2. Epithelial differentiation
The epithelial architecture of the pancreas, organized into branched tubes, and of the thyroid gland, organized into closed follicles, dictates their ultimate function, exocrine vs endocrine. Our team studies the cellular and molecular mechanisms controlling the differentiation of the pancreatic and thyroid epithelial monolayers. Understanding the mechanisms underlying the formation of these epithelial structures is important for developmental biology and could also shed light on human pathologies characterized by epithelial disorganization and dedifferentiation such as carcinomas and cystinosis.
During embryogenesis, the epithelial cells of the pancreas and thyroid gland first form a proliferating mass of non-polarized cells that reorganizes into specialized monolayers. Once fully differentiated, epithelial monolayers possess three distinct membrane domains, each able to transmit signals to transcription factors in the nucleus.
Branching morphogenesis in the pancreas. Reorganization in the early pancreatic bud of the multicellular mass of epithelial cells labelled for E-cadherin (left, red) into polarized monolayers with distinct apical domains (mucin, green) and their merging to create tubules (right). Laminin (blue) delineates basement membranes (From Hick et al., 2009).
Formation of epithelial monolayers requires a coordinate and dynamic interaction with their environment, composed of mesenchymal and endothelial cells. We identified SDF-1 (Stromal cell-Derived Factor-1) as an important signal, produced by the mesenchymal cells, for the reorganization of the salivary and pancreatic epithelial masses into monolayers (Hick et al., 2009). By three-dimensional analysis of the developing pancreas, we also uncovered a dense and close association of the epithelium with endothelial cells.
Epithelial: endothelial interactions in the pancreas. Projections of 40 confocal images showing the dense and close association of pancreatic epithelial cells, labelled for E-cadherin (green), with endothelial cells, labelled for PECAM (red), in the embryonic pancreas.
Our in vivo and in vitro data show that endothelial cell recruitment depends on VEGF production by the pancreatic epithelium and that endothelial cells, in turn, focally restrict acinar differentiation (Pierreux et al., 2010). These data demonstrate that paracrine epithelial:mesenchyme and epithelial:endothelial interactions are crucial for organ differentiation. Current work focuses (i) on the network of reciprocal juxtacrine communications between epithelial cells and blood vessels, and (ii) on its intracellular decoding by epithelial transcription factors during mouse development, and their reversion during human carcinogenesis.
Under several pathological conditions, polarized epithelial cells dedifferentiate and loose their functional properties. A paradigmatic example is cystinosis, an inherited multisystemic lysosomal storage disease. Lysosomal cystine accumulation, due to genetic inactivation of the transmembrane transporter, Cystinosin (Ctns), induces progressive renal and thyroid dysfunction. Current project aims at (i) clarifying the molecular mechanisms linking the loss of Ctns to epithelial dedifferentiation and (ii) elucidating how engraftment of hematopoietic stem cells (Ctns+/+) into the interstitium of injured tissues (Ctns-/-) successfully corrects the defect in adjacent epithelia.
To know more... (pdf chapter of the last de Duve Institute report)
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