VEGF family members (VEGF, VEGF-B, VEGF-C, and VEGF-D) are intimately involved in vascular and lymphatic development, growth, and function. These four factors signal through three receptor tyrosine kinases, VEGF R1 (Flt-1), VEGF R2 (Flk-1, KDR), and VEGF R3 (Flt-4), to affect gene expression. While VEGF R2 had been implicated previously as the VEGF receptor involved in embryonic as well as in postnatal wound healing and tumor-associated lymphangiogenesis,1-5 new evidence suggests that VEGF R3 is also important for these processes.4,5
First indications that VEGF R3 may play a role in embryonic lymphangiogenesis came with the observation that mutations in VEGF R3 are associated with hereditary lymphatic diseases and that VEGF R3-deficient mouse embryos perish due to poorly developed vasculature.6,7 Subsequently, VEGF R3 expression was described in an endothelial cell subpopulation early in lymphatic development.4,5 Further studies with knockout mice suggested that VEGF R3, as well as VEGF R2, is critical for lymphangiogenesis.8 The developmental mechanism of lymphangiogenesis is not known. The embryonic lymphatic system may be derived directly from the embryonic vascular system, which forms first, or may be created independently by as yet undescribed lymphatic endothelial precursor cells.4
A recent report by Salven et al. identifies a novel, phenotypically and functionally distinct population of CD34+ CD133+ VEGF R3+ endothelial stem and precursor cells with a potential role in lymphangiogenesis (Figure 1).9 These investigators first examined human fetal liver, cord blood, and adult peripheral blood samples for CD34+ VEGF R3+ cells. VEGF R3 was expressed on a small number of CD34+ fetal liver and cord blood cells and an even smaller number of adult peripheral blood cells. As CD34 does not mark a particular maturity level for endothelial cells, these cells were examined next for expression of the stem cell marker CD133. Almost the entire population of CD34+ VEGF R3+ cells were also CD133+ and it appeared that approximately half also expressed VEGF R2. Endothelial cell growth media containing VEGF, VEGF-C, and FGF basic elicited proliferation of non-adherent CD34+ CD133+ VEGF R3+ cells, which differentiated into adherent cells that ceased expressing CD133.9 These new findings describe the existence of a unique stem cell population that may contribute to both embryonic and adult lymphangiogenesis.
|Figure 1. As cells progress toward committing to an endothelial cell fate, various endothelial cell precursor subsets express different populations of markers. A new cohort of endothelial cells expresses VEGF R3 and is implicated in both embryonic and adult lymphangiogenesis.
- Neufeld, G. et al. (1999) FASEB J. 13:9.
- Veikkola, T. et al. (2000) Cancer Res. 60:203.
- Ziegler, B.L. et al. (1999) Science 285:1553.
- Alitalo, K. & P. Carmeliet (2002) Cancer Cell 1:219.
- Detmar, M. & S. Hirakawa (2002) J. Exp. Med. 196:719.
- Karkkainen, M.J. et al. (2001) Trends Mol. Med. 7:18.
- Dumont, T.J. et al. (1998) Science 282:946.
- Saaristo, A. et al. (2002) J. Exp. Med. 196:719.
- Salven, P. et al. (2003) Blood 101:168.