Abstract
Endothelial cells play multiple roles during pancreas organogenesis. First, they are required to instruct endoderm-derived pancreatic progenitor cells to initiate branching morphogenesis. Later, blood vessels promote β-cell differentiation but also limit acinar development. In this work, we show how endothelial cells might signal to pancreatic progenitors and spatially regulate acinar differentiation. Using an ex vivo culture system of undifferentiated E12.5 pancreata, we demonstrate that embryonic endothelial progenitor cells and their conditioned medium prevent the expression of two members of the pro-acinar transcriptional PTF1L-complex. This effect is not mediated by SPARC, a protein abundantly released in the medium conditioned by endothelial progenitors. On the contrary, heterotrimeric laminin-α1β1γ1, also produced by endothelial progenitor cells, can repress acinar differentiation when used on its own on pancreatic explants. Lastly, we found that laminin-α1 is predominantly found in vivo around the pancreatic trunk cells, as compared to the tip cells, at E14.5. In conclusion, we propose that expression or deposition of laminin-α1β1γ1 around the trunk cells, where blood vessels are predominantly localized, prevent acinar differentiation of these cells. On the contrary, transient decreased expression or deposition of laminin-α1β1γ1 around the tip cells would allow PTF1L-complex formation and acinar differentiation.
Highlights
The pancreas is an amphicrine gland composed of an endocrine compartment involved in the regulation of glycaemia, and an exocrine compartment implicated in digestion
We analyzed the expression of the tip-and-acinar cell marker Carboxypeptidase A (Cpa), and of the mature acinar cell marker Amylase (Amy) (Fig. 1b)
By RT-qPCR, we observed a ± 2-fold increase in Cpa expression and a ± 7-fold increase in Amy expression from D2 to D3. This expression profile qualitatively mimics the changes in Cpa and Amy mRNA levels observed in vivo from E14.5 to E15.5
Summary
The pancreas is an amphicrine gland composed of an endocrine compartment involved in the regulation of glycaemia, and an exocrine compartment implicated in digestion. PTF1A binds to RBPJ and another basic helix-loop-helix protein to form the trimeric PTF1J-complex. This complex controls the expression of several genes, among which Rbpjl. RBPJL accumulates and progressively replaces RBPJ within the PTF1J-complex, thereby forming a different PTF1L-complex This triggers a switch in the PTF1-complex target genes that initiates acinar differentiation and digestive enzyme (e.g. Amylase) production[3,4]. We demonstrated that forced expression of VEGF-A in tip cells (using Ptf1a/Ela-VEGF-A mice), induced endothelial cell recruitment around tip cells and inhibition of acinar cell differentiation[12]. Our data further suggest that laminin-α1β1γ1 preferential deposition around the trunk cells, could prevent the acinar differentiation program in those pancreatic cells, but not in tip cells
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