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.

Science 3 September 1999:
Vol. 285. no. 5433, pp. 1553 - 1558
DOI: 10.1126/science.285.5433.1553
Prev | Table of Contents | Next

Reports

KDR Receptor: A Key Marker Defining Hematopoietic Stem Cells

B. L. Ziegler, *1 M. Valtieri, *23 G. Almeida Porada, 4 R. De Maria, 23 R. Müller, 1 B. Masella, 2 M. Gabbianelli, 3 I. Casella, 2 E. Pelosi, 3 T. Bock, 1 E. D. Zanjani, 4 C. Peschle 23dagger

Studies on pluripotent hematopoietic stem cells (HSCs) have been hindered by lack of a positive marker, comparable to the CD34 marker of hematopoietic progenitor cells (HPCs). In human postnatal hematopoietic tissues, 0.1 to 0.5% of CD34+ cells expressed vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR). Pluripotent HSCs were restricted to the CD34+KDR+ cell fraction. Conversely, lineage-committed HPCs were in the CD34+KDR- subset. On the basis of limiting dilution analysis, the HSC frequency in the CD34+KDR+ fraction was 20 percent in bone marrow (BM) by mouse xenograft assay and 25 to 42 percent in BM, peripheral blood, and cord blood by 12-week long-term culture (LTC) assay. The latter values rose to 53 to 63 percent in LTC supplemented with VEGF and to greater than 95 percent for the cell subfraction resistant to growth factor starvation. Thus, KDR is a positive functional marker defining stem cells and distinguishing them from progenitors.

1 Department of Hematology and Oncology, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
2 Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107-5541, USA.
3 Department of Hematology and Oncology, Istituto Superiore di Sanità, V. le Regina Elena 299, 00161 Rome, Italy.
4 Department of Veterans Affairs, University of Nevada, Reno, NV 89520, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: cesare.peschle{at}mail.tju.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy.
D. H. Kim, W. Xu, S. Kamel-Reid, X. Liu, C. W. Jung, S. Kim, and J. H. Lipton (2009)
Ann. Onc.
   Abstract »    Full Text »    PDF »
Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity.
B. J. Capoccia, D. L. Robson, K. D. Levac, D. J. Maxwell, S. A. Hohm, M. J. Neelamkavil, G. I. Bell, A. Xenocostas, D. C. Link, D. Piwnica-Worms, et al. (2009)
Blood 113, 5340-5351
   Abstract »    Full Text »    PDF »
Cell therapies for therapeutic angiogenesis: back to the bench.
D. P Sieveking and M. K. Ng (2009)
Vascular Medicine 14, 153-166
   Abstract »    PDF »
Potential use of endothelial progenitor cells for regeneration of the vasculature.
K. Yamahara and H. Itoh (2009)
Therapeutic Advances in Cardiovascular Disease 3, 17-27
   Abstract »    PDF »
Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors.
S. Patyna, C. Arrigoni, A. Terron, T.-W. Kim, J. K. Heward, S. L. Vonderfecht, R. Denlinger, S. E. Turnquist, and W. Evering (2008)
Toxicol Pathol 36, 905-916
   Abstract »    Full Text »    PDF »
Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth.
S. Purhonen, J. Palm, D. Rossi, N. Kaskenpaa, I. Rajantie, S. Yla-Herttuala, K. Alitalo, I. L. Weissman, and P. Salven (2008)
PNAS 105, 6620-6625
   Abstract »    Full Text »    PDF »
Gene and stem cell therapy in peripheral arterial occlusive disease.
C Kalka and I. Baumgartner (2008)
Vascular Medicine 13, 157-172
   Abstract »    PDF »
Endothelial Differentiation of Hematopoietic Stem and Progenitor Cells from Patients with Multiple Myeloma.
R. Ria, C. Piccoli, T. Cirulli, F. Falzetti, G. Mangialardi, D. Guidolin, A. Tabilio, N. Di Renzo, A. Guarini, D. Ribatti, et al. (2008)
Clin. Cancer Res. 14, 1678-1685
   Abstract »    Full Text »    PDF »
Enhanced functional response of CD133+ circulating progenitor cells in patients early after acute myocardial infarction.
S. Voo, J. Eggermann, M. Dunaeva, C. Ramakers-van Oosterhoud, and J. Waltenberger (2008)
Eur. Heart J. 29, 241-250
   Abstract »    Full Text »    PDF »
Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF.
Y. Huang, X. Chen, M. M. Dikov, S. V. Novitskiy, C. A. Mosse, L. Yang, and D. P. Carbone (2007)
Blood 110, 624-631
   Abstract »    Full Text »    PDF »
Endothelial Outgrowth Cells Are Not Derived From CD133+ Cells or CD45+ Hematopoietic Precursors.
F. Timmermans, F. Van Hauwermeiren, M. De Smedt, R. Raedt, F. Plasschaert, M. L. De Buyzere, T. C. Gillebert, J. Plum, and B. Vandekerckhove (2007)
Arterioscler Thromb Vasc Biol 27, 1572-1579
   Abstract »    Full Text »    PDF »
Progenitor Cell Isolation From Muscle-derived Cells Based on Adhesion Properties.
K. Rouger, B. Fornasari, V. Armengol, G. Jouvion, I. Leroux, L. Dubreil, M. Feron, L. Guevel, and Y. Cherel (2007)
J. Histochem. Cytochem. 55, 607-618
   Abstract »    Full Text »    PDF »
Comparison Between Total Endothelial Progenitor Cell Isolation Versus Enriched Cd133+ Culture.
A. Casamassimi, M. L. Balestrieri, C. Fiorito, C. Schiano, C. Maione, R. Rossiello, V. Grimaldi, V. Del Giudice, C. Balestrieri, B. Farzati, et al. (2007)
J. Biochem. 141, 503-511
   Abstract »    Full Text »    PDF »
Switching on Reparative Angiogenesis: Essential Role of the Vascular Erythropoietin Receptor.
P. Madeddu and C. Emanueli (2007)
Circ. Res. 100, 599-601
   Full Text »    PDF »
The kinase insert domain-containing receptor is an angiogenesis-associated antigen recognized by human cytotoxic T lymphocytes.
Y. Sun, S. Stevanovic, M. Song, A. Schwantes, C. J. Kirkpatrick, D. Schadendorf, and K. Cichutek (2006)
Blood 107, 1476-1483
   Abstract »    Full Text »    PDF »
Analysis of tumor-associated stromal cells using SCID GFP transgenic mice: contribution of local and bone marrow-derived host cells.
T. Udagawa, M. Puder, M. Wood, B. C. Schaefer, and R. J. D'Amato (2006)
FASEB J 20, 95-102
   Abstract »    Full Text »    PDF »
Deletion of the selection cassette, but not cis-acting elements, in targeted Flk1-lacZ allele reveals Flk1 expression in multipotent mesodermal progenitors.
M. Ema, S. Takahashi, and J. Rossant (2006)
Blood 107, 111-117
   Abstract »    Full Text »    PDF »
MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.
N. Felli, L. Fontana, E. Pelosi, R. Botta, D. Bonci, F. Facchiano, F. Liuzzi, V. Lulli, O. Morsilli, S. Santoro, et al. (2005)
PNAS 102, 18081-18086
   Abstract »    Full Text »    PDF »
Circulating Inflammatory Endothelial Cells Contribute to Endothelial Progenitor Cell Dysfunction in Patients with Vasculitis and Kidney Involvement.
C. Holmen, E. Elsheikh, P. Stenvinkel, A. R. Qureshi, E. Pettersson, S. Jalkanen, and S. Sumitran-Holgersson (2005)
J. Am. Soc. Nephrol. 16, 3110-3120
   Abstract »    Full Text »    PDF »
Circulating endothelial precursors: identification of functional subpopulations.
S. Dimmeler (2005)
Blood 106, 2231-2232
   Full Text »    PDF »
Activation of Vascular Endothelial Growth Factor Receptor-2 in Bone Marrow Leads to Accumulation of Myeloid Cells: Role of Granulocyte-Macrophage Colony-Stimulating Factor.
B. Larrivee, I. Pollet, and A. Karsan (2005)
J. Immunol. 175, 3015-3024
   Abstract »    Full Text »    PDF »
Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells.
D. A. Ingram, N. M. Caplice, and M. C. Yoder (2005)
Blood 106, 1525-1531
   Abstract »    Full Text »    PDF »
CD14+CD34low Cells With Stem Cell Phenotypic and Functional Features Are the Major Source of Circulating Endothelial Progenitors.
P. Romagnani, F. Annunziato, F. Liotta, E. Lazzeri, B. Mazzinghi, F. Frosali, L. Cosmi, L. Maggi, L. Lasagni, A. Scheffold, et al. (2005)
Circ. Res. 97, 314-322
   Abstract »    Full Text »    PDF »
Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial.
M. Schmidt, S. Hacein-Bey-Abina, M. Wissler, F. Carlier, A. Lim, C. Prinz, H. Glimm, I. Andre-Schmutz, C. Hue, A. Garrigue, et al. (2005)
Blood 105, 2699-2706
   Abstract »    Full Text »    PDF »
Differential Roles of Vascular Endothelial Growth Factor Receptors 1 and 2 in Dendritic Cell Differentiation.
M. M. Dikov, J. E. Ohm, N. Ray, E. E. Tchekneva, J. Burlison, D. Moghanaki, S. Nadaf, and D. P. Carbone (2005)
J. Immunol. 174, 215-222
   Abstract »    Full Text »    PDF »
Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization.
J. LeCouter, C. Zlot, M. Tejada, F. Peale, and N. Ferrara (2004)
PNAS 101, 16813-16818
   Abstract »    Full Text »    PDF »
Hemangiopoietin, a novel human growth factor for the primitive cells of both hematopoietic and endothelial cell lineages.
Y. J. Liu, S. H. Lu, B. Xu, R. C. Yang, Q. Ren, B. Liu, B. Li, M. Lu, F. Y. Yan, Z. B. Han, et al. (2004)
Blood 103, 4449-4456
   Abstract »    Full Text »    PDF »
Targeting Vascular Endothelial Growth Factor for Relapsed and Refractory Adult Acute Myelogenous Leukemias: Therapy with Sequential 1-{beta}-D-Arabinofuranosylcytosine, Mitoxantrone, and Bevacizumab.
J. E. Karp, I. Gojo, R. Pili, C. D. Gocke, J. Greer, C. Guo, D. Qian, L. Morris, M. Tidwell, H. Chen, et al. (2004)
Clin. Cancer Res. 10, 3577-3585
   Abstract »    Full Text »    PDF »
Endothelial Progenitor Cells: More Than an Inflammatory Response?.
T. J. Rabelink, H. C. de Boer, E. J.P. de Koning, and A.-J. van Zonneveld (2004)
Arterioscler Thromb Vasc Biol 24, 834-838
   Abstract »    Full Text »
VEGF-A165 augments erythropoietic development from human embryonic stem cells.
C. Cerdan, A. Rouleau, and M. Bhatia (2004)
Blood 103, 2504-2512
   Abstract »    Full Text »    PDF »
Myocardial Replacement Therapy.
T. Siminiak and M. Kurpisz (2003)
Circulation 108, 1167-1171
   Full Text »    PDF »
VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.
J. E. Ohm, D. I. Gabrilovich, G. D. Sempowski, E. Kisseleva, K. S. Parman, S. Nadaf, and D. P. Carbone (2003)
Blood 101, 4878-4886
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Receptor-2 Induces Survival of Hematopoietic Progenitor Cells.
B. Larrivee, D. R. Lane, I. Pollet, P. L. Olive, R. K. Humphries, and A. Karsan (2003)
J. Biol. Chem. 278, 22006-22013
   Abstract »    Full Text »    PDF »
Hematopoietic stem cells: can old cells learn new tricks?.
A. D. Ho and M. Punzel (2003)
J. Leukoc. Biol. 73, 547-555
   Abstract »    Full Text »    PDF »
Endothelial progenitor cell culture and differentiation in vitro: a methodological comparison using human umbilical cord blood.
J. Eggermann, S. Kliche, G. Jarmy, K. Hoffmann, U. Mayr-Beyrle, K.-M. Debatin, J. Waltenberger, and C. Beltinger (2003)
Cardiovasc Res 58, 478-486
   Abstract »    Full Text »    PDF »
Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor.
I. Casella, T. Feccia, C. Chelucci, P. Samoggia, G. Castelli, R. Guerriero, I. Parolini, E. Petrucci, E. Pelosi, O. Morsilli, et al. (2003)
Blood 101, 1316-1323
   Abstract »    Full Text »    PDF »
Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells.
P. E. Burger, S. Coetzee, W. L. McKeehan, M. Kan, P. Cook, Y. Fan, T. Suda, R. P. Hebbel, N. Novitzky, W. A. Muller, et al. (2002)
Blood 100, 3527-3535
   Abstract »    Full Text »    PDF »
Identification of the hemangioblast in postnatal life.
E. Pelosi, M. Valtieri, S. Coppola, R. Botta, M. Gabbianelli, V. Lulli, G. Marziali, B. Masella, R. Muller, C. Sgadari, et al. (2002)
Blood 100, 3203-3208
   Abstract »    Full Text »    PDF »
New Approaches to the Treatment of Myelodysplasia.
A. F. List (2002)
Oncologist 7, 39-49
   Abstract »    Full Text »    PDF »
A Genetic Determinant That Specifically Regulates the Frequency of Hematopoietic Stem Cells.
S. J. Morrison, D. Qian, L. Jerabek, B. A. Thiel, I.-K. Park, P. S. Ford, M. J. Kiel, N. J. Schork, I. L. Weissman, and M. F. Clarke (2002)
J. Immunol. 168, 635-642
   Abstract »    Full Text »    PDF »
The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors.
C. W. Scharenberg, M. A. Harkey, and B. Torok-Storb (2002)
Blood 99, 507-512
   Abstract »    Full Text »    PDF »
Bone Marrow-derived Cells Contribute to Tumor Neovasculature and, When Modified to Express an Angiogenesis Inhibitor, Can Restrict Tumor Growth in Mice.
A. M. Davidoff, C. Y. C. Ng, P. Brown, M. A. Leary, W. W. Spurbeck, J. Zhou, E. Horwitz, E. F. Vanin, and A. W. Nienhuis (2001)
Clin. Cancer Res. 7, 2870-2879
   Abstract »    Full Text »    PDF »
Effect of Bone Morphogenetic Protein-2-Expressing Muscle-Derived Cells on Healing of Critical-Sized Bone Defects in Mice.
J. Y. Lee, D. Musgrave, D. Pelinkovic, K. Fukushima, J. Cummins, A. Usas, P. Robbins, F. H. Fu, and J. Huard (2001)
J. Bone Joint Surg. Am. 83, 1032-1039
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor and Angiopoietin-1 Stimulate Postnatal Hematopoiesis by Recruitment of Vasculogenic and Hematopoietic Stem Cells.
K. Hattori, S. Dias, B. Heissig, N. R. Hackett, D. Lyden, M. Tateno, D. J. Hicklin, Z. Zhu, L. Witte, R. G. Crystal, et al. (2001)
J. Exp. Med. 193, 1005-1014
   Abstract »    Full Text »    PDF »
Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells: confirmation of assignments by expression profiling of cytokine receptor transcripts.
F. Billia, M. Barbara, J. McEwen, M. Trevisan, and N. N. Iscove (2001)
Blood 97, 2257-2268
   Abstract »    Full Text »    PDF »
High Levels of Vascular Endothelial Growth Factor Receptor-2 Correlate with Shortened Survival in Chronic Lymphocytic Leukemia.
A. Ferrajoli, T. Manshouri, Z. Estrov, M. J. Keating, S. O’Brien, S. Lerner, M. Beran, H. M. Kantarjian, E. J. Freireich, and M. Albitar (2001)
Clin. Cancer Res. 7, 795-799
   Abstract »    Full Text »
Different expression of CD41 on human lymphoid and myeloid progenitors from adults and neonates.
N. Debili, C. Robin, V. Schiavon, R. Letestu, F. Pflumio, M.-T. Mitjavila-Garcia, L. Coulombel, and W. Vainchenker (2001)
Blood 97, 2023-2030
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Effects on Nuclear Factor-{{kappa}}B Activation in Hematopoietic Progenitor Cells.
M. M. Dikov, T. Oyama, P. Cheng, T. Takahashi, K. Takahashi, T. Sepetavec, B. Edwards, Y. Adachi, S. Nadaf, T. Daniel, et al. (2001)
Cancer Res. 61, 2015-2021
   Abstract »    Full Text »
Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes.
W. T. Bellamy, L. Richter, D. Sirjani, C. Roxas, B. Glinsmann-Gibson, Y. Frutiger, T. M. Grogan, and A. F. List (2001)
Blood 97, 1427-1434
   Abstract »    Full Text »    PDF »
Special Considerations in the Evaluation of the Hematology and Hemostasis of Mutant Mice.
B. D. Car and V. M. Eng (2001)
Vet. Pathol. 38, 20-30
   Abstract »    Full Text »    PDF »
Rational Approaches to Design of Therapeutics Targeting Molecular Markers.
R. J. Klasa, A. F. List, and B. D. Cheson (2001)
Hematology 2001, 443-462
   Abstract »    Full Text »    PDF »
Hematopoietic stem cells express Tie-2 receptor in the murine fetal liver.
H.-C. Hsu, H. Ema, M. Osawa, Y. Nakamura, T. Suda, and H. Nakauchi (2000)
Blood 96, 3757-3762
   Abstract »    Full Text »    PDF »
Donor stromal cells from human blood engraft in NOD/SCID mice.
S.-R. Goan, I. Junghahn, M. Wissler, M. Becker, J. Aumann, U. Just, G. Martiny-Baron, I. Fichtner, and R. Henschler (2000)
Blood 96, 3971-3978
   Abstract »    Full Text »    PDF »
In Silico Cloning of Novel Endothelial-Specific Genes.
L. Huminiecki and R. Bicknell (2000)
Genome Res. 10, 1796-1806
   Abstract »    Full Text »
Clonal Isolation of Muscle-Derived Cells Capable of Enhancing Muscle Regeneration and Bone Healing.
J. Y. Lee, Z. Qu-Petersen, B. Cao, S. Kimura, R. Jankowski, J. Cummins, A. Usas, C. Gates, P. Robbins, A. Wernig, et al. (2000)
J. Cell Biol. 150, 1085-1100
   Abstract »    Full Text »    PDF »
Mouse Jagged2 is differentially expressed in hematopoietic progenitors and endothelial cells and promotes the survival and proliferation of hematopoietic progenitors by direct cell-to-cell contact.
S. Tsai, J. Fero, and S. Bartelmez (2000)
Blood 96, 950-957
   Abstract »    Full Text »    PDF »
A Pentamer Transcriptional Complex Including tal-1 and Retinoblastoma Protein Downmodulates c-kit Expression in Normal Erythroblasts.
L. Vitelli, G. Condorelli, V. Lulli, T. Hoang, L. Luchetti, C. M. Croce, and C. Peschle (2000)
Mol. Cell. Biol. 20, 5330-5342
   Abstract »    Full Text »
Nuclear Factor-{kappa}B and cAMP Response Element Binding Protein Mediate Opposite Transcriptional Effects on the Flk-1/KDR Gene Promoter.
B. Illi, P. Puri, L. Morgante, M. C. Capogrossi, and C. Gaetano (2000)
Circ. Res. 86 , e110-e117
   Abstract »    Full Text »    PDF »
The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice.
A. Peled, O. Kollet, T. Ponomaryov, I. Petit, S. Franitza, V. Grabovsky, M. M. Slav, A. Nagler, O. Lider, R. Alon, et al. (2000)
Blood 95, 3289-3296
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor in Human Colon Cancer: Biology and Therapeutic Implications.
L. M. Ellis, Y. Takahashi, W. Liu, and R. M. Shaheen (2000)
Oncologist 5, 11-15
   Abstract »    Full Text »
Regulation of Angiogenesis via Vascular Endothelial Growth Factor Receptors.
T. Veikkola, M. Karkkainen, L. Claesson-Welsh, and K. Alitalo (2000)
Cancer Res. 60, 203-212
   Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)