Abstract
IntroductionTo assess if an impaired cross-talk between endothelial cells (ECs) and perivascular/multipotent mesenchymal stem cells (MSCs) might induce a perturbation of vascular repair and leading to a phenotypic switch of MSC toward myofibroblast in Systemic Sclerosis (SSc).MethodsWe investigated different angiogenic and profibrotic molecules in a tridimentional matrigel assay, performing co-cultures with endothelial cells (ECs) and bone marrow derived MSCs from patients and healthy controls (HC). After 48 hours of co-culture, cells were sorted and analyzed for mRNA and protein expression.ResultsECs-SSc showed a decreased tube formation ability which is not improved by co-cultures with different MSCs. After sorting, we showed: i. an increased production of vascular endothelial growth factor A (VEGF-A) in SSc-MSCs when co-cultured with SSc-ECs; ii. an increased level of transforming growth factor beta (TGF-β) and platelet growth factor BB (PDGF-BB) in SSc-ECs when co-cultured with both HC- and SSc-MSCs; iii. an increase of TGF-β, PDGF-R, alpha smooth muscle actin (α-SMA) and collagen 1 (Col1) in both HC- and SSc-MSCs when co-cultured with SSc-ECs.ConclusionWe showed that during SSc, the ECs-MSCs crosstalk resulted in an altered expression of different molecules involved in the angiogenic processes, and mainly SSc-ECs seem to modulate the phenotypic switch of perivascular MSCs toward a myofibroblast population, thus supporting the fibrotic process.
Highlights
To assess if an impaired cross-talk between endothelial cells (ECs) and perivascular/multipotent mesenchymal stem cells (MSCs) might induce a perturbation of vascular repair and leading to a phenotypic switch of MSC toward myofibroblast in Systemic Sclerosis (SSc)
When these cells were co-cultured with healthy controls (HC)- and SSc-MSCs, we observed a significant improvement in tube-formation ability without a statistically significant difference
Impaired production of angiogenic and fibrotic molecules in SSc-ECs and SSc-MSCs sorted after 48 hrs of co-culture vascular endothelial growth factor (VEGF)-A/VEGFR2 expression in MSCs When MSCs were cultured alone, a statistically significant increase in vascular endothelial growth factor A (VEGF-A) transcript levels was observed in SScMSCs compared to HC-MSCs (2.11 (1.76 to 3.10) versus 1.11 (0.80 to 1.46), respectively, P
Summary
To assess if an impaired cross-talk between endothelial cells (ECs) and perivascular/multipotent mesenchymal stem cells (MSCs) might induce a perturbation of vascular repair and leading to a phenotypic switch of MSC toward myofibroblast in Systemic Sclerosis (SSc). During the normal angiogenic process, mesenchymal pericyte progenitors are recruited in the vascular sprouts in response to growth factors, mainly PDGF, which is produced by ECs [10]. The contact between ECs and perivascular progenitors is a pivotal step for inducing ECs to produce active transforming growth factor-β (TGF-β) [11], which is able to induce maturation of mural cells [12,13], promoting blood vessel stabilization and function [14]. Vascular endothelial growth factor (VEGF), produced by mesenchymal stem cells (MSCs), makes ECs unresponsive to other proangiogenic stimuli
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