DOI: 10.1126/science.1064344. Induction of Pancreatic Differentiation by Signals from Blood Vessels

Induction of Pancreatic Differentiation by Signals from Blood Vessels

10.1126/science.1064344

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Blood vessels supply developing organs with metabolic sustenance. Here, we demonstrate a role for blood vessels as a source of developmental signals during pancreatic organogenesis. In vitro experiments with embryonic mouse tissues demonstrate that blood vessel endothelium induces insulin expression in isolated endoderm. Removal of the dorsal aorta in Xenopus laevis embryos results in the failure of insulin expression in vivo. Furthermore, using transgenic mice, we show that ectopic vascularization in the posterior foregut leads to ectopic insulin expression and islet hyperplasia. These results indicate that vessels not only provide metabolic sustenance, but also provide inductive signals for organ development.

Bibliography

Lammert, E., Cleaver, O., & Melton, D. (2001). Induction of Pancreatic Differentiation by Signals from Blood Vessels. Science, 294(5542), 564â567.

Authors 3

Eckhard Lammert (first)
Ondine Cleaver (additional)
Douglas Melton (additional)

References 30 Referenced 879

10.1038/376066a0
10.1038/376062a0
10.1007/s001099900019
10.1002/aja.1002030109
10.1038/380435a0
10.1038/380439a0
Banting F. G., Best C. H., J. Lab. Clin. Med. 115, 254 (1990). / J. Lab. Clin. Med. by Banting F. G. (1990)
10.1038/371606a0
10.1242/dev.122.3.983
Supplementary Web material is available at Science Online at www.sciencemag.org/cgi/content/full/1064344/DC1
Mouse pancreatic development is initially symmetric (Fig. 1 A through G and Fig. 5A) with three buds forming adjacent to the dorsal aorta and the two vitelline veins. This is also seen in frog embryos where the dorsal bud contacts the dorsal aorta and each ventral bud is adjacent to a vitelline vein plexus (22). In mice we observed that only one of the two ventral pancreatic buds develops into pancreatic tissue whereas the other bud regresses coinciding with a developing asymmetry of vitelline veins. The ventral bud adjacent to the endothelium of the right vitelline (portal) vein continues to grow and develop whereas the left ventral bud disappears together with the left vitelline vein.
Christofori G., Naik P., Hanahan D., Mol. Endocrinol. 9, 1760 (1995). / Mol. Endocrinol. by Christofori G. (1995)
10.1016/0012-1606(87)90246-6
10.1242/dev.127.8.1563
Aortic endothelium is removed at 8.25 to 8.5 dpc a stage when endothelial cells have just recently coalesced into tubes and when supporting mural cells have not yet started to envelop the endothelium of the blood vessels. To ensure isolation of purified endothelium we used enzymatic treatment to remove any adhering mesenchymal cells (10).
10.1242/dev.124.21.4243
There are two possible explanations for the difference in insulin expression induced by the notochord in chick and mouse endodermal explants. There may be a fundamental mechanistic difference between chick and mouse. However we favor the possibility that chick endodermal explants may have contained contaminating endothelial cells. Endothelial tissues are pervasive and difficult to detect at early stages of chick development. Without enzymatic treatment to eliminate adhering endothelium or specific assays to detect endothelial cells it is difficult to rule out contamination.
10.1242/dev.125.19.3905
During the removal of the intermediate mesoderm damage to the underlying endoderm results in immediate extrusion of yolky cellular material from the large endodermal cells. Any embryo incurring such damage was identifiable and immediately discarded (10).
10.1126/science.7754368
10.1002/(SICI)1097-4695(199701)32:1<45::AID-NEU5>3.0.CO;2-E
10.1002/1097-0177(2000)9999:9999<::AID-DVDY1027>3.0.CO;2-8
10.1073/pnas.90.17.8268
10.1016/S0925-4773(97)00092-0
A total of 11 fluorescent Pdx-VEGF animals derived from independent microinjections were analyzed (five at 15.5 dpc five at birth and one stable line). Five of five fluorescent neonates displayed a hyperplastic distribution of islets at birth. To rule out nonspecific effects of Pdx1 -driven EGFP a transgene driving only IRES-EGFP under the Pdx1 promoter was used. Three of three fluorescent Pdx-EGFP transgenic mice had a normal distribution of insulin expressing islets and amylase expressing acini.
10.1128/MCB.17.10.6002
It is likely that islet hyperplasia in transgenics is caused by an increased number of blood vessels rather than a direct effect of VEGF on pancreatic epithelium. Two different anti-VEGFR2 antibodies stain blood vessels but not pancreatic epithelial cells suggesting that the latter tissue cannot respond directly to VEGF. Our results agree with a study showing VEGF receptor expression in capillary endothelium within the pancreas (12).
10.1016/S0925-4773(00)00317-8
Brekken R. A., Huang X., King S. W., Thorpe P. E., Cancer Res. 58, 1952 (1998). / Cancer Res. by Brekken R. A. (1998)
We thank J. Dubauskaite for the production of transgenic mice. We are grateful to R. Brekken C. V. Wright A. Nagy and P. A. Krieg for essential reagents (10). We also thank A. P. McMahon P. A. Krieg Y. Dor J. Wells A. Grapin-Botton L. Murtaugh and T. Carroll for critical comments. E.L. was supported by the Deutsche Forschungsgemeinschaft (La 1216/1-1) and is currently supported by the American Diabetes Association O.C. is supported by the Cancer Research Fund of the Damon Runyon–Walter Winchell Foundation Fellowship (DRG 1534) and D.M. is an investigator of the Howard Hughes Medical Institute.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:54 a.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 5:52 p.m.)
Indexed	1 hour, 19 minutes ago (Sept. 2, 2025, 6:35 a.m.)
Issued	23 years, 10 months ago (Oct. 19, 2001)
Published	23 years, 10 months ago (Oct. 19, 2001)
Published Print	23 years, 10 months ago (Oct. 19, 2001)

Funders 0

None

BibTeX

@article{Lammert_2001, title={Induction of Pancreatic Differentiation by Signals from Blood Vessels}, volume={294}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1064344}, DOI={10.1126/science.1064344}, number={5542}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Lammert, Eckhard and Cleaver, Ondine and Melton, Douglas}, year={2001}, month=oct, pages={564–567} }

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