title: Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden 2300, the Netherlands.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2300, the Netherlands.
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Orlova
authors.affiliation: Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Internal Medicine, Endocrine Section, VU University Medical Center, P.O. Box 7057, Amsterdam 1007, the Netherlands.
authors.forename: Elisabeth M W
authors.initials: EMW
authors.lastname: Eekhoff
authors.affiliation: Department of Endocrinology, Tongji Hospital Affiliated with Tongji University, Shanghai 200065, China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Pan
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2300, the Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden 2300, the Netherlands. Electronic address: p.ten_dijke@lumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009221:Myositis Ossificans / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010012:Osteogenesis; D020286:Pericytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I