Study on osteoblast differentiation of Costello syndrome-derived induced pluripotent stem cells

Abstract

The generation of human induced pluripotent stem cells (iPSCs) via cellular reprogramming of somatic cells from individuals with genetic disorders can provide a great opportunity to understand pathophysiology of the genetic disorders in vitro. Costello syndrome (CS) is one of RASopathies that are a group of genetic disorders having mutations on RAS/MAPK pathway. Constitutive activation of HRAS resulting from HRAS mutation causes CS. CS patients have severe musculoskeletal abnormalities such as short stature, stooped standing posture, hip dysplasia, kyphoscoliosis and osteoporosis. To elucidate molecular mechanism of musculoskeletal defects in CS, CS-iPSCs were generated from patient fibroblasts by ec-topic expression of OCT4, SOX2, C-MYC and KLF4. Mesenchymal stem cells (MSCs) were differentiated from CS-iPSCs by two separate methods. MSCs could be developed through neural crest (NC) and paraxial mesoderm (PM) lineages, respectively. NC-MSCs expressed MSC-surface markers such as CD73, CD90 and CD105 and normally differenti-ated into chondrocytes and functional osteoblasts. However, PM-MSCs did not express CD105 and failed further differentiation into osteoblasts and chondrocytes. The results in-dicate that aberrant osteogenesis in paraxial mesoderm lineage may be responsible for mus-culoskeletal defects in CS patients.