Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor

Abstract

.FI T.V.Petrova and T.Ma Èkinen contributed equally to this workLymphatic vessels are essential for¯uid homeostasis, immune surveillance and fat adsorption, and also serve as a major route for tumor metastasis in many types of cancer. We found that isolated human primary lymphatic and blood vascular endothelial cells (LECs and BECs, respectively) show interesting differences in gene expression relevant for their distinct functions in vivo. Although these phenotypes are stable in vitro and in vivo, overexpression of the homeobox transcription factor Prox-1 in the BECs was capable of inducing LEC-speci®c gene transcription in the BECs, and, surprisingly, Prox-1 suppressed the expression of~40% of the BEC-speci®c genes. Prox-1 did not have global effects on the expression of LEC-speci®c genes in other cell types, except that it up-regulated cyclin E1 and E2 mRNAs and activated the cyclin e promoter in various cell types. These data suggest that Prox-1 acts as a cell proliferation inducer and a fate determination factor for the LECs. Furthermore, the data provide insights into the phenotypic diversity of endothelial cells and into the possibility of transcriptional reprogramming of differentiated endothelial cells.

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

“…It is worth noting that CCL21 is produced also by lymphatic endothelial cells (LECs) (Saeki et al, 1999). In addition to CCL21, LECs derived from inflammation-induced lymphangiomas produce a number of chemokines including CXCL9 and CXCL10 (Mancardi et al, 2003), although LECs isolated from normal human skin do not appear to produce them (Petrova et al, 2002). Inflammation-induced chemokines including the CXCR3 ligands are transported via lymphatic vessels to the draining LNs (Palframan et al, 2001).…”

Development of the lymphatic vascular system: A mystery unravels

“…These cells maintain their lineage-specific differentiation even after several passages in vitro. Comparative microarray analyses of their specific transcriptomes revealed that the majority of all genes investigated (approximately 98%) were expressed at comparable levels by the two endothelial cell types (Petrova et al, 2002;Hirakawa et al, 2003), corroborating their close genetic relationship. Whereas the specific function of many of the differentially expressed genes still remains elusive, several molecules have been studied in genetic mouse models and have been found to play important roles in lymphatic development and function (Table 1).…”

“…Indeed, we and others have shown that ectopic expression of Prox1 in differentiated blood vascular endothelial cells (BEC) was sufficient to reprogram BEC to adopt a lymphatic phenotype. This reprogramming was associated with repression of several BEC-specific genes such as E-selectin, interleukin-8, laminin, collagens, neuropilin-1, and VEGF-C, and with induction of several lymphatic-specific genes, including VEGFR-3, podoplanin, and desmoplakin I and II (Hong et al, 2002;Petrova et al, 2002). In addition to its function in reprogramming transcriptional profiles, Prox1 might specify cell fates also by promoting the exit of progenitor cells from the cell cycle and by inducing postmitotic differentiation programs, as has been found during the development of the mammalian retina and the eye lens Dyer et al, 2003;Edqvist and Hallbook, 2004).…”

“…Podoplanin is a mucin-type transmembrane glycoprotein that is expressed by lymphatic, but not by blood vascular endothelial cells in vivo and in vitro (Wetterwald et al, 1996;Kriehuber et al, 2001;Petrova et al, 2002;Hirakawa et al, 2003;Schacht et al, 2003). In addition, podoplanin is expressed by several other cell types, including type I alveolar cells of the lung, cells of the choroid plexus, ciliary epithelial cells of the eye, osteocytes and kidney podocytes, and multiple synonyms have been used in the literature, such as RTI40, murine gp38, canine gp40, human gp36, and murine PA2.26 Schacht et al, 2003).…”

Origine veineuse des vaisseaux lymphatiques chez les mammifères : L’hypothèse de Sabin vérifiée

“…La production de cellules à partir de la veine cardinale est bien induite, mais les cellules conservent une identité veineuse sanguine et le processus avorte [7]. De plus, la surexpression de Prox1 dans un contexte de CE vasculaires conduit à l'activation de marqueurs lymphatiques et la répression de marqueurs veineux [8,9]. L'ensemble de ces données contribue à considérer Prox1 comme un gène maître de la différenciation lymphatique.…”