Paracrine communications control reorganization of epithelial masses into polarized monolayers
(2012)
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- (en) The pancreas, submandibular and thyroid glands originally derive from the endoderm and undergo two opposite epithelial transitions to reach their mature tissue organization. During the first transition, endodermal cells at specified sites loose polarity and proliferate so as to generate an undifferentiated three-dimensional cell mass. In the second transition, the bud reorganizes to form polarized epithelial monolayers. A final choice of epithelial architecture is lumen fusion into branched tubes (exocrine pancreas and submandibular glands) vs closed follicles (endocrine thyroid). The aim of my thesis was to better understand the cellular and molecular mechanisms controlling the second epithelial transition. I first described precisely this transition in the three organs, and found that epithelial cells composing the mass are always in close contact with the mesenchyme and the endothelium during reorganization into polarized monolayers. This raised the possibility of paracrine communications between these different cell types. In the pancreas and submandibular glands, we found that the chemokine Stromal cell-Derived Factor-1 (SDF-1) is produced by the mesenchyme while its main receptor is expressed by the epithelium. SDF-1 binding to CXCR4 is necessary for branching morphogenesis of both organs. Of further interest, SDF-1 production by the submandibular mesenchyme could also target the CXCR7-expressing blood vessels, which, in turn, produce an as yet unidentified signal that promotes submandibular gland branching. Combining my results on thyroid development with those on pancreas development reveals that VEGF-A expression by the epithelium may be either regionalized (restricted to the trunk cells in the pancreas) or global (all epithelial cells of the thyroid). Accordingly, VEGFR2+ endothelial cells are either recruited only near trunk cells in the pancreas, or uniformly in the thyroid. Using transgenic mouse models and an original thyroid explant culture system, we showed that endothelial cells signal back to the epithelium. In the pancreas, they restrict acinar differentiation to tip cells and support endocrine progenitors. In the thyroid, endothelial cells promote folliculogenesis and expression of calcitonin by C-cells. We further demonstrated in the thyroid that these effects depend on a secreted factor released by endothelial cells, rather than on contacts. In conclusion, we have shown that reciprocal paracrine interactions govern the reorganization of a mass of epithelial cells into polarized monolayers. In particular: (i) mesenchymal SDF-1 controls pancreas and submandibular glands branching; (ii) epithelial VEGFA recruits blood vessels; and (iii) blood vessels control pancreas differentiation and thyroid gland morphogenesis and differentiation.
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Citations
Hick, A.-C. (2012). Paracrine communications control reorganization of epithelial masses into polarized monolayers. https://hdl.handle.net/2078.5/47718