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WIREs Dev Biol
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Blood vessel crosstalk during organogenesis—focus on pancreas and endothelial cells

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Blood vessels form a highly branched, interconnected, and largely stereotyped network of tubes that sustains every organ and tissue in vertebrates. How vessels come to take on their particular architecture, or how they are ‘patterned,’ and in turn, how they influence surrounding tissues are fundamental questions of organogenesis. Decades of work have begun to elucidate how endothelial progenitors arise and home to precise locations within tissues, integrating attractive and repulsive cues to build vessels where they are needed. Conversely, more recent findings have revealed an exciting facet of blood vessel interaction with tissues, where vascular cells provide signals to developing organs and progenitors therein. Here, we discuss the exchange of reciprocal signals between endothelial cells and neighboring tissues during embryogenesis, with a special focus on the developing pancreas. Understanding the mechanisms driving both sides of these interactions will be crucial to the development of therapies, from improving organ regeneration to efficient production of cell based therapies. Specifically, elucidating the interface of the vasculature with pancreatic lineages, including endocrine cells, will instruct approaches such as generation of replacement beta cells for Type I diabetes. WIREs Dev Biol 2016, 5:598–617. doi: 10.1002/wdev.240 This article is categorized under: Signaling Pathways > Cell Fate Signaling Vertebrate Organogenesis > Musculoskeletal and Vascular Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches
EC–tissue crosstalk. ECs of a vessel dynamically communicate with surrounding tissues. Tissues provide positive and negative patterning cues, such as VEGF or Semaphorins (respectively), which influence EC migration and thereby shape the vasculature. ECs, in turn, provide signals to tissues regulating their growth and homeostasis, which remain largely unknown.
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Vascular impact on organogenesis. (a) Perturbations in vasculature disrupt lung development. Branching stereotypy is altered, tubules are dilated and sacculation is incomplete in both hyper‐vascularized and hypo‐vascularized lungs. Hyper‐vascularized lungs also fail to differentiate alveolar epithelial type I cells and have immature columnar epithelial cells in their alveoli instead. (b) Hypo‐vascularization leads to a failure in glomerular development. Mesangial cells are depleted and the mesangial matrix is altered upon reduction of glomerular capillaries. (c) Early removal of aortic ECs prior to pancreatic specification (E8.25) results in a failure of normal pancreatic bud formation, although the PDX1 domain is specified. Later manipulations of the pancreatic vasculature during epithelial branching also have dramatic effects on pancreas development. Schematic representation of early pancreatic buds (E10.0, left), and phenotypes at later stages (E13.5, right) are shown. Hyper‐vascularization results in abnormal branching and reduction of tips. In these pancreata, the undifferentiated trunk epithelium is expanded, while exocrine differentiation as well as endocrine commitment and differentiation are compromised. By contrast, hypo‐vascularization during epithelial branching causes ablation of the trunk and expansion of tips. Markers used here to distinguish pancreatic cell lineages: PDX1, PTF1A, CPA1, and NGN3, as described in text. Epi, epithelium; AECI, alveolar epithelial cell type I; AECII, alveolar epithelial cell type II; ColC, columnar cell; CubC, cuboidal cell; EndocrineC, endocrine cell; EpiC, epithelial cell; MesangC, mesangial cell; ParC, parietal cell; TipC, tip cell.
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Endothelial niche for stem cell self renewal versus differentiation. (a) Neuronal progenitor cells receive diverse signals from niche cells, including ECs, which regulate their fate. EC‐derived Notch, BDNF, PIGF‐2, and PEDF have all been demonstrated to induce self‐renewal of neuronal progenitors, while NT‐3, EPHRIN‐B2, and JAGGED1 promote quiescence. ECs can also prompt cell cycle exit of neuronal progenitors through Bmps. (b) In the liver, Wnt ligands secreted by ECs induce self‐renewal of hepatic progenitors during homeostasis. Also under injury, ECs promote hepatic progenitor renewal via WNT2, HGF, and CXCL12. (c) During pancreas development, EGFL7 supplied by ECs maintains pancreatic progenitors by promoting their renewal. (d) Hematopoietic stem cells in the bone marrow rely on EC‐derived signals, such as CXCL12 and JAGGED1, for renewal and maintenance. BDNF, brain‐derived neurotrophic factor; EFNB2, EPHRIN‐B2; HepaProg, hepatic progenitor; HGF, hepatocyte growth factor; HSC, hematopoietic stem cell; JAG1, JAGGED1; NeuProg, neuronal progenitor; NT‐3, neurotrophin‐3; PancProg, pancreatic progenitor; PEDF, pigment epithelium‐derived factor; PlGF‐2, placental growth factor 2.
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Vascularization of the pancreas during development. Sections through embryonic mouse pancreas are shown at stages indicated. Blue, DAPI; green, pancreatic epithelium stained for E‐cadherin; red, blood vessels stained for PECAM. (a) Angioblasts and early vessels arise in the mesoderm which surrounds the pancreatic epithelium. The stratified pancreatic epithelium is initially avascular (E10.0). (b) As the pancreas branches, the mesodermal mesenchyme containing blood vessels associates with the epithelium. ECs become densely packed around the trunk, while tips are relatively devoid of vasculature. Scale bars, 50 µm.
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Stereotyped architecture of adult human pancreatic vasculature. Simplified schematic of major blood vessels is shown in the mature pancreas. Two sources of splanchnic arteries supply blood to the pancreas. The head of the pancreas, derived from the dorsal bud, receives blood from the superior mesenteric arteries. The rest of the pancreas, namely the neck, body, and tail, are supplied by the splenic arteries. Blood is then drained via the splenic vein into the portal vein. Blue, veins; red, arteries.
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Vascularization of organs. Blood vessels emerging in the mesoderm form an initial net‐like plexus around the organ primordium. As development proceeds and organs grow in size, the vasculature is remodeled coordinately. Branching organs of endodermal origin, like pancreas and lung, codevelop epithelial branches with arteriovenous networks. In these organs, arteries and veins align with nearly every branch, both large and small.
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Basic principles of cue integration during vessel formation and patterning. (a) In de novo vasculogenesis, angioblasts migrate and proliferate in a directed manner following their specification. They migrate toward sources of attractive cues (blue) and away from those of negative cues (orange). As a result, they encounter each other, coalesce, and assemble into cords at genetically determined locations. They then undergo tubulogenesis to form a functional vessel. (b) Sprouting angiogenesis is similarly governed by attractive and repulsive cues, which direct migration of the activated ECs at the tip of the emerging sprout. This way, a new vessel arises from an existing one at specific, genetically determined locations.
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Vertebrate Organogenesis > Musculoskeletal and Vascular
Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches
Signaling Pathways > Cell Fate Signaling