ソマティック変異は慢性肝疾患における肝臓のクローン機能と再生を増加させる
Min Zhu1, Tianshi Lu2, Yuemeng Jia1
1Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell
|April 9, 2019
まとめ
非癌性肝細胞の体内変異は,クローン拡張を促し,慢性肝疾患の組織再生を促進します. これらの遺伝子変化,特にPKD1とARID1Aは,がんの発症とは無関係に肝臓の修復を助けます.
科学分野:
- 遺伝学とゲノミクス
- ヘパトロジー
- 細胞生物学
背景:
- 正常な組織は年齢とともに 遺伝的変化を蓄積します
- 慢性退行性疾患における非悪性細胞のクローン拡張における体内変異の役割は不明である.
- 肝硬変は重要な組織損傷と線維症を伴う.
研究 の 目的:
- 慢性肝疾患における非悪性細胞のクローン増殖を促進するかどうかを調査する.
- このプロセスに関わる特定の遺伝子や変異を特定する.
- これらの変異が肝臓の再生と損傷への反応に及ぼす機能的影響を決定する.
主な方法:
- 82人の肝硬変患者の肝臓サンプルを エクソム配列化しました
- 繰り返し発生する変異を特定するために 超深層配列解析
- 147の遺伝子のCRISPRスクリーニングを 組み合わせました
- マウスモデルにおける条件付きヘテロジゴス遺伝子の削除
主要な成果:
- PKD1,PPARGC1B,KMT2D,ARID1Aにおける再発性突然変異を伴う,肝硬変で特定された複雑な変異の状況.
- ミュータントのクローンの数と大きさは 線維症の段階と組織損傷と相関しています
- Pkd1,Kmt2d,Arid1aの喪失はクローンの拡大を促進することが示された.
- マウスの損傷モデルでは,これらの遺伝子の条件付きヘテロジゴス欠損が肝臓保護をもたらした.
結論:
- ソマティック変異は悪性でない肝細胞のクローン拡張を誘発する.
- これらの変異は組織再生を促し,発がんに潜在的に依存しない.
- 発見は,組織修復メカニズムにおける体的変化の新たな役割を示唆しています.
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