Vascular instruction of pancreas development

Abstract

Blood vessels course through organs, providing them with essential nutrient and gaseous exchange. However, the vasculature has also been shown to provide non-nutritional signals that play key roles in the control of organ growth, morphogenesis and homeostasis. Here, we examine a decade of work on the contribution of vascular paracrine signals to developing tissues, with a focus on pancreatic β-cells. During the early stages of embryonic development, blood vessels are required for pancreas specification. Later, the vasculature constrains pancreas branching, differentiation and growth. During adult life, capillaries provide a vascular niche for the maintenance of β-cell function and survival. We explore the possibility that the vasculature constitutes a dynamic and regionalized signaling system that carries out multiple and changing functions as it coordinately grows with the pancreatic epithelial tree.

Fig. 1.

Close association of vessels with pancreas and liver epithelium throughout development into adulthood. (A) The early pancreatic bud is encased in capillaries (red) that pervade the gut mesenchyme. Endocrine cells (green) emerge within the bud epithelium (yellow). (B) The developing pancreatic tree grows coordinately with its vasculature, with vessels (red/blue) running along ducts. Islets (green) are embedded within the more abundant exocrine tissue (yellow). (C) The early liver bud shows intercalation of early hepatocytes (brown) and capillaries (red) within the septum transversum. (D) The developing liver contains a dense vascular network – the sinusoidal endothelium (purple). a, acini; bv, blood vessel; d, pancreatic duct; dp, dorsal pancreas; g, gut tube; h, hepatocytes; lb, liver bud; t, triad of hepatic artery, portal vein and bile duct; thv, terminal hepatic vein.

Fig. 2.

Vascular niches in neural and hematopoietic tissues. (A) Neural stem cells (NSCs, dark blue) associate with both ependymal (brown) and endothelial (red) cells as they transition into transit amplifying cells (neural progenitor cells, NPCs, yellow), become neuroblasts (orange) and eventually differentiate into neurons. (B) Hematopoietic stem cell (HSC) mobilization and homing occur in coupled osteoblastic and vascular niches. In response to changes in the levels of stromal-derived factor 1 (SDF1) secreted by stromal CXCL12-abundant reticular (CAR) cells (green), HSCs (orange) leave the bone microniche (osteoblastic niche) where they remain quiescent, passage through the stromal environment and enter the vascular niche, where they proliferate and further differentiate.

Fig. 3.

The pancreatic progenitor epithelium gives rise to endocrine, exocrine and ductal lineages. Schematic of early (left) and late (right) pancreatic epithelium. Multipotent progenitor cells (MPCs, pink) at epithelial tips proliferate to give rise to more MPC-bearing tips, as well as bipotent ‘trunk’ epithelium (light purple). The latter generates delaminating endocrine cells (green) and differentiates into ductal epithelium (dark purple) following the secondary transition. At this time, MPC potential becomes restricted and branch tips terminally differentiate into acinar cells (red), which form clusters called acini.

Fig. 4.

Blood vessel and pancreatic tissues interface throughout development and into adulthood. (A,B,D) The developing pancreatic buds and neighboring blood vessels. In A and B, anterior is leftwards, posterior is rightwards. (A) The paired dorsal aortae (red) of mammalian embryos contact the pre-pancreatic endoderm (yellow) during specification, during embryonic day 8. Aortic endothelium has been shown to be required for endocrine specification, PTF1A expression and bud outgrowth. (B) As the pancreatic bud grows, the dorsal aortae fuse into a single vessel. Mesenchyme accumulates around the bud epithelium and displaces the aorta further dorsally. Within the bud mesenchyme, a capillary plexus forms, surrounding the pancreatic epithelium, whereas the portal vein develops and wraps the posterior aspect of the bud. (C) During stratification of the pancreatic progenitor epithelium, it remains strictly avascular. Subsequent vascularization of the bud is coordinated with de-stratification. (D) During pancreatic outgrowth, blood vessels pervade the branching organ, with vessels intercalating among developing branches. There is a particularly high density of blood vessels along the core of the bud, whereas more peripheral acinar-rich regions display lower vascularity. (E) Blood vessels course through islets, forming dense networks of capillaries, with each β-cell contacting more than one vessel. (F) Islet beta cells (yellow) are organized in rosettes around islet capillaries, into which they secrete endocrine hormones (via their lateral surfaces, which are covered with microvilli). a, artery; b, β-cell; bv, blood vessel; d, duodenum; da, dorsal aorta; dp, dorsal pancreas; e, endoderm; g, gut tube; se, stratified epithelium; st, stomach; v, vein.

Fig. 5.

Blood vessel signals restrain branching and differentiation of the late-developing pancreas. (A) Blood vessels surround the progenitor epithelium prior to tip formation and endocrine/exocrine differentiation. As the multipotent progenitor cell-laden tips develop, they avoid the vascular-rich environment that surrounds the central epithelium, branching out into the surrounding mesenchyme. Acini subsequently display lower vascular density than the central epithelium of the pancreatic tree. (B) Both genetic and explant data identify perfusion-independent signals from the vascular endothelium that inhibit pancreas branching, reduce differentiation into both endocrine and acinar fates, and eventually act to restrict organ size. The endothelium appears to act by interfering with Delta-Notch signaling within the epithelium. We hypothesize that blood vessels promote self-renewal of proto-differentiated trunk epithelium, at the expense of tip formation (branching) and endocrine/exocrine differentiation. Cell types are indicated in the key.