ニューロトロフィク因子受容体RETは,血液形成幹細胞の生存と機能を駆動する

Diogo Fonseca-Pereira¹, Sílvia Arroz-Madeira¹, Mariana Rodrigues-Campos²

¹1] Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Avenida Professor Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal [2].

Nature

|August 1, 2014

まとめ

ニューロトロフィック因子受容体RETは,造血幹細胞 (HSC) の生存と増殖に不可欠である. RETを活性化すると,HSCの機能と移植効率が向上し,治療的可能性が生まれます.

科学分野:

血液学ヘマトロジ
発達生物学発達生物学について
神経科学は神経科学である.

背景:

血液形成は静止している血液形成性幹細胞 (HSC) からすべての血液細胞を生成します.
HSCのホメオスタシスと機能を調節するメカニズムは完全に理解されていません.
HSCは,生理学的要求に応えるため,自己更新および拡張能力を必要とします.

研究の目的:

HSCの調節におけるニューロトロフィク因子受容体RETの役割を調査する.
HSCにおける RET の下流にあるシグナル伝達経路を解明する.
HSC移植におけるRET活性化の治療の可能性を調査する.

主な方法:

HSCとその環境におけるRET表現の分析.
HSC機能を評価するためにマウスモデルにおけるRetの遺伝的アブレーション.
HSCの生存,拡大,分化,移植の可能性の評価.
p38 MAPK,CREB,Bcl2,Bcl2l1.1.を含む下流信号伝達経路の調査
人間の帯血の祖先に対する神経栄養因子の効果の評価.

主要な成果:

HSCはRETを発現し,そのリガンドはHSCの微環境に存在します.
リートアブレーションは,HSCの生存率と数を低下させ,ストレス反応と再構成に影響を及ぼします.
RETシグナリングはp38 MAPKとCREBを活性化し,Bcl2とBcl2l1の発現につながり,HSCの生存に不可欠です.
Bcl2またはBcl2l1の強制表現は,Retの原始原始機能を救出する.
RETの活性化により,HSCの生存,拡張,移植の効率が向上する.
ニューロトロフィック要因は,ヒトの帯血の祖先の拡張と移植を強化する.

結論:

ニューロトロフィク因子受容体RETは,HSCの生存,拡張,および機能の重要な調節体です.
P38 MAPK/CREBとBcl2/Bcl2l1経由のRETシグナリングは,HSCホメオスタシスとストレス反応に不可欠である.
RETアゴニストは,ヒトにおけるHSC移植の成果を向上させる有望な治療戦略です.

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