Differentiation of Hypertrophic Chondrocytes from Human iPSCs for the In Vitro Modeling of Chondrodysplasias

Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, we...

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Bibliographic Details
Published in:Stem cell reports 2021-03, Vol.16 (3), p.610-625
Main Authors: Pretemer, Yann, Kawai, Shunsuke, Nagata, Sanae, Nishio, Megumi, Watanabe, Makoto, Tamaki, Sakura, Alev, Cantas, Yamanaka, Yoshihiro, Xue, Jing-Yi, Wang, Zheng, Fukiage, Kenichi, Tsukanaka, Masako, Futami, Tohru, Ikegawa, Shiro, Toguchida, Junya
Format: Article
Language:English
Subjects:
chondrodysplasia
COL10A1
iPSC
MATN3
unfolded protein response
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Summary:Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, we developed a three-dimensional culture protocol to differentiate hypertrophic chondrocytes from induced pluripotent stem cells (iPSCs) and examine the phenotype caused by MATN3 and COL10A1 mutations. Intracellular MATN3 or COL10 retention resulted in increased ER stress markers and ER size in most mutants, but activation of the UPR was dependent on the mutation. Transcriptome analysis confirmed a UPR with wide-ranging changes in bone homeostasis, extracellular matrix composition, and lipid metabolism in the MATN3 T120M mutant, which further showed altered cellular morphology in iPSC-derived growth-plate-like structures in vivo. We then applied our in vitro model to drug testing, whereby trimethylamine N-oxide led to a reduction of ER stress and intracellular MATN3. •A new induction method enables hypertrophic chondrocyte differentiation from iPSCs•Chondrodysplasia mutants show intracellular MATN3 or COL10 accumulation•Some, but not all, mutants have ER stress with an unfolded protein response•This induction system is applicable to transcriptomic analysis and drug development Chondrodysplasias are highly heterogeneous genetic cartilage diseases. Here, Toguchida and colleagues establish a new induction system to differentiate hypertrophic chondrocytes from iPSCs and analyze these disorders in vitro. They found that different chondrodysplasia mutants, despite mutations being in the same gene, showed varying phenotypes and transcriptomic changes. This system provides an initial platform for further investigation and drug development.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2021.01.014