Mesenchymal epimorphin is important for pancreatic duct morphogenesis

Abstract

Epithelial-mesenchymal interactions are crucial for the proper development of many organs, including the pancreas. Within the pancreas, the ducts are thought to harbor stem/progenitor cells, and possibly to give rise to pancreatic ductal carcinoma. Little is known about the mechanism of formation of pancreatic ducts in the embryo. Pancreatic mesenchyme contains numerous soluble factors which help to sustain the growth and differentiation of exocrine and endocrine structures. Here, we report that one such morphoregulatory mesenchymal protein, epimorphin, plays an important role during pancreatic ductal proliferation and differentiation. We found that epimorphin is expressed in pancreatic mesenchyme during early stages of development, and at mesenchymal-epithelial interfaces surrounding the ducts at later stages. Strong upregulation of epimorphin expression was seen during in vitro pancreatic duct differentiation. Similarly, in vitro pancreatic duct formation was inhibited by a neutralizing antibody against epimorphin, whereas addition of recombinant epimorphin partially rescued duct formation. Together, our study demonstrates the role of epimorphin in pancreatic ductal morphogenesis.

Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar–ductal metaplasia

“…More recent studies that aimed to define epithelial lineage-specific responses to mesenchymal signals demonstrated that removal of the pancreatic mesenchyme disrupted acinar cell morphogenesis, thus inhibiting epithelial branching and outgrowth (Gittes et al 1996;Miralles et al 1998). These results clearly defined the dependence of pancreatic epithelial cell fate decisions on mesenchymal cues, and subsequent work has demonstrated that FGF (Bhushan et al 2001), EGF (Tulachan et al 2006), retinoic acid (Stafford et al 2006), WNT (Jonckheere et al 2008), and bone morphogenetic protein (Ahnfelt-Rønne et al 2010) are important mediators of this process. Similar to pancreatic epithelial cell development during organogenesis, the paracrine signaling networks between the pancreatic epithelium and its adjacent stroma in cancer development have been the subject of intense scrutiny.…”

Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-κB

“…One question is which factor in Matrigel leads to spheroid formation, since Matrigel contains various growth factors and ECM [32]. Matrigel has been reported to contain epimorphin [47] and an epimorphin-neutralizing antibody blocks development of the cystic ductal structures cultured on Matrigel [48]. It remains a possibility that proteases derived from Matrigel but not from hepatocytes contribute to spheroid formation, because Matrigel has been reported to contain inactive proteases [49].…”

Exocrine ontogenies: On the development of pancreatic acinar, ductal and centroacinar cells

“…Specifically, 9- cis retinoic acid (9cRA) inhibits acinar differentiation in the developing pancreas, in favor of ducts, and 9cRA does not induce ductal differentiation in the absence of mesenchyme or following inhibition of laminin signaling [69]. Another mesenchyme-derived soluble factor selectively promoting pancreatic ductal proliferation and differentiation is epimorphin (syntaxin 2), which is also known to induce epithelial branching in a variety of tissues [71, 72]. …”