Role of endothelial cells in heterotopic ossification using FOP iPS cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 199-233-Bone Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-220
Emilie Barruet*1, Christopher R Schlieve1, Hannah Kim1, Ashley Urrutia1, Mark P White2, Christina Theodoris2, Deepak Srivastava2 and Edward C. Hsiao1
1University of California, San Francisco, San Francisco, CA, 2Gladstone Institute of Cardiovascular Disease, San Francisco, CA
Musculoskeletal disorders affecting the bones and joints are major health problems for children and adults. Unfortunately, treatments for skeletal diseases are still rudimentary. The recent advent of human induced pluripotent stem cells (hiPSCs) provides an unparalleled opportunity to identify novel therapies for human skeletal diseases. One major regulatory pathway in bone formation involves bone morphogenetic proteins (BMPs). Patients with mutations in the Activin A Type I receptor (ACVR1), a BMP receptor, develop the debilitating disease fibrodysplasia ossificans progressiva (FOP). They show progressive ossification of muscle and tendon. The majority of ACVR1 mutations occur in a single amino acid (R206H) that may increase ACVR1 signaling activity. Recent data suggest that human endothelial cells carrying the ACVR1 R206H mutation may contribute to the formation of FOP lesions. Our overall hypothesis is that activated BMP signaling in endothelial cells increases heterotopic bone formation by increasing osteogenesis. In this study, we use a series of human iPSCs created from normal control and FOP donors. We previously showed that the FOP iPSCs not only demonstrate increased mineralization and enhanced chondrogenesis but also increased levels of genes expressed by endothelial cells (PECAM) when cultured in osteogenic conditions. To determine if the ACVR1 R206H mutation leads to increased endothelial cell production, we used a recently-developed protocol to create human iPSC-derived endothelial cells. We successfully derived endothelial precursors from our iPS lines. We found a yield of 25% phenotypic endothelial precursors (CD31+/KDR+) from both control and FOP iPS lines. Since there was no significant difference in endothelial precursors production, we are now testing if the altered BMP signaling in FOP endothelial precursors and endothelial cells affects their osteogenic properties. These studies use iPSCs created from patients with FOP, a rare and dramatic disease of massive heterotopic ossification, to establish a robust in vitro model of human skeletal tissue formation that may be extended to iPSCs created from other skeletal conditions. The cellular mechanistic insights gained from these studies will establish a solid foundation for understanding the roles of non-bone tissues such as endothelial cells in skeletal formation and for identifying new therapies not only for FOP but also other diseases of abnormal skeletal formation.

Nothing to Disclose: EB, CRS, HK, AU, MPW, CT, DS, ECH

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: CIRM Training Grant; March of Dimes; UCSF