Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation
- Equal contributors
1 Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku 606-8507, Kyoto, Japan
2 Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku 606-8507, Kyoto, Japan
3 Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
4 Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
5 Department of Medicine, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
6 Department of Medicine, Division of Endocrinology and Metabolism and the Institute for Human Genetics, University of California-San Francisco, 513 Parnassus Ave., HSE901G, San Francisco, CA 94143-0794, USA
7 Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
8 Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
9 Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
10 Department of Medicine and Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94143, USA
Orphanet Journal of Rare Diseases 2013, 8:190 doi:10.1186/1750-1172-8-190Published: 9 December 2013
Abnormal activation of endochondral bone formation in soft tissues causes significant medical diseases associated with disability and pain. Hyperactive mutations in the bone morphogenetic protein (BMP) type 1 receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive ossification in soft tissues. However, the specific cellular mechanisms are unclear. In addition, the difficulty obtaining tissue samples from FOP patients and the limitations in mouse models of FOP hamper our ability to dissect the pathogenesis of FOP.
To address these challenges and develop a “disease model in a dish”, we created human induced pluripotent stem cells (iPS cells) derived from normal and FOP dermal fibroblasts by two separate methods, retroviral integration or integration-free episomal vectors. We tested if the ability to contribute to different steps of endochondral bone formation was different in FOP vs. control iPS cells.
Remarkably, FOP iPS cells showed increased mineralization and enhanced chondrogenesis in vitro. The mineralization phenotypes could be suppressed with a small-molecule inhibitor of BMP signaling, DMH1. Our results indicate that the FOP ACVR1 R206H mutation favors chondrogenesis and increases mineral deposition in vitro.
Our findings establish a FOP disease cell model for in vitro experimentation and provide a proof-of-concept for using human iPS cell models to understand human skeletal disorders.