Abstract
BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Recently, the exosome, which can transport a diverse suite of macromolecules, has gained attention as a novel intercellular communication tool. However, the potential role of the exosome in PlaMSC therapeutic action is not well understood. The purpose of this study was to evaluate PlaMSC-derived exosome angiogenesis promotion in vitro and in vivo.MethodsMSCs were isolated from human term placental tissue by enzymatic digestion. Conditioned medium was collected after 48-h incubation in serum-free medium (PlaMSC-CM). Angiogenic factors present in PlaMSC-CM were screened by a growth factor array. Exosomes were prepared by ultracentrifugation of PlaMSC-CM, and confirmed by transmission electron microscopy, dynamic light scattering, and western blot analyses. The proangiogenic activity of PlaMSC-derived exosomes (PlaMSC-exo) was assessed using an endothelial tube formation assay, a cell migration assay, and reverse transcription-PCR analysis. The in-vivo angiogenic activity of PlaMSC-exo was evaluated using a murine auricle ischemic injury model.ResultsPlaMSC-CM contained both angiogenic and angiostatic factors, which enhanced endothelial tube formation. PlaMSC-exo were incorporated into endothelial cells; these exosomes stimulated both endothelial tube formation and migration, and enhanced angiogenesis-related gene expression. Laser Doppler blood flow analysis showed that PlaMSC-exo infusion also enhanced angiogenesis in an in-vivo murine auricle ischemic injury model.ConclusionsPlaMSC-exo enhanced angiogenesis in vitro and in vivo, suggesting that exosomes play a role in the proangiogenic activity of PlaMSCs. PlaMSC-exo may be a novel therapeutic approach for treating ischemic diseases.
Highlights
The therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines
We found that the depletion of the exosomes significantly reduced the proangiogenic effects of MSC isolated from human term placental tissue (PlaMSC)-conditioned medium (CM)
PlaMSC-exo were incorporated into endothelial cells, where they induced migration, tube formation, and angiogenic gene expression (Fig. 4a–f), suggesting that the angiogenic effects of PlaMSC-CM were partly due to the direct stimulation of endothelial cells by exosomes
Summary
The therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Various studies have reported previously that MSCs could elicit therapeutic effects via differentiation and/or secretion of factors such as growth factors, cytokines, and. Several studies have demonstrated that term placenta-derived MSCs (PlaMSCs) enhanced angiogenesis. König et al [10] reported that paracrine effects of conditioned medium (CM) from human PlaMSCs enhanced endothelial cell viability, migration, and tube formation, and elevated the secretion of proangiogenic proteins such as angiogenin, angiopoietin-1, angiopoietin-2, GRO, interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), thrombopoietin, Tie, and VEGF
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