Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 294 (5542): 559-563

Copyright © 2001 by the American Association for the Advancement of Science

Liver Organogenesis Promoted by Endothelial Cells Prior to Vascular Function

Kunio Matsumoto,12* Hideyuki Yoshitomi,1* Janet Rossant,13 Kenneth S. Zaret1dagger

The embryonic role of endothelial cells and nascent vessels in promoting organogenesis, prior to vascular function, is unclear. We find that early endothelial cells in mouse embryos surround newly specified hepatic endoderm and delimit the mesenchymal domain into which the liver bud grows. In flk-1 mutant embryos, which lack endothelial cells, hepatic specification occurs, but liver morphogenesis fails prior to mesenchyme invasion. We developed an embryo tissue explant system that permits liver bud vasculogenesis and show that in the absence of endothelial cells, or when the latter are inhibited, there is a selective defect in hepatic outgrowth. We conclude that vasculogenic endothelial cells and nascent vessels are critical for the earliest stages of organogenesis, prior to blood vessel function.

1 Cell and Developmental Biology Program, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.
2 Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5T 1K5, Canada.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: zaret{at}fccc.edu



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Endothelial Cell-Derived Angiopoietin-2 Controls Liver Regeneration as a Spatiotemporal Rheostat.
J. Hu, K. Srivastava, M. Wieland, A. Runge, C. Mogler, E. Besemfelder, D. Terhardt, M. J. Vogel, L. Cao, C. Korn, et al. (2014)
Science 343, 416-419
   Abstract »    Full Text »    PDF »
The septum transversum mesenchyme induces gall bladder development.
Y. Saito, T. Kojima, and N. Takahashi (2013)
Biology Open 2, 779-788
   Abstract »    Full Text »    PDF »
Geometric control of vascular networks to enhance engineered tissue integration and function.
J. D. Baranski, R. R. Chaturvedi, K. R. Stevens, J. Eyckmans, B. Carvalho, R. D. Solorzano, M. T. Yang, J. S. Miller, S. N. Bhatia, and C. S. Chen (2013)
PNAS 110, 7586-7591
   Abstract »    Full Text »    PDF »
Vascular instruction of pancreas development.
O. Cleaver and Y. Dor (2012)
Development 139, 2833-2843
   Abstract »    Full Text »    PDF »
Overactivation of Hedgehog Signaling Alters Development of the Ovarian Vasculature in Mice.
Y. Ren, R. G. Cowan, F. F. Migone, and S. M. Quirk (2012)
Biol Reprod 86, 174
   Abstract »    Full Text »    PDF »
Acetaminophen-Induced Hepatotoxicity in a Liver Tissue Model Consisting of Primary Hepatocytes Assembling around an Endothelial Cell Network.
Y. Toyoda, M. Tamai, K. Kashikura, S. Kobayashi, Y. Fujiyama, T. Soga, and Y.-i. Tagawa (2012)
Drug Metab. Dispos. 40, 169-177
   Abstract »    Full Text »    PDF »
Blood vessels restrain pancreas branching, differentiation and growth.
J. Magenheim, O. Ilovich, A. Lazarus, A. Klochendler, O. Ziv, R. Werman, A. Hija, O. Cleaver, E. Mishani, E. Keshet, et al. (2011)
Development 138, 4743-4752
   Abstract »    Full Text »    PDF »
Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for {beta}-Cell Function.
J. Olerud, D. Mokhtari, M. Johansson, G. Christoffersson, J. Lawler, N. Welsh, and P.-O. Carlsson (2011)
Diabetes 60, 1946-1954
   Abstract »    Full Text »    PDF »
A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways.
A. Lazarus, P. M. Del-Moral, O. Ilovich, E. Mishani, D. Warburton, and E. Keshet (2011)
Development 138, 2359-2368
   Abstract »    Full Text »    PDF »
Endoderm and mesoderm reciprocal signaling mediated by CXCL12 and CXCR4 regulates the migration of angioblasts and establishes the pancreatic fate.
K. Katsumoto and S. Kume (2011)
Development 138, 1947-1955
   Abstract »    Full Text »    PDF »
Liver stem/progenitor cells: their characteristics and regulatory mechanisms.
M. Tanaka, T. Itoh, N. Tanimizu, and A. Miyajima (2011)
J. Biochem. 149, 231-239
   Abstract »    Full Text »    PDF »
Vascular-mesenchymal cross-talk through Vegf and Pdgf drives organ patterning.
J. Cool, T. J. DeFalco, and B. Capel (2011)
PNAS 108, 167-172
   Abstract »    Full Text »    PDF »
Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome.
J. J. Hofmann, A. C. Zovein, H. Koh, F. Radtke, G. Weinmaster, and M. L. Iruela-Arispe (2010)
Development 137, 4061-4072
   Abstract »    Full Text »    PDF »
Histology Atlas of the Developing Mouse Hepatobiliary System with Emphasis on Embryonic Days 9.5-18.5.
L. W. Crawford, J. F. Foley, and S. A. Elmore (2010)
Toxicol Pathol 38, 872-906
   Abstract »    Full Text »    PDF »
Parasympathetic Innervation Maintains Epithelial Progenitor Cells During Salivary Organogenesis.
S. M. Knox, I. M. A. Lombaert, X. Reed, L. Vitale-Cross, J. S. Gutkind, and M. P. Hoffman (2010)
Science 329, 1645-1647
   Abstract »    Full Text »    PDF »
Concurrent Vasculogenesis and Neurogenesis From Adult Neural Stem Cells.
M. Ii, H. Nishimura, H. Sekiguchi, N. Kamei, A. Yokoyama, M. Horii, and T. Asahara (2009)
Circ. Res. 105, 860-868
   Abstract »    Full Text »    PDF »
Directed Differentiation of Pluripotent Stem Cells: From Developmental Biology to Therapeutic Applications.
S. Irion, M.C. Nostro, S.J. Kattman, and G.M. Keller (2009)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Generation and Regeneration of Cells of the Liver and Pancreas.
K. S. Zaret and M. Grompe (2008)
Science 322, 1490-1494
   Abstract »    Full Text »    PDF »
Pioneer Factors, Genetic Competence, and Inductive Signaling: Programming Liver and Pancreas Progenitors from the Endoderm.
K.S. Zaret, J. Watts, J. Xu, E. Wandzioch, S.T. Smale, and T. Sekiya (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
The Stem Cell Movement.
N. Smart and P. R. Riley (2008)
Circ. Res. 102, 1155-1168
   Abstract »    Full Text »    PDF »
Zebrafish cdx1b regulates expression of downstream factors of Nodal signaling during early endoderm formation.
P.-Y. Cheng, C.-C. Lin, C.-S. Wu, Y.-F. Lu, C. Y. Lin, C.-C. Chung, C.-Y. Chu, C.-J. Huang, C.-Y. Tsai, S. Korzh, et al. (2008)
Development 135, 941-952
   Abstract »    Full Text »    PDF »
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver.
S. L. Friedman (2008)
Physiol Rev 88, 125-172
   Abstract »    Full Text »    PDF »
A tissue-engineered model of fetal distal lung tissue.
M. J. Mondrinos, S. Koutzaki, P. I. Lelkes, and C. M. Finck (2007)
Am J Physiol Lung Cell Mol Physiol 293, L639-L650
   Abstract »    Full Text »    PDF »
Human hepatic stem cells from fetal and postnatal donors.
E. Schmelzer, L. Zhang, A. Bruce, E. Wauthier, J. Ludlow, H.-l. Yao, N. Moss, A. Melhem, R. McClelland, W. Turner, et al. (2007)
J. Exp. Med. 204, 1973-1987
   Abstract »    Full Text »    PDF »
Endothelial potential of human embryonic stem cells.
S. Levenberg, J. Zoldan, Y. Basevitch, and R. Langer (2007)
Blood 110, 806-814
   Abstract »    Full Text »    PDF »
Involvement of vessels and PDGFB in muscle splitting during chick limb development.
S. Tozer, M.-A. Bonnin, F. Relaix, S. Di Savino, P. Garcia-Villalba, P. Coumailleau, and D. Duprez (2007)
Development 134, 2579-2591
   Abstract »    Full Text »    PDF »
Zonal Gene Expression in Mouse Liver Resembles Expression Patterns of Ha-ras and {beta}-Catenin Mutated Hepatomas.
A. Braeuning, C. Ittrich, C. Kohle, A. Buchmann, and M. Schwarz (2007)
Drug Metab. Dispos. 35, 503-507
   Abstract »    Full Text »    PDF »
Two populations of Thy1-positive mesenchymal cells regulate in vitro maturation of hepatic progenitor cells.
N. Kamo, K. Yasuchika, H. Fujii, T. Hoppo, T. Machimoto, T. Ishii, N. Fujita, T. Tsuruo, J. K. Yamashita, H. Kubo, et al. (2007)
Am J Physiol Gastrointest Liver Physiol 292, G526-G534
   Abstract »    Full Text »    PDF »
Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway.
I. Shiojima and K. Walsh (2006)
Genes & Dev. 20, 3347-3365
   Abstract »    Full Text »    PDF »
Islet Microvasculature in Islet Hyperplasia and Failure in a Model of Type 2 Diabetes.
X. Li, L. Zhang, S. Meshinchi, C. Dias-Leme, D. Raffin, J. D. Johnson, M. K. Treutelaar, and C. F. Burant (2006)
Diabetes 55, 2965-2973
   Abstract »    Full Text »    PDF »
Epithelial stem cells of the lung: privileged few or opportunities for many?.
E. L. Rawlins and B. L. M. Hogan (2006)
Development 133, 2455-2465
   Abstract »    Full Text »    PDF »
Regulation of early lung morphogenesis: questions, facts and controversies.
W. V. Cardoso and J. Lu (2006)
Development 133, 1611-1624
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload.
Y. Izumiya, I. Shiojima, K. Sato, D. B. Sawyer, W. S. Colucci, and K. Walsh (2006)
Hypertension 47, 887-893
   Abstract »    Full Text »    PDF »
Loss of PECAM-1 Function Impairs Alveolarization.
H. M. DeLisser, B. P. Helmke, G. Cao, P. M. Egan, D. Taichman, M. Fehrenbach, A. Zaman, Z. Cui, G. S. Mohan, H. S. Baldwin, et al. (2006)
J. Biol. Chem. 281, 8724-8731
   Abstract »    Full Text »    PDF »
COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model.
C.-H. Cho, H.-K. Sung, K.-T. Kim, H. G. Cheon, G. T. Oh, H. J. Hong, O.-J. Yoo, and G. Y. Koh (2006)
PNAS 103, 4946-4951
   Abstract »    Full Text »    PDF »
Antiangiogenic therapy decreases integrin expression in normalized tumor blood vessels..
V. J. Yao, M. G. Ozawa, A. S. Varner, I. M. Kasman, Y. H. Chanthery, R. Pasqualini, W. Arap, and D. M. McDonald (2006)
Cancer Res. 66, 2639-2649
   Abstract »    Full Text »    PDF »
Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa.
X. Gao, X. Chen, M. Taglienti, B. Rumballe, M. H. Little, and J. A. Kreidberg (2005)
Development 132, 5437-5449
   Abstract »    Full Text »    PDF »
Arachidonic Acid Predominates in the Membrane Phosphoglycerides of the Early and Term Human Placenta.
D. Bitsanis, M. A. Crawford, T. Moodley, H. Holmsen, K. Ghebremeskel, and O. Djahanbakhch (2005)
J. Nutr. 135, 2566-2571
   Abstract »    Full Text »    PDF »
Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development.
M. J. Hilton, X. Tu, J. Cook, H. Hu, and F. Long (2005)
Development 132, 4339-4351
   Abstract »    Full Text »    PDF »
VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.
B. Carpenter, Y. Lin, S. Stoll, R. L. Raffai, R. McCuskey, and R. Wang (2005)
Development 132, 3293-3303
   Abstract »    Full Text »    PDF »
GATA6 Is Essential for Embryonic Development of the Liver but Dispensable for Early Heart Formation.
R. Zhao, A. J. Watt, J. Li, J. Luebke-Wheeler, E. E. Morrisey, and S. A. Duncan (2005)
Mol. Cell. Biol. 25, 2622-2631
   Abstract »    Full Text »    PDF »
Angiogenesis: a curse or cure?.
K Gupta and J Zhang (2005)
Postgrad. Med. J. 81, 236-242
   Abstract »    Full Text »    PDF »
Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme.
J. Edsbagge, J. K. Johansson, F. Esni, Y. Luo, G. L. Radice, and H. Semb (2005)
Development 132, 1085-1092
   Abstract »    Full Text »    PDF »
Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing.
M. Stadtfeld and T. Graf (2005)
Development 132, 203-213
   Abstract »    Full Text »    PDF »
Role of oxygen and vascular development in epithelial branching morphogenesis of the developing mouse lung.
M. van Tuyl, J. Liu, J. Wang, M. Kuliszewski, D. Tibboel, and M. Post (2005)
Am J Physiol Lung Cell Mol Physiol 288, L167-L178
   Abstract »    Full Text »    PDF »
Formation of human hepatocytes by human hematopoietic stem cells in sheep.
G. Almeida-Porada, C. D. Porada, J. Chamberlain, A. Torabi, and E. D. Zanjani (2004)
Blood 104, 2582-2590
   Abstract »    Full Text »    PDF »
Endothelial progenitor cells for postnatal vasculogenesis.
T. Asahara and A. Kawamoto (2004)
Am J Physiol Cell Physiol 287, C572-C579
   Abstract »    Full Text »    PDF »
Targets for Vascular Protection After Acute Ischemic Stroke.
S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul (2004)
Stroke 35, 2220-2225
   Abstract »    Full Text »    PDF »
Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment.
D.-A. Lacorre, E. S. Baekkevold, I. Garrido, P. Brandtzaeg, G. Haraldsen, F. Amalric, and J.-P. Girard (2004)
Blood 103, 4164-4172
   Abstract »    Full Text »    PDF »
NEUROSCIENCE: Cellular Interactions in the Stem Cell Niche.
A. E. Wurmser, T. D. Palmer, and F. H. Gage (2004)
Science 304, 1253-1255
   Abstract »    Full Text »    PDF »
VEGFA is necessary for chondrocyte survival during bone development.
E. Zelzer, R. Mamluk, N. Ferrara, R. S. Johnson, E. Schipani, and B. R. Olsen (2004)
Development 131, 2161-2171
   Abstract »    Full Text »    PDF »
Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a.
H. Yoshitomi and K. S. Zaret (2004)
Development 131, 807-817
   Abstract »    Full Text »    PDF »
Vegfc is required for vascular development and endoderm morphogenesis in zebrafish.
E. A. Ober, B. Olofsson, T. Makinen, S.-W. Jin, W. Shoji, G. Y. Koh, K. Alitalo, and D. Y. R. Stainier (2004)
EMBO Rep. 5, 78-84
   Abstract »    Full Text »    PDF »
Islet Regeneration During the Reversal of Autoimmune Diabetes in NOD Mice.
S. Kodama, W. Kuhtreiber, S. Fujimura, E. A. Dale, and D. L. Faustman (2003)
Science 302, 1223-1227
   Abstract »    Full Text »    PDF »
Paracrine Regulation of Angiogenesis and Adipocyte Differentiation During In Vivo Adipogenesis.
D. Fukumura, A. Ushiyama, D. G. Duda, L. Xu, J. Tam, V. Krishna, K. Chatterjee, I. Garkavtsev, and R. K. Jain (2003)
Circ. Res. 93, e88-e97
   Abstract »    Full Text »    PDF »
Nestin-Lineage Cells Contribute to the Microvasculature but Not Endocrine Cells of the Islet.
M. K. Treutelaar, J. M. Skidmore, C. L. Dias-Leme, M. Hara, L. Zhang, D. Simeone, D. M. Martin, and C. F. Burant (2003)
Diabetes 52, 2503-2512
   Abstract »    Full Text »    PDF »
Endothelial cell diversity revealed by global expression profiling.
J.-T. Chi, H. Y. Chang, G. Haraldsen, F. L. Jahnsen, O. G. Troyanskaya, D. S. Chang, Z. Wang, S. G. Rockson, M. van de Rijn, D. Botstein, et al. (2003)
PNAS 100, 10623-10628
   Abstract »    Full Text »    PDF »
TTF-1 Phosphorylation Is Required for Peripheral Lung Morphogenesis, Perinatal Survival, and Tissue-specific Gene Expression.
M. deFelice, D. Silberschmidt, R. DiLauro, Y. Xu, S. E. Wert, T. E. Weaver, C. J. Bachurski, J. C. Clark, and J. A. Whitsett (2003)
J. Biol. Chem. 278, 35574-35583
   Abstract »    Full Text »    PDF »
Functional, Persistent, and Extended Liver to Pancreas Transdifferentiation.
I. Ber, K. Shternhall, S. Perl, Z. Ohanuna, I. Goldberg, I. Barshack, L. Benvenisti-Zarum, I. Meivar-Levy, and S. Ferber (2003)
J. Biol. Chem. 278, 31950-31957
   Abstract »    Full Text »    PDF »
Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad.
K. Jeays-Ward, C. Hoyle, J. Brennan, M. Dandonneau, G. Alldus, B. Capel, and A. Swain (2003)
Development 130, 3663-3670
   Abstract »    Full Text »    PDF »
Nestin Is Expressed in Vascular Endothelial Cells in the Adult Human Pancreas.
T. Klein, Z. Ling, H. Heimberg, O. D. Madsen, R. S. Heller, and P. Serup (2003)
Journal of Histochemistry & Cytochemistry 51, 697-706
   Abstract »    Full Text »    PDF »
Human embryonic stem cells for cardiovascular repair.
S. G. Nir, R. David, M. Zaruba, W.-M. Franz, and J. Itskovitz-Eldor (2003)
Cardiovasc Res 58, 313-323
   Abstract »    Full Text »    PDF »
Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad.
J. Brennan, C. Tilmann, and B. Capel (2003)
Genes & Dev. 17, 800-810
   Abstract »    Full Text »    PDF »
BIOMEDICINE: Love, Honor, and Protect (Your Liver).
A. J. Davidson and L. I. Zon (2003)
Science 299, 835-837
   Abstract »    Full Text »    PDF »
Angiogenesis-Independent Endothelial Protection of Liver: Role of VEGFR-1.
J. LeCouter, D. R. Moritz, B. Li, G. L. Phillips, X. H. Liang, H.-P. Gerber, K. J. Hillan, and N. Ferrara (2003)
Science 299, 890-893
   Abstract »    Full Text »    PDF »
The Yolkless Egg and the Evolution of Eutherian Viviparity.
I. Rothchild (2003)
Biol Reprod 68, 337-357
   Abstract »    Full Text »    PDF »
Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor, and naive dendritic cells.
T. Kikuchi, M. Maemondo, K. Narumi, K. Matsumoto, T. Nakamura, and T. Nukiwa (2002)
Blood 100, 3950-3959
   Abstract »    Full Text »    PDF »
Adipose tissue mass can be regulated through the vasculature.
M. A. Rupnick, D. Panigrahy, C.-Y. Zhang, S. M. Dallabrida, B. B. Lowell, R. Langer, and M. J. Folkman (2002)
PNAS 99, 10730-10735
   Abstract »    Full Text »    PDF »
Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) -dependent signaling.
R. HUMAR, F. N. KIEFER, H. BERNS, T. J. RESINK, and E. J. BATTEGAY (2002)
FASEB J 16, 771-780
   Abstract »    Full Text »    PDF »
Endothelial cells derived from human embryonic stem cells.
S. Levenberg, J. S. Golub, M. Amit, J. Itskovitz-Eldor, and R. Langer (2002)
PNAS 99, 4391-4396
   Abstract »    Full Text »    PDF »
Endothelial cells derived from human embryonic stem cells.
S. Levenberg, J. S. Golub, M. Amit, J. Itskovitz-Eldor, and R. Langer (2002)
PNAS 99, 4391-4396
   Abstract »    Full Text »    PDF »
Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair.
V. V. Kalinichenko, Y. Zhou, B. Shin, D. B. Stolz, S. C. Watkins, J. A. Whitsett, and R. H. Costa (2002)
Am J Physiol Lung Cell Mol Physiol 282, L1253-L1265
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882