JP7174408B2 - 肝線維症のモデル系ならびにその作製および使用方法 - Google Patents
肝線維症のモデル系ならびにその作製および使用方法 Download PDFInfo
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Description
この出願は、2016年2月10日に出願された米国仮特許出願第62/293,469号の利益を主張し、その仮出願の開示は、全体として参照により本明細書の一部をなすものとする。
初代肝細胞を含有する生物工学的肝臓モデルを、肝臓細胞外マトリックス(脱細胞化肝臓ディスク)上に作製した。3週間にわたるインビトロでの成熟により、生物工学的肝臓は、天然の肝臓解剖学的形態および肝臓関連機能を有する、小さいオルガノイドを形成した。
肝臓オルガノイドは、肝臓前駆細胞(LPC)、肝星細胞(HSC)、およびクッパー細胞(KC)を同時播種することにより形成される。線維化誘発条件に応答して、HSCは、オルガノイドにおいて活性化状態になり、増殖し、線維化過程を惹起する。線維性肝臓オルガノイドは、範囲定量的測定により厳密に検査される。インビトロおよびインビボにおける実験は、HSCの筋線維芽細胞への移行/活性化におけるEZH2の役割を決定するために、HSCにおけるEZH2発現の評価により(相関的測定)、および特異的EZH2阻害を用いることにより(直接的測定)、実施され得る。
インビトロおよびインビボで、オルガノイドにおいて肝線維症を調節するためにHSCを操作する。例えば、線維症が誘発され、EZH2活性は、そのような活性について知られた作用物質(例えば、GSK126)で阻害され得る。オルガノイドにおいてHSCの大部分があるが、それらは標準肝臓分化/維持培地下で線維性表現型を誘発しないことが見出された。これは、これらが初代/静止HSCであるという事実による可能性がある。
Claims (19)
- 肝線維症のためのモデル系であって、前記系が、肝臓細胞外マトリックスと、前記マトリックス上における哺乳動物肝細胞の組合せとを含み、前記組合せが、
(a)肝臓前駆細胞、
(b)クッパー細胞、および
(c)肝星細胞
を含み、前記肝星細胞が、EZH2を発現する活性化肝星細胞および/または筋線維芽細胞を含み、前記マトリックス上における前記哺乳動物肝細胞の組合せが1~4週間インビトロで培養されている、モデル系。 - 前記肝臓細胞外マトリックスおよび前記マトリックス上における前記哺乳動物肝細胞の組合せが、スフェロイドの形で提供される、請求項1に記載のモデル系。
- 前記組合せが、数で、70パーセントから90パーセントまでの肝臓前駆細胞、5パーセントから20パーセントまでのクッパー細胞、および5パーセントから20パーセントまでの肝星細胞を含む、請求項1または請求項2に記載のモデル系。
- 前記肝臓細胞外マトリックスが、脱細胞化肝組織(例えば、脱細胞化肝臓ディスク)を含む、請求項1~3のいずれか1項に記載のモデル系。
- 前記系が組織培養皿にて提供される、請求項1~4のいずれか1項に記載のモデル系。
- 前記系が、モジュラーおよび/またはマイクロ流体デバイスにて提供される、請求項1~5のいずれか1項に記載のモデル系。
- 前記系がインビボに埋め込み可能である、請求項1~6のいずれか1項に記載のモデル系。
- 前記肝臓前駆細胞、クッパー細胞、および/または肝星細胞がヒト細胞である、請求項1~7のいずれか1項に記載のモデル系。
- 前記肝臓細胞外マトリックスが非ヒト哺乳動物の肝臓細胞外マトリックスである、請求項1~8のいずれか1項に記載のモデル系。
- 胆管構造および/またはクラスター化した肝実質細胞のような肝臓構造を含む、請求項1~9のいずれか1項に記載のモデル系。
- 肝線維症を調節することにおける関心対象の作用物質の活性をスクリーニングする方法であって、
(a)請求項1~10のいずれか1項に記載のモデル系を提供するステップ、
(b)前記関心対象の作用物質を前記モデル系に接触させるステップ、
(c)前記モデル系において線維症を測定するステップ、および
(d)線維症が前記接触に応答して増加するか、または減少するかを決定するステップ
を含み、それにより肝線維症を調節することにおける関心対象の作用物質の活性をスクリーニングする、方法。 - 前記モデル系が組織培養皿にて提供される、請求項11に記載の方法。
- 前記モデル系が、モジュールおよび/またはマイクロ流体デバイスにて提供される、請求項11または請求項12に記載の方法。
- 肝線維症を調節することにおける関心対象の作用物質の活性をスクリーニングする方法であって、
(a)請求項1~10のいずれか1項に記載のモデル系を提供するステップ、
(b)前記関心対象の作用物質を前記モデル系に接触させるステップ、
(c)前記モデル系において線維症を測定するステップ、および
(d)線維症が前記接触に応答して増加するか、または減少するかを決定するステップ
を含み、ここで、前記モデル系が、インビボで非ヒト肝組織上または非ヒト肝組織中に埋め込まれており、それにより肝線維症を調節することにおける関心対象の作用物質の活性をスクリーニングする、方法。 - 前記測定ステップが、前記モデル系においてEZH2の活性を測定することを含む、請求項11~14のいずれか1項に記載の方法。
- 前記測定ステップが光学的透明化(例えば、inCITE光学的透明化)および分析を含む、請求項11~15のいずれか1項に記載の方法。
- 前記関心対象の作用物資が、EZH2阻害剤(例えば、GSK-126)、アンジオテンシン1型(AT1)受容体遮断剤(例えば、ロスタチン)、ハロフジノン、リジルオキシダーゼもしくはlox様酵素阻害剤、A2Bアデノシン受容体アンタゴニスト、またはモノクローナル抗体(例えば、GS-6624(シムツズマブ))である、請求項11~16のいずれか1項に記載の方法。
- 請求項1~10のいずれか1項に記載のモデル系を作製する方法であって、
(a)前記肝臓細胞外マトリックスを供給するステップと、
(b)前記肝臓前駆細胞、クッパー細胞、および肝星細胞を前記肝臓細胞外マトリックス上に播種するステップと、その後
(c)インビトロで、前記マトリックス上で前記細胞を成長させるステップと
を含み、ここで、前記成長させるステップが、1週間から3週間までの期間にわたり実行され、それにより、肝線維症のための前記モデル系を形成させる、方法。 - 線維形成促進性サイトカインまたは化学物質を前記モデル系に投与することにより、前記肝星細胞を活性化するステップをさらに含む、請求項18に記載の方法。
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JP2019510480A (ja) | 2019-04-18 |
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US20200377863A1 (en) | 2020-12-03 |
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WO2017139455A1 (en) | 2017-08-17 |
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