Abstract
Membrane-derived microvesicles (MVs) are released from the cell surface and are implicated in cell-to-cell communication. We evaluated whether MVs derived from endothelial progenitor cells (EPCs) are able to trigger angiogenesis. We found that EPC-derived MVs were incorporated in endothelial cells by interaction with alpha4 and beta1 integrins expressed on the MV surface. In vitro, MVs promoted endothelial cell survival, proliferation, and organization in capillary-like structures. In vivo, in severe combined immunodeficient (SCID) mice, MV-stimulated human endothelial cells organized in patent vessels. When incubated with RNase, despite their internalization into endothelial cells, MVs failed to induce in vitro and in vivo angiogenic effects. mRNA transfer was shown by transduction of GFP protein in endothelial cells by MVs containing GFP-mRNA and the biologic relevance by the angiogenic effect of MV-mRNA extract delivered by lipofectamine. Microarray ana-lysis and quantitative reverse transcription-polymerase chain reaction (RT-PCR) of MV-mRNA extract indicated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated with the PI3K/AKT signaling pathway. Protein expression and functional studies showed that PI3K and eNOS play a critical role in the angiogenic effect of MVs. These results suggest that EPCs may activate angiogenesis in endothelial cells by releasing MVs able to trigger an angiogenic program.
Highlights
MV-stimulated human endothelial cells organized in patent vessels
fluorescence-activated cell sorting (FACS) analysis showed the expression by MVs of several adhesion molecules known to be present on endothelial progenitor cells (EPCs) plasma membrane such as intracellular adhesion molecule-1 (ICAM-1), ␣4 integrin, CD44, and CD29 (1 integrin) but not ␣3 integrin and ␣6 integrin adhesion molecules (Figure 1D)
These results indicate that MVs express on their surface several adhesion molecules of plasma membranes of EPCs from which they originated
Summary
MV-stimulated human endothelial cells organized in patent vessels. When incubated with RNase, despite their internalization into endothelial cells, MVs failed to induce in vitro and in vivo angiogenic effects. mRNA transfer was shown by transduction of GFP protein in endothelial cells by MVs containing GFP-mRNA and the biologic relevance by the angiogenic effect of MV-mRNA extract delivered by lipofectamine. Some studies have suggested an engraftment of stem cells by transdifferentiation or fusion in targeted organs.[1,2,3] a growing number of evidences indicate that transient cell localization in the injured tissue may be sufficient to favor functional and regenerative events, suggesting the release of paracrine mediators.[1,2,3] Several mechanisms involved in cell-tocell communication have been identified, including secretion of growth factors, cytokines, surface receptors, and nucleotides.[4,5,6,7] It has been suggested that microvesicles (MVs) actively released from cells may play an important role in cell-to-cell communication.[8,9,10,11]. Embryonic stem cells were recently shown to represent an abundant source of MVs, and it was suggested that MVs derived from these cells may represent one of the critical components supporting self-renewal and expansion of stem cells.[18,19] In addition, Ratajczak et al[18] demonstrated that embryonic stem cell–derived MVs are able to reprogram hematopoietic progenitors by a horizontal transfer of mRNA and protein delivery
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