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大学・研究所にある論文を検索できる 「自己複製能を獲得し幹細胞にリプログラミングされた造血前駆細胞の機能解析」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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自己複製能を獲得し幹細胞にリプログラミングされた造血前駆細胞の機能解析

岡部, 基人 東京大学 DOI:10.15083/0002008310

2023.12.27

概要

【別紙 2】
審査の結果の要旨
氏名 岡部基人

本研究は、遺伝子導入によるリプログラミング技術を応用し、造血幹細胞の活性に強く関
わる遺伝子を造血前駆細胞に遺伝子導入を行うことで自己複製能をもつ造血幹細胞を誘導
する方法の確立を試みたものであり、下記の結果を得た。
⒈ 既報から造血幹細胞活性の増強に寄与すると報告のあった 8 つの遺伝子(Hes1、
Klf10、HoxA9、FosB、Runx1、PU.1、Hdac1、HoxB4)を抽出し、レトロウイルスベク
ターを用いて造血前駆細胞に遺伝子導入を行った。遺伝子導入後の造血前駆細胞を用
いて競合的骨髄再構築法を用いて評価を行ったところ、HoxA9 遺伝子を導入した群と
HoxB4 遺伝子を導入した群でのみ、ドナー細胞の再構築を認めた。骨髄における造血
幹細胞分画でのドナー細胞のキメリズムを評価したところ、HoxB4 遺伝子を導入した
群でのみドナー細胞が認められた。
⒉ 一次レシピエントマウスの全骨髄細胞を用いて二次移植を行ったところ、HoxB4 遺伝
子を導入した群でのみ末梢血中にドナー細胞を認めるとともに、二次レシピエントマ
ウスの骨髄中の造血幹細胞分画においてもドナー細胞を認めることができた。これら
のことから、HoxB4 遺伝子の導入により造血前駆細胞は多分化能および自己複製能を
獲得しうることが示された。
⒊ HoxB4 遺伝子が制御する下流の遺伝子を探索するため、HoxB4 遺伝子の導入を行った
造血前駆細胞を用いて網羅的に遺伝子発現解析を行った。その結果、造血前駆細胞に
比べて造血幹細胞および HoxB4 遺伝子を導入した造血前駆細胞において特異的に発現
が高い、あるいは低い遺伝子が複数確認され、これらの遺伝子変化が造血前駆細胞の
HoxB4 によるリプログラムに関与する可能性が示唆された。
以上、本論文は造血前駆細胞に遺伝子導入を行うことで自己複製能をもつ造血幹細胞を誘
導する方法を示したものであり、慢性的なドナー不足の解消へのアプローチとして、一つ
の臨床応用可能な方策を提示する意義のあるものであると考えられる。
よって本論文は博士(医学)の学位請求論文として合格と認められる。

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8. 謝辞

本稿の作製にあたり、研究の機会を与えてくださりご指導ご鞭撻を賜りまし

た、東京大学医科学研究所附属病院

先端医療研究センター

分野

東條有伸前教授に心より御礼を申し上げ

南谷泰仁教授、分子療法分野

造血病態制御学

ます。また、研究を進めるにあたり、親身なご指導ならびにご助言を賜りました

東京大学医科学研究所

中内啓光東京大学特任教授に深く感謝を申し上げます。

また研究の遂行にあたりご協力いただいた北里大学医学部輸血部

大津真博士

に深く感謝申し上げます。

ウイルスベクターの作製や評価システムの構築に多大なる助言をしていただ

いた京都大学高等研究院

山本玲博士、フローサイトメトリー解析でご支援い

ただいた東京大学医科学研究所幹細胞治療研究センターの山崎裕治氏に深く感

謝申し上げます。研究生活全般にわたりご協力およびご支援いただきました津

久井弘子氏、岡田京子氏に深く感謝申し上げます。

最後に、研究の継続を支持し心身ともに支えてくれた妻子および両親に心か

らの謝意を記します。

72

...

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