iPS cell-based disease modeling for fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva (FOP), or Stone Man Syndrome, is a rare but devastating disease where the human body solidifies to become like a statue. FOP is the result of a mutation on the ACVR1 gene and results in tissue ossifying either in response to trauma or idiopathy. Moreover, there is very little available in terms of treatment.
Many groups have investigated the disease by introducing the mutation into animal and human cell models, but the ideal model would use diseased cells from FOP patients. This option is risky, however, because patients are few and the acquisition of these cells could suffice as trauma that stimulates the uncontrolled ossification. iPS cells circumvent this second problem, since non-cartilage cells can be harvested without stimulating the disease.
Accordingly, the labs of Junya Toguchida and Makoto Ikeya, both of the Dept. of Cell Growth and Differentiation, together produced FOP-iPS cells and corrected the mutation in a subset to produce rescued (res) FOP-iPS cells. They then compared the molecular signaling between the two. Both cell types had similar morphology and growth until they were perturbed into chondrogenesis, which was accelerated in FOP-iPS cells. By the end of chondrogenesis, FOP-iPS cells were significantly larger due to enhanced secretion of extracellular matrix proteins, indicating that the disease enhances chondrogenic differentiation and maturation, not cell proliferation.
To identify the molecular triggers of this effect, the team looked at gene expression profiles. FOP-iPS cells and resFOP-iPS cells initially had similar profiles, but these profiles progressively differed as the cells proceeded with chondrogenesis, as nearly 300 genes showed significantly different expression levels at the end. In particular, the SMAD1/5/8 and SMAD2/3 pathways, which regulate a wide variety of cellular functions, were more active. Additional tests recognized PAI1 and MMP genes as two good targets, and application of inhibitors for the gene products reduced chondrogenesis in both cell types such that cell sizes were approximately equal.
Although this work is only preliminary, Ikeya is excited about the prospect, as the identification of certain genes provides promising targets in drug discovery. "That's the main point of this paper. We are looking for drugs."
Read the paper here Stem Cells
Matsumoto Y, Ikeya M, Hino K et al. (2015) New protocol to optimize iPS cells for genome analysis of fibrodysplasia ossificans progressiva. Stem Cells
Online publication: March 13, 2015
Image: Rescued FOP cells (resFOP) from two different iPS cell lines (cl1 and cl2) grow to normal size, unlike FOP cells which grow much larger.