The healing effects of placental extracellular vesicles (EVs) on induced dermal cells function in chronic Graft vs. Host Disease

Alloreactivity of the graft in chronic Graft-versus-host-disease (cGVHD) may induce dermal inflammation and subsequently fibrosis. Several studies have reported the use of mesenchymal stromal cells (MSCs) or their derived extracellular vesicles (EVs) for the treatment of cGVHD. MSCs cells can be derived from the placenta.

We hypothesized that Placenta-derived EVs may be used as a future treatment for cGVHD.

This study compares two sources of placental EVs derived from Placental eXpanded (PLX) cells (Pluristem) and from Human Villous Trophoblasts (HVT) cells and explores their anti-inflammatory and anti-fibrotic activity.

EVs derived from PLX and HVT cell were characterized. Their anti-inflammatory and anti-fibrotic effects on cytokine-induced epidermal keratinocytes cells (HACAT) and normal human dermal fibroblasts (NHDF) were explored using flow cytometry, western blot, proliferation/apoptosis assay and RT PCR.

We found that both PLX and HVT-EVs express mesenchymal markers (CD29/CD73/CD105). Placental EVs bound and penetrated to HACAT cells and modified their function. HACAT cells that were exposed to cytokines (TNFα & INFγ) had reduction in proliferation of at least 50% (p<0.001) and increase in cell apoptosis (p<0.05) compared to the control. Similarly, placental EVs moderated the cytokines effects. HVT-EVs improved cell proliferation by 2 time, and decreased the expression ratio of the apoptotic gene BAX/BCL2 (P<0.001). NHDF cells that were exposed to TGFβ, had an increase in the fibrosis-related-signal transduction proteins expression. PLX-EVs neutralized α-Smooth muscle actin (α-SMA) and doubled the level of the fibrosis inhibitor SMAD7.

Conclusion: placental EVs can regulate dermal inflammation and fibrosis and may lead to new therapeutic approach.