Differentiation of vascular stem cells contributes to ectopic calcification of atherosclerotic plaque

The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis. Stem Cells2016;34:913-92

Differentiation of vascular stem cells contributes to ectopic calcification of atherosclerotic plaque

The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis. Stem Cells 2016;34:913-923.Irish Research Council for Science, Engineering and Technology and Science Foundation Ireland under Grant No. 09/SRC/B179

Mesenchymal stem cell inhibition of t-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin e2 via the ep4 receptor

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naive T cells remain unclear. MSC influence on the differentiation of naive and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naive- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naive and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4

Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4+ T cells toward the Th17 phenotype was examined. CD4+ T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell–cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.Deposited by bulk impor