Hypothetical model of macrophages-induced developmental effects on embryonic pancreatic epithelium.

<p>(A) Interactions of M2 macrophages with proliferating ductal epithelial cells induce expression of NCAM in delaminating progenitors. Concomitantly, high levels of ΔPD-PAX6 are induced. This latter change results in slowing-down the cell cycle, allowing for the initiation of differentiative events in progenitors committed to endocrine lineages. At the same time, NCAM induction, through disruption of E-cadherin and/or potentiation of FGF signaling, facilitates sorting of committed progenitors out of the ductal lining. (B) Motility of the committed progenitors increases as high levels of ΔPD-PAX6 progressively wear off, allowing their delamination and migration away from the ducts. Eventually, expression of ΔPD-PAX6 returns to very low levels in endocrine-committed cells, permitting migration arrest and resumption of proliferation in response to pro-proliferative cues provided by stromal cells, leading to the formation of islet cell clusters. We suggest that regulation of such ΔPD-PAX6-driven functions, reliant on cell-cell interactions with M2 macrophages and exquisitely sensitive to gene dosage, provides a novel mechanism explaining how cell cycle withdrawal and initiation of cell migration may be functional linked and coordinated in epithelial cells committed to leave ductal progenitor pools.