Background-Emerging evidence has suggested a contribution of bone marrow (BM) cells to lymphatic vessel formation; however, the exact phenotype of the cells with lymphatic endothelial progenitor cell function has yet to be identified. Here, we investigate the identity of BM-derived lymphatic endothelial progenitor cells and their role in lymphatic neovascularization. Methods and Results-Culture of BM-mononuclear cells in the presence of vascular endothelial growth factors A and C and endothelial growth factor resulted in expression of lymphatic endothelial cell markers. Among these cells, podoplanin ϩ cells were isolated by magnetic-activated cell sorting and characterized by fluorescence-activated cell sorter analysis and immunocytochemistry. These podoplanin ϩ cells highly express markers for lymphatic endothelial cells, hematopoietic lineages, and stem/progenitor cells; on further cultivation, they generate lymphatic endothelial cells. We further confirmed that podoplanin ϩ cells exist in small numbers in BM and peripheral blood of normal mice but are significantly (15-fold) augmented on lymphangiogenic stimuli such as tumor implantation. Next, to evaluate the potential of podoplanin ϩ cells for the formation of new lymphatic vessels in vivo, we injected culture-isolated or freshly isolated BM-derived podoplanin ϩ cells into wound and tumor models. Immunohistochemistry demonstrated that the injected cells were incorporated into the lymphatic vasculature, displayed lymphatic endothelial cell phenotypes, and increased lymphatic vascular density in tissues, suggesting lymphvasculogenesis. Podoplanin ϩ cells also expressed high levels of lymphangiogenic cytokines and increased proliferation of lymphatic endothelial cells during coculture, suggesting a lymphangiogenic or paracrine role. Conclusions-Our

Therapeutic, IV.

F-GP1 is a derivative of elarofiban with a high affinity to activated platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and favorable in vivo characteristics for thrombus imaging in preclinical models. We aimed to explore the detection rate of thromboembolic foci with F-GP1 positron emission tomography/computed tomography (PET/CT) in patients with acute venous thromboembolism (VTE), and to evaluate the safety, biodistribution, pharmacokinetics, and metabolism ofF-GP1. We studied patients who had signs or symptoms of acute deep vein thrombosis (DVT) of the leg or acute pulmonary embolism (PE) within 14 days prior toF-GP1 PET/CT, and had thromboembolic foci confirmed by conventional imaging ( = 10 for DVT and = 10 for PE). Dynamic whole-body PET/CT images were acquired for up to 140 minutes after injection of 250 MBq ofF-GP1. F-GP1 PET/CT was well tolerated without any drug-related adverse events, and showed high initial uptake in spleen, kidney, and blood pool, followed by rapid clearance. The overall image quality was excellent and allowed interpretation in all patients.F-GP1 PET/CT identified thromboembolic foci in all 20 patients with either DVT or PE. Vessel-level analysis revealed that F-GP1 PET/CT detected 89% (68/76) of vessels with DVT, and 60% (146/245) for PE. Importantly,F-GP1 PET/CT showed increased uptake in 32 vessels that were not detected by conventional imaging, of which 25 were located in distal veins of the lower extremity in 12 patients. A positive correlation was found between F-GP1 uptake and P-selectin-positive circulating platelets ( = 0.656, = 0.002).F-GP1 is a promising PET tracer for imaging acute VTE in patients. F-GP1 PET/CT may identify thrombi in distal veins of the leg, where conventional imaging has limitations.