Objective-We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration. Methods and Results-Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but afterdifferentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60 -negative cells were also positive for platelet-derived growth factor receptor ␣ and ␤ chains and could be effectively differentiated into both VE-cadherin ϩ endothelial cell and ␣-smooth muscle actin ϩ mural cell. VE-cadherin ϩ cells, which were also CD34 ϩ and VEGF-R2 ϩ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow. Conclusions-We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine. (Arterioscler Thromb Vasc

[(18)F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [(11)C]PIB PET.

The combined and separate effects of exercise training and bisphosphonate (etidronate) therapy on bone mineral in postmenopausal women were compared. Forty-eight postmenopausal women were randomly assigned (double blind) to groups that took intermittent cyclical etidronate; performed strength training (3 d/week) and received matched placebo; combined strength training with etidronate; or took placebo and served as nonexercising controls. Bone mineral, lean tissue, and fat mass were assessed by dual-energy X-ray absorptiometry before and after 12 months of intervention. After removal of outlier results, changes in bone mineral density (BMD) of the lumbar spine and bone mineral content (BMC) of the whole body were greater in the subjects given etidronate (+2.5 and +1.4%, respectively) compared with placebo (-0.32 and 0%, respectively) (p < 0.05), while exercise had no effect. There was no effect of etidronate or exercise on the proximal femur and there was no interaction between exercise and etidronate at any bone site. Exercise training resulted in significantly greater increases in muscular strength and lean tissue mass and greater loss of fat mass compared with controls. We conclude that etidronate significantly increases lumbar spine BMD and whole-body BMC and that strength training has no additional effect. Strength training favourably affects body composition and muscular strength, which may be important for prevention of falls.

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Background— We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells. Methods and Results— In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2–positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2 + VEcadherin − cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1 + cells surrounded by SMA + cells. In addition, these differentiated VEGF-R2 + cells can form tube-like structures in a 3-dimensional culture. Conclusion— Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2 + VEcadherin − cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.