Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway
Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway
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DOI：
10.1242/jcs.182584
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Frey, Mark R.
中科院分区：
文献类型：
--
作者：
Miguel, Jennifer C.;Maxwell, Adrienne A.;Frey, Mark R.
细胞从肠绒毛脱落是组织更新的关键要素，对维持健康和体内平衡至关重要。然而，调节这一过程的信号并没有得到很好的理解。我们询问脱落是否由表皮生长因子受体（EGFR）控制，EGFR是肠道生长和分化的重要驱动因素。在3D回肠类肠培养和细胞培养模型（MDCK，IEC-6和IPEC-J2细胞），挤出事件被抑制EGF，通过直接计数释放的细胞或罗丹明-鬼笔环肽标记的凝聚肌动蛋白环。阻断MEK-ERK途径，而不是其他下游途径，如磷酸肌醇3-激酶（PI 3 K）或蛋白激酶C（PKC），逆转EGF对脱落的抑制。这些影响不是由于细胞活力的变化造成的。此外，EGF驱动的MAPK信号转导抑制caspase依赖性和非依赖性脱落途径。在一种新的斑马鱼肠上皮脱落模型中，在体内也发现了类似的结果。两者合计，数据表明，EGF抑制细胞脱落在肠上皮细胞通过选择性MAPK依赖性途径影响多种挤出机制。EGFR信号传导可能是以过度细胞更新为特征的疾病（如炎症性肠病）的治疗靶点。
Cell shedding from the intestinal villus is a key element of tissue turnover that is essential to maintain health and homeostasis. However, the signals regulating this process are not well understood. We asked whether shedding is controlled by epidermal growth factor receptor (EGFR), an important driver of intestinal growth and differentiation. In 3D ileal enteroid culture and cell culture models (MDCK, IEC-6 and IPEC-J2 cells), extrusion events were suppressed by EGF, as determined by direct counting of released cells or rhodamine-phalloidin labeling of condensed actin rings. Blockade of the MEK-ERK pathway, but not other downstream pathways such as phosphoinositide 3-kinase (PI3K) or protein kinase C (PKC), reversed EGF inhibition of shedding. These effects were not due to a change in cell viability. Furthermore, EGF-driven MAPK signaling inhibited both caspase-independent and -dependent shedding pathways. Similar results were found in vivo, in a novel zebrafish model for intestinal epithelial shedding. Taken together, the data show that EGF suppresses cell shedding in the intestinal epithelium through a selective MAPK-dependent pathway affecting multiple extrusion mechanisms. EGFR signaling might be a therapeutic target for disorders featuring excessive cell turnover, such as inflammatory bowel diseases.