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1.  Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva 
Stem Cell Reports  2015;5(6):963-970.
Summary
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by progressive ossification of soft tissues, for which there is no effective treatment. Mutations in the bone morphogenetic protein (BMP) type I receptor activin receptor-like kinase 2 (ACVR1/ALK2) are the main cause of FOP. We generated human induced pluripotent stem cells (hiPSCs) from FOP patients with the ALK2 R206H mutation. The mutant ALK2 gene changed differentiation efficiencies of hiPSCs into FOP bone-forming progenitors: endothelial cells (ECs) and pericytes. ECs from FOP hiPSCs showed reduced expression of vascular endothelial growth factor receptor 2 and could transform into mesenchymal cells through endothelial-mesenchymal transition. Increased mineralization of pericytes from FOP hiPSCs could be partly inhibited by the ALK2 kinase inhibitor LDN-212854. Thus, differentiated FOP hiPSCs recapitulate some aspects of the disease phenotype in vitro, and they could be instrumental in further elucidating underlying mechanisms of FOP and development of therapeutic drug candidates.
Highlights
•A pluripotent cell model of FOP was established•The generation and maintenance of FOP hiPSC-derived ECs were impaired•FOP hiPSC-derived pericytes demonstrated increased osteoblast differentiation•LDN-212854 partly blocks osteoblast differentiation of pericytes from FOP hiPSCs
In this article, ten Dijke and colleagues established hiPSCs from urine-derived cells of fibrodysplasia ossificans progressiva (FOP) patients. The mutant FOP gene ALK2 impaired the differentiation of hiPSC-derived endothelial cells and enhanced the differentiation of hiPSC-derived pericytes to osteoblasts. These hiPSCs will be a valuable resource for further mechanistic research and new drug identification for FOP treatment.
doi:10.1016/j.stemcr.2015.10.020
PMCID: PMC4682290  PMID: 26626181
2.  A novel function of Junctional Adhesion Molecule-C in mediating melanoma cell metastasis 
Cancer research  2011;71(12):4096-4105.
Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified Junctional Adhesion Molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells, promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C−/− mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.
doi:10.1158/0008-5472.CAN-10-2794
PMCID: PMC3117056  PMID: 21593193
3.  A possible crosstalk between DNA repair pathways and angiogenesis 
Cell cycle (Georgetown, Tex.)  2009;8(21):3438-3439.
Postnatal neovascularization is triggered by tissue hypoxia and the hypoxia-inducible transcription factor dependent upregulation of vascular growth factors. At the same time hypoxia is associated with replication stress and can induce a cellular DNA repair response including the phosphorylation of histone H2AX. Recent findings point to a role of H2AX in endothelial cell proliferation under hypoxia and thereby in hypoxia-driven neovascularization.
PMCID: PMC2783752  PMID: 19838053
5.  Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin–mediated cell–cell contacts 
The Journal of Experimental Medicine  2006;203(12):2703-2714.
We recently reported that junctional adhesion molecule (JAM)-C plays a role in leukocyte transendothelial migration. Here, the role of JAM-C in vascular permeability was investigated in vitro and in vivo. As opposed to macrovascular endothelial cells that constitutively expressed JAM-C in cell–cell contacts, in quiescent microvascular endothelial cells, JAM-C localized mainly intracellularly, and was recruited to junctions upon short-term stimulation with vascular endothelial growth factor (VEGF) or histamine. Strikingly, disruption of JAM-C function decreased basal permeability and prevented the VEGF- and histamine-induced increases in human dermal microvascular endothelial cell permeability in vitro and skin permeability in mice. Permeability increases are essential in angiogenesis, and JAM-C blockade reduced hyperpermeability and neovascularization in hypoxia-induced retinal angiogenesis in mice. The underlying mechanisms of the JAM-C–mediated increase in endothelial permeability were studied. JAM-C was essential for the regulation of endothelial actomyosin, as revealed by decreased F-actin, reduced myosin light chain phosphorylation, and actin stress fiber formation due to JAM-C knockdown. Moreover, the loss of JAM-C expression resulted in stabilization of VE-cadherin–mediated interendothelial adhesion in a manner dependent on the small GTPase Rap1. Together, through modulation of endothelial contractility and VE-cadherin–mediated adhesion, JAM-C helps to regulate vascular permeability and pathologic angiogenesis.
doi:10.1084/jem.20051730
PMCID: PMC2118160  PMID: 17116731

Results 1-5 (5)