Comments for:
Abstract
This study demonstrates that a CD34–, vascular endothelial cadherin– (VE-cadherin–), AC133+, and fetal liver kinase+ (Flk1+) multipotent adult progenitor cell (MAPC) that copurifies with mesenchymal stem cells from postnatal human bone marrow (BM) is a progenitor for angioblasts. In vitro, MAPCs cultured with VEGF differentiate into CD34+, VE-cadherin+, Flk1+ cells — a phenotype that would be expected for angioblasts. They subsequently differentiate into cells that express endothelial markers, function in vitro as mature endothelial cells, and contribute to neoangiogenesis in vivo during tumor angiogenesis and wound healing. This in vitro model of preangioblast-to-endothelium differentiation should prove very useful in studying commitment to the angioblast and beyond. In vivo, MAPCs can differentiate in response to local cues into endothelial cells that contribute to neoangiogenesis in tumors. Because MAPCs can be expanded in culture without obvious senescence for more than 80 population doublings, they may be an important source of endothelial cells for cellular pro- or anti-angiogenic therapies.
Authors
Morayma Reyes, Arkadiusz Dudek, Balkrishna Jahagirdar, Lisa Koodie, Paul H. Marker, Catherine M. Verfaillie
C-type lectins DC-SIGN and DC-SIGNR may assist in determination of the origin of endothelial cells
Submitter: Elizabeth J. Soilleux | ejs17@cam.ac.uk
Hutchison/ M.R.C. Research Centre, Cambridge, CB2 2XY U.K.
Published February 11, 2002
I read with interest the paper "Origin of endothelial progenitors in human postnatal bone marrow" by Reyes et al (1), in which they demonstrated the potential of multipotential adult progenitor cells (MAPC) to generate cells with an endothelial surface phenotype and certain endothelial functional characteristics. Since MAPC precede both haemangioblasts and angioblasts in differentiation, it is probable that this common precursor cell gives rise both to a proportion of endothelial cells (EC) and to haematopoietic cells (1).
My own work has focused on the C-type lectins DC-SIGN and DC-SIGNR, which can both bind ICAM-3 and HIV (2-6). DC-SIGN (and probably DC-SIGNR) is important in the early phase of T cell activation by dendritic cells (DC) (6). DC-SIGN, DC-SIGNR and CD23 (the C-type lectin low affinity receptor for immunoglobulin E) are encoded in a 100 kB region of chromosome 19p13.3 (3). It is interesting that, while the expression of CD23 and DC-SIGN appears almost entirely restricted to leucocytes, DC- SIGNR protein expression is restricted to endothelial cells at three specific endothelial sites (2, 7, 8). However, DC-SIGNR RNA can be detected at a low level in activated KG1 cells (phenotypically similar to immature dendritic cells) and in monocyte derived dendritic cells (3, 9).
In addition, it is puzzling that DC-SIGNR protein expression is restricted to endothelial cells at three specific sites in man, namely, liver sinusoidal endothelium, lymph node sinus endothelium and placental capillary endothelium (2). A similar pattern of expression is seen in rhesus macaque, although DC-SIGNR expression has also been reported on approximately half of capillaries in the terminal ileum (10). Endothelial cells at sites expressing DC-SIGNR are not all of a particular type (e.g., continuous or discontinuous) (11). In addition, activation state does not appear to be important in the induction of DC-SIGNR expression (11).
One further unexpected finding was the capacity of up to 20% lymph node sinus endothelial cells to express the DC-SIGN, the expression of which is otherwise restricted to subsets of DC and specialised macrophages (11). The observations of the restricted endothelial expression of DC- SIGNR and DC-SIGN, together with reports suggesting that endothelial cells at those sites may act as efficient antigen presenting cells, make it tempting to speculate that the EC expressing DC-SIGN and DC-SIGNR may be derived from a bi-potential haematopoietic / endothelial cell precursor. This fascinating work by Reyes et al. adds further credence to this debate (1).
The system used by Reyes et al. is ingenious in that the origin of EC can be clearly demonstrated by differential use of human (donor MAPC- derived EC) and mouse (recipient derived EC) markers (12). At present, investigation of the origin of human EC, for example in biopsy material, is complicated by the lack of such specific markers. However, in the future, investigation of EC expression of a wide panel of markers, may make the situation in man very much clearer. Such markers might include DC -SIGN and DC-SIGNR and perhaps, Lyve-1, a recently described CD44-related molecule expressed mainly by lymphatic endothelia (12)
1.Reyes, M., Dudek, A., Jahagirdar, B., Koodie, L., Marker, P.H., and Verfaillie, C.M. 2002. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109:337-346.
2.Pohlmann, S., Soilleux, E.J., Baribaud, F., Leslie, G.J., Morris, L.S., Trowsdale, J., Lee, B., Coleman, N., and Doms, R.W. 2001. DC-SIGNR, a DC- SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc Natl Acad Sci U S A 98:2670-2675.
3.Soilleux, E.J., Barten, R., and Trowsdale, J. 2000. DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J Immunol 165:2937-2942.
4.Soilleux, E.J., Morris, L.S., Lee, B., Pohlmann, S., Trowsdale, J., Doms, R.W., and Coleman, N. 2001. Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV. J Pathol 195:586-592.
5.Bashirova, A.A., Geijtenbeek, T.B., van Duijnhoven, G.C., van Vliet, S.J., Eilering, J.B., Martin, M.P., Wu, L., Martin, T.D., Viebig, N., Knolle, P.A., et al. 2001. A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med 193:671-678.
6.Geijtenbeek, T.B., Torensma, R., van Vliet, S.J., van Duijnhoven, G.C., Adema, G.J., van Kooyk, Y., and Figdor, C.G. 2000. Identification of DC- SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100:575-585.
7.Bonnefoy, J.Y., Gauchat, J.F., Life, P., Graber, P., Aubry, J.P., and Lecoanet-Henchoz, S. 1995. Regulation of IgE synthesis by CD23/CD21 interaction. Int Arch Allergy Immunol 107:40-42.
8.Soilleux, E.J., Morris, L.S., Leslie, G., Chehimi, J., Luo, Q., Levroney, E., Trowsdale, J., Montaner, L.J., Doms, R.W., Weissman, D., et al. 2002. Constitutive and Induced Expression of DC-SIGN on Dendritic Cell and Macrophage Subpopulations in situ and in vitro. J. Leukocyte Biol. In press.
9.Mummidi, S., Catano, G., Lam, L., Hoefle, A., Telles, V., Begum, K., Jimenez, F., Ahuja, S.S., and Ahuja, S.K. 2001. Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts. J Biol Chem 276:33196-33212.
10.Jameson, B., Baribaud, F., Pohlmann, S., Ghavimi, D., Mortari, F., Doms, R.W., and Iwasaki, A. 2002. Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J Virol 76:1866-1875.
11.Soilleux, E.J., Morris, L.S., Rushbrook, S.M., Lee, B., Coleman, N. 2002. Expression of HIV binding lectin DC-SIGNR: Consequences for Immunity and HIV. Huma Pathology In press.
12.Prevo, R., Banerji, S., Ferguson, D.J., Clasper, S., and Jackson, D.G. 2001. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 276:19420-19430.
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