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Decreased Expression of Angiopoetin 1 on Perivascular Mesenchymal Stem Cells from Ssc Patients Induces an Anti Angiogenetic Effect, when Co-cultured with Endothelial Cells

Paola Di Benedetto, Vasiliki Liakouli, Francesco Carubbi, Piero Ruscitti, Onorina Berardicurti, Ilenia Pantano, Antonio Francesco Campese, Edoardo Alesse, Isabella Screpanti, Roberto Giacomelli and Paola Cipriani

Introduction: The Angiopoietin (Ang)/Tie2 system plays crucial roles in vascular functions, regulating endothelialpericyte interaction and promoting vascular stabilization. We assessed if an impaired cross-talk, in Systemic Sclerosis (SSc), between endothelial cells (ECs) and perivascular mesenchymal stem cells (MSCs) may affect the normal interaction among Ang1, Ang2 and Tie2 thus contributing of the impaired angiogenesis in SSc.
Methods: We investigated Ang1, Ang2 and their receptor performing co-cultures with ECs and bone marrow MSCs obtained from patients and healthy controls (HC). After 48 hours, cells were sorted and analysed for molecular assays. Furthermore, we investigated, by ELISA assay, the proteins released in the supernatants. Finally, we silenced Ang-1 expression in HC-MSCs by siRNA-Ang1.
Results: At molecular level, SSc-MSCs, cultured alone, expressed lower amount of Ang1 when compared to HC-MSCs. After co-culture, a significant decreased of Ang1 mRNA levels was observed in the SSc-MSCs/SSc-ECs. On the contrary, SSc-ECs expressed higher levels of Ang2 and Tie2 in each co-culture condition, when compared to the expressions of cells cultured alone. The WB and ELISA assays mirrored the results observed in gene expression. HC-MSCs transfected with siRNA-Ang1 lacked the ability to support the formation of tube like structure.
Conclusions: In this work we provided evidence that an imbalance of Ang1/Ang2 molecules and a decreased expression of their receptor, Tie2, during ECs-perivascular MSCs interplay, may modulate vessel stability, and vascular tube formation, thus contributing to the angiogenic alteration observed during SSc.