Modeling human genetic skeletal disorders in vitro. (A) Modeling the human cartilage disorder, hypochondrogenesis. COL2A1 G1113C mutant (MCRIi019-A-7) iPSC-derived chondronoids at D48 have reduced collagen II ECM immunostaining compared to the isogenic control (MCRIi019-A) and intracellular collagen II aggregates (white arrows). (Scale bar is 200 µm.) (B) TEM shows reduced and disorganized collagen II fibrils in COL2A1 G1113C mutant cartilage. (Scale bar is 500 nm.) (C) Modeling the human brittle bone disorder, osteogenesis imperfecta. COL1A1 W1312C mutant (MCRIi018-A) iPSC-derived osteogenic organoids at D73 have reduced collagen I ECM immunostaining compared to the isogenic control (MCRIi018-B). Organoids were fixed and then scanned with microCT. Representative images (F) are the samples shown in red in D and E. (Scale bars are 500 µm.), color scale indicates mineral structure size. (D) Total organoid volume. (E) Mineral volume. Data in D and E were compared using a Student’s t test, N = 5, **P < 0.005.