Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors

Abstract

Pancreatic organogenesis has been a classic example of epitheliomesenchymal interactions. The nature of this interaction, and the way in which endocrine, acinar and ductal cell lineages are generated from the embryonic foregut has not been determined. It has generally been thought that mesenchyme is necessary for all aspects of pancreatic development. In addition islets have been thought to derive, at least in part, from ducts. We microdissected 11-day embryonic mouse pancreas and developed several culture systems for assays of differentiation: (i) on transparent filters; (ii) suspended in a collagen I gel; (iii) suspended in a basement membrane rich gel; (iv) under the renal capsule of an adult mouse. Epithelia were grown either with or without mesenchyme, and then assayed histologically and immunohistochemically. Epithelium with its mesenchyme (growth systems i-iv) always grew into fully differentiated pancreas (acinar, endocrine, adn ductal elements). In the basement membrane-rich gel, epithelium without mesenchyme formed ductal structures. Under the renal capsule of the adult mouse the epithelium without mesenchyme exclusively formed clusters of mature islets. These latter results represent the first demonstration of pure islets grown from early pancreatic precursor cells. In addition, these islets seemed not to have originated from ducts. We propose that the default path for growth of embryonic pancreatic epithelium is to form islets. In the presence of basement membrane constituents, however, the pancreatic analage epithelium appears to be programmed to form ducts. Mesenchyme seems not to be required for all aspects of pancreatic development, but rather only for the formation of acinar structures. In addition, the islets seem to form from early embryonic epithelium (which only express non-acinar genes). This formation occurs without any specific embryonic signals, and without any clear duct or acinus formation.

Single cell transcriptomic and spatial landscapes of the developing human pancreas

“…A similar mesenchyme-acinar trajectory was predicted in situ from our spatial transcriptomics data, and we identified significant enrichment of gene ontologies involved in acinar cell differentiation, such as positive regulation of canonical Wnt-beta-catenin signalling, planar cell polarity and glandular epithelial cell development (Murtaugh, 2008; Wells et al, 2007). This points to the importance of the mesenchyme in appropriate differentiation of acinar cells in the developing human pancreas, which is in agreement with a previous study where mouse exocrine pancreas failed to develop in the absence of pancreatic mesenchyme (Gittes et al, 1996).…”

Valproic Acid Initiates Transdifferentiation of the Human Ductal Adenocarcinoma Cell-line Panc-1 Into α-Like Cells

“…1, Figure S2, Figure S10). Reciprocal epitheliomesenchymal [52] and endothelioepithelial [53,54] interactions are crucial for the development and differentiation of the endocrine pancreas. The topmost differentially regulated genes included DLL1 (delta-like canonical notch ligand 1) and JAG1 (jagged 1) which regulate early endocrine differentiation [55,56], and EPHB1/2 encoding for Ephrin receptors which are involved in angiogenesis [57] and serve as endocrine progenitor markers [58].…”

Pathophysiologic Basis of Exocrine Pancreatic Dysfunction in Childhood

“…Differentiation of ductal epithelium is important for subsequent exocrine and endocrine development, especially as endocrine stem cells are thought to arise from ductal epithelia (3,20). In a murine model of pancreatic embryogenesis, duct formation occurs following differentiation of the pancreatic epithelium under the influence of the surrounding milieu (17). Expression of the basement membrane glycoprotein, laminin-1, is of critical importance for the formation of pancreatic ducts (18) which occurs during a crucial "window of competence" in the first two weeks of gestation (19,20).…”