Strategic research on cartilage development and regeneration using the chondrocyte differentiation method of human iPS cells by small-molecule compounds

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16645
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kawata Manabu 東京大学, 医学部附属病院, 登録研究員 (10803174)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 軟骨細胞 / 多能性幹細胞 / 低分子化合物

Outline of Final Research Achievements

I developed a differentiation method of human pluripotent stem cells (hPSCs) into chondrocytes by simple combination of two compounds, a glycogen synthase kinase 3 inhibitor, and a retinoic acid receptor (RAR) agonist, within 5-9 days.
Comprehensive gene expression and open chromatin analyses at each stage of our protocol showed step-by-step differentiation toward chondrocytes. Genome-wide analysis by RAR and β-catenin ChIP-seq demonstrated that RA and Wnt/β-catenin signaling collaboratively regulated the key marker genes at each differentiation stage.
Particles prepared from hPSC-derived cells differentiated under our protocol formed hyaline cartilaginous tissues when transplanted into knee joints and subcutaneous spaces of immunodeficient mice.

Free Research Field

整形外科学

Academic Significance and Societal Importance of the Research Achievements

本研究により得られた解析結果や知見をベースとして、軟骨分化過程に関わる様々なシグナルに注目した解析を実施していくことが可能である。また本誘導法を元にして、より軟骨分化能や軟骨成熟を促進する化合物や、半月板細胞等の他の運動器系統細胞への分化を促進する化合物を化合物ライブラリーを活用して同定していく研究等を発展させることが期待される。