Study of the pathogenesis of Ullrich congenital muscular dystrophy by transplantation of iPSC derived MSC

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15119
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kyoto University
• Principal Investigator: Takenaka Nana 京都大学, iPS細胞研究所, 特定研究員 (20792849)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: iPS細胞 / 6型コラーゲン / ウルリッヒ型筋ジストロフィー / MSC / 骨格筋再生 / 病態メカニズム

Outline of Final Research Achievements

Type 6 collagen (COL6) is produced by mesenchymal stromal cells (MSC) in skeletal muscle, and its gene mutation is the cause of Ullrich congenital muscular dystrophy (UCMD). To test whether COL6 supplementation has a therapeutic effect for UCMD, we conducted in vivo and in vitro experiments using healthy induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) and COL6-deficient iMSCs (KO-iMSCs).
The transplantation of iMSCs into the skeletal muscle of immunodeficient UCMD model mice demonstrated that muscle regeneration and maturation were promoted only in the region supplemented with COL6. In addition, co-culture experiments of skeletal muscle satellite cells derived from UCMD model mice (Col6a1KO-MuSCs) showed iMSCs but not KO-iMSCs could improve the proliferation, differentiation, and maturation of Col6a1KO-MuSCs.
These findings indicate that COL6 supplementation improves muscle regeneration and maturation in UCMD model mice.

Free Research Field

再生医学

Academic Significance and Societal Importance of the Research Achievements

現時点では、UCMDに対する有効な治療法は存在しておらず、COL6の欠損がどのようなメカニズムを介してUCMDの病態を引き起こすかという点も正確には明らかとなっていない。
当該研究では、健常者由来iPS細胞から作成したiMSCと、健常者由来iPS細胞に遺伝子操作を加えてCOL6を欠損させたiPS細胞から作成したCOL6KO-iMSCを、それぞれUCMDモデルマウスに移植する実験を介して、細胞移植によりCOL6を補充することで、骨格筋の再生・成熟が促進され、UCMDの病態が改善されることをはじめて明らかとした。この成果は、将来、細胞移植治療法の確立や、創薬開発にもつながると考えている。