Identification and implication of tissue-enriched ligands in epithelial–endothelial crosstalk during pancreas development

Abstract

Development of the pancreas is driven by an intrinsic program coordinated with signals from other cell types in the epithelial environment. These intercellular communications have been so far challenging to study because of the low concentration, localized production and diversity of the signals released. Here, we combined scRNAseq data with a computational interactomic approach to identify signals involved in the reciprocal interactions between the various cell types of the developing pancreas. This in silico approach yielded 40,607 potential ligand-target interactions between the different main pancreatic cell types. Among this vast network of interactions, we focused on three ligands potentially involved in communications between epithelial and endothelial cells. BMP7 and WNT7B, expressed by pancreatic epithelial cells and predicted to target endothelial cells, and SEMA6D, involved in the reverse interaction. In situ hybridization confirmed the localized expression of Bmp7 in the pancreatic epithelial tip cells and of Wnt7b in the trunk cells. On the contrary, Sema6d was enriched in endothelial cells. Functional experiments on ex vivo cultured pancreatic explants indicated that tip cell-produced BMP7 limited development of endothelial cells. This work identified ligands with a restricted tissular and cellular distribution and highlighted the role of BMP7 in the intercellular communications contributing to vessel development and organization during pancreas organogenesis.

Pathological mechanisms of type 1 diabetes in children: investigation of the exosomal protein expression profile

“…Semaphorin-6D (SEMA6D) belongs to the semaphorin family of proteins, playing a crucial role in vascular formation, immune regulation, and organogenesis. Sema6d was highly enriched in the endothelial cells of the pancreatic tissue in mouse embryos, suggesting that it may have potential impacts on the development and morphogenesis of the pancreas ( 39 ). In addition, mutations at its gene locus have been found to be closely associated with the occurrence of diabetic nephropathy ( 40 ), implying that SEMA6D may play a significant role in the onset and progression of diabetes.…”

“…The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the iProX partner repository ( 39 ) with the dataset identifier PXD043146.…”

In-Depth Analysis of the Pancreatic Extracellular Matrix during Development for Next-Generation Tissue Engineering

“…Additionally, the PLXNA2 receptor for the axon-guidance molecule family, SEMAPHORINS, might also deserve further investigation. Indeed, interactomics analysis highlighted that the PLXNA1-SEMA6D pair could be involved in endothelial-to-epithelial communication during pancreas development [ 32 ]. Given the potential roles of SMOC2 and PLXNA2, further investigation is needed in the context of pancreatic development.…”