Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva

Abstract

SummaryFibrodysplasia 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.

Fibrodysplasia ossificans progressiva: Basic understanding and experimental models

“…The induction of iPSc in vitro rapidly and effectively indicates the phenotype of disease in an individual specific background. A variety of somatic cells can be (54) reprogrammed into stem cells, including skin fibroblasts (32) and kidney epithelial cells (48), and Sendai virus and non-integration vector can be used as programming tools (49). (50).…”

Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases

“…Investigating a rare disorder presents many challenges, but UiPSCs represent a world of potential applications -for recreating the phenotypic and pathological variants and also for identifying drug candidates and transplanting autologous cells into patients. Two studies have posited that new treatments for rare diseases can be developed in the future using UiPSCs-based models with integration-free episomal vectors (61,64).…”

“…Many groups of researchers have successfully generated patient-specific UiPSCs. These cells are derived from patients with conditions such as renal disease (59), pediatric disease (60), a bleeding disorder (61), neurological disease (62), and a bone disorder (63,64). Obtaining these cells is the critical first step to elucidating the mechanisms that underlie the pathology of those diseases.…”

“…Moreover, use of ALK2 inhibitor led to a reduction in alkaline phosphatase (ALP) activity. Models such as FOP iPSCs provide a useful tool to determine the underlying mechanisms of endothelial-mesenchymal transition (EndMT), to explore the bioactivity of ALK2 inhibitors, and to screen drugs (64).…”

“…Because iPSCs resemble ESCs in terms of pluripotency and the potential for self-renewal, patient-specific iPSCs could represent a promising strategy for investigating the molecular mechanisms of disease and discovery of drugs to treat them (93,94). Recent studies have reported that generating UiPSCs from patients with rare diseases would provide insight into the mechanisms of those diseases (59)(60)(61)(62)(63)(64). The availability of limitless amounts of diseased cells from patients with a rare disease could, along with gene editing, prove useful in clinical practice (Figure 1).…”