)-positive (SMA(+)) cells. At 1 week after ischemic injury, a large number of canonical-Wnt-positive cells accumulated in the infarct area during granulation tissue formation. Coincidently with canonical Wnt activation, endothelial-to-mesenchymal transition (EndMT) was also triggered after MI. Using cell lineage tracing, we show that a significant portion of the canonical-Wnt-marked SMA(+) mesenchymal cells is derived from endothelial cells. Canonical Wnt signaling induces mesenchymal characteristics in cultured endothelial cells, suggesting a direct role in EndMT. In conclusion, our study demonstrates that canonical Wnt activation and EndMT are molecular and cellular responses to MI and that canonical Wnt signaling activity is a characteristic property of EndMT-derived mesenchymal cells that take part in cardiac tissue repair after MI. These findings could lead to new strategies to improve the course of cardiac repair by temporal and cell-type-specific manipulation of canonical Wnt signaling.
尽管有可用的治疗方法，但心肌梗死 (MI) 仍然是全球范围内主要的死亡原因。更好地了解调节心脏修复的分子和细胞机制，应该有助于改善 MI 患者的临床预后。使用报告基因小鼠系 TOPGAL，我们显示经典（β-catenin 依赖性）Wnt 信号在实验性 MI 后 4 天在心脏外膜内皮细胞和血管周围平滑肌肌动蛋白 (SMA)-阳性 (SMA(+)) 细胞中被诱导。在缺血性损伤后 1 周，大量经典-Wnt 阳性细胞在肉芽组织形成过程中在梗死区积累。与经典 Wnt 激活同时发生的是，MI 后还引发了内皮到间充质转化 (EndMT)。通过细胞谱系追踪，我们表明，在经典-Wnt 标记的 SMA(+)间充质细胞中有很大一部分是来自内皮细胞。经典 Wnt 信号诱导培养的内皮细胞具有间充质特征，表明其在 EndMT 中具有直接作用。总之，我们的研究表明，经典 Wnt 激活和 EndMT 是 MI 的分子和细胞反应，并且经典 Wnt 信号活性是参与 MI 后心脏组织修复的 EndMT 衍生间充质细胞的特征特性。这些发现可能导致通过经典 Wnt 信号的时间和细胞类型特异性操纵来改善心脏修复过程的新策略。
