Investigation of the molecular mechanism involving the transdifferentiation of human embryonic stem cells into extraembryonic lineage

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16135
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44020:Developmental biology-related
• Research Institution: Tohoku University
• Principal Investigator: KOBAYASHI Norio 東北大学, 医学系研究科, 助教 (10803885)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 栄養膜幹細胞（TS細胞） / 胚体外細胞系譜 / 胚体外細胞系 / 分化転換

Outline of Final Research Achievements

Little is known about the epigenetic mechanisms of the first cell fate commitment in humans. We show that naive human embryonic stem (ES) cells can transdifferentiate into trophoblast stem (TS) cells, but primed ES cells cannot. Our transcriptome and methylome analyses reveal that a primate-specific miRNA cluster on chromosome 19 (C19MC) is active in naive ES cells but epigenetically silenced in primed ones. Moreover, genome and epigenome editing using CRISPR/Cas systems reveal that C19MC is essential for the maintenance of TS cells and activation of C19MC allows the derivation of TS cells from primed ES cells. Thus, we reveal that C19MC activation confers differentiation potential into trophoblast lineages on human ES cells. Since C19MC is exclusively expressed in the placenta after implantation, we propose that silencing of C19MC in the epiblast lineage may function as an epigenetic barrier preventing ectopic differentiation of trophoblast cells.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

霊長類特異的なインプリント遺伝子C19MCはTS細胞では高発現しているが、ES細胞および分化転換細胞では発現しておらず、ES細胞からTS細胞への分化転換を阻害するエピジェネティック障壁として機能していた。よって、ヒト受精卵における胚体と胚体外細胞の運命決定にC19MCのインプリント制御が関与している可能性が考えられる。また、C19MCの遺伝子座は霊長類に高度に保存されており齧歯類では保存されていない。今後、ヒト特異的な発生機構の解明が、不妊や流産の原因の解明や安全な生殖補助医療の提供などに役立つと期待される。