JP2019502382A - 幹細胞由来ヒト肝細胞を使用した微小組織形成 - Google Patents
幹細胞由来ヒト肝細胞を使用した微小組織形成 Download PDFInfo
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Abstract
Description
I.定義
II.微小組織の作成
A.多能性幹細胞由来肝細胞
1.多能性幹細胞
a.胚性幹細胞
この未分化ES細胞を「継代培養」するプロセスは、未分化ES細胞を含有する細胞株を作成するために複数回、反復可能である(米国特許第5,843,780号、第6,200,806号、第7,029,913号)。ES細胞は、それらの多能性を維持しつつ増殖する潜在性を有する。例えば、ES細胞は、細胞分化を制御する細胞及び遺伝子の研究において有用である。ES細胞の多能性の遺伝子操作及び選択との組み合わせは、遺伝形質転換マウス、キメラマウス、及びノックアウトマウスの生成によるインビボにおける遺伝子解析研究に使用することができる。
b.誘導型多能性幹細胞
c.体細胞核移植により導入される胚性幹細胞
2.PSC由来肝細胞のプログラミング因子
1.PSC由来肝細胞の細胞浮遊液
2.細胞接着促進成分による補給
3.非接着性細胞培養面
C.微小組織の特徴付け
III.微小組織の使用
A.試験化合物のスクリーニング
B.肝臓の治療及び移植
C.肝臓補助装置における使用
D.商用、治療、及び研究を目的とした流通
IV.実施例
実施例1−微小組織生成のためのパラメータの評価
実施例2−PSC由来肝細胞からの3D微小組織の生成
実施例3−微小組織機能の特徴付け
[参考文献]
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Claims (55)
- 多能性幹細胞(PSC)由来肝細胞から微小組織を作成するインビトロ法であって、
微小組織を得るための原則的に細胞非付着性の底部を有する培養容器内において、1つ以上の細胞外基質たんぱく質又はそのフラグメントの存在下で、PSC由来肝細胞の細胞浮遊液を培養することを備える方法。 - 多能性幹細胞(PSC)由来肝細胞の細胞浮遊液を得ることをさらに備える請求項1に記載の方法。
- 前記細胞浮遊液に1つ以上の細胞外基質たんぱく質又はそのフラグメントを補給することをさらに備える請求項2に記載の方法。
- 前記培養容器は、超低接着プレートである請求項1に記載の方法。
- 前記培養容器は、足場又は基質の重層を備えない請求項1〜4のいずれか一項に記載の方法。
- 前記細胞浮遊液は、粘着性ではない請求項5に記載の方法。
- 前記培養容器の前記底部は、凹状である請求項6に記載の方法。
- 前記多能性幹細胞は、ヒトである請求項1〜4のいずれか一項に記載の方法。
- 前記多能性幹細胞は、胚性幹細胞である請求項8に記載の方法。
- 前記多能性幹細胞は、誘導型多能性幹細胞である請求項8に記載の方法。
- 前記PSC由来肝細胞の細胞浮遊液にPSC−由来マクロファージを補給することをさらに備える請求項1〜4のいずれか一項に記載の方法。
- 前記PSC由来肝細胞の細胞浮遊液にPSC−由来内皮細胞を補給することをさらに備える請求項1〜4のいずれか一項に記載の方法。
- 前記PSC由来肝細胞の細胞浮遊液にPSC−由来マクロファージ及びPSC−由来内皮細胞を補給することをさらに備える請求項1〜4のいずれか一項に記載の方法。
- 前記培養することは、約24時間〜約48時間実施される請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質は、ラミニン、IV型コラーゲン、エンタクチン、ヘパリン硫酸プロテオグリカン、I型コラーゲン、フィブロネクチン、基質細胞外リン糖たんぱく質(MEPE)、ニドゲン−1、F−スポンジン、R−スポンジン、テネイシン、テスティカン、ビトロネクチン、及びデコリンからなる群より選択される請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質は、ラミニン、IV型コラーゲン、エンタクチン、及びヘパリン硫酸プロテオグリカンである請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質又はそのフラグメントは、I型コラーゲン組換ペプチドである請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質又はそのフラグメントは、CELLNEST(商標)である請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質又はそのフラグメントは、GELTREX(登録商標)である請求項1に記載の方法。
- 前記1つ以上の細胞外基質たんぱく質は、組換体である請求項1又は15に記載の方法。
- 前記細胞浮遊液は、約5%〜約30%の前記1つ以上の細胞外基質たんぱく質又はそのフラグメントを含有する請求項1又は15に記載の方法。
- 前記細胞浮遊液は、約10%〜約20%の前記1つ以上の細胞外基質たんぱく質又はそのフラグメントを含有する請求項1又は15に記載の方法。
- 前記細胞浮遊液は、約0.005mg/mL〜約0.05mg/mLの前記1つ以上の細胞外基質たんぱく質又はそのフラグメントを含有する請求項1又は15に記載の方法。
- 前記細胞浮遊液は、約0.02mg/mL〜約0.04mg/mLの濃度の前記1つ以上の細胞外基質たんぱく質又はそのフラグメントを含有する請求項1又は15に記載の方法。
- 前記PSC由来肝細胞の細胞浮遊液を得ることは、
(i)凍結保存PSC由来肝細胞を解凍することと、
(ii)2次元(2D)培養で前記PSC由来肝細胞を培養することと、
(iii)前記PSC由来肝細胞を細胞分離試薬で分離して細胞浮遊液を得ることとを備える請求項2に記載の方法。 - 前記培養することは、オンコスタチンMの存在下において実施される請求項25に記載の方法。
- 前記2次元培養は、接着面上で実施される請求項25に記載の方法。
- 前記接着面は、基質である請求項27に記載の方法。
- 前記基質は、少なくとも1つの細胞外基質たんぱく質を含有する請求項28に記載の方法。
- 前記少なくとも1つの細胞外基質たんぱく質は、コラーゲン、ラミニン、又はフィブロネクチンである請求項29に記載の方法。
- 前記細胞分離試薬は、ACCUTASE(登録商標)である請求項25に記載の方法。
- 前記PSC由来肝細胞は、原則的に単一細胞に分離されない請求項25に記載の方法。
- 前記分離は、細胞のクラスタを中断させない請求項25に記載の方法。
- 前記微小組織は、薬物誘導型シトクロムP450(CYP)活性を有する請求項1に記載の方法。
- 前記CYP活性は、CYP1A2及び/又はCYP3A4の誘導により判定される請求項34に記載の方法。
- 前記微小組織の前記薬物誘導型CYP活性は、前記PSC由来肝細胞の2D培養に比して増大させられる請求項25に記載の方法。
- 前記薬物誘導型CYP活性の増大は、少なくとも1.5倍である請求項36に記載の方法。
- 前記微小組織のサイズを調整することをさらに備える請求項1に記載の方法。
- 調整することは、
(i)前記細胞浮遊液の細胞密度を判定することと、
(ii)前記細胞を約5,000個/cm2〜約250,000個/cm2の細胞密度で播種することにより、約100μm〜約800μmの直径の微小組織を得ることとを備える請求項38に記載の方法。 - 調整することにより、非調整微小組織に比して、前記微小組織の肝の特異的機能を増大させる請求項39に記載の方法。
- 前記肝の特異的機能は、薬物誘導型CYP活性によって測定される請求項40に記載の方法。
- 調整することにより、非調整微小組織に比して、内在PSC由来肝細胞の細胞死を低減させる請求項39に記載の方法。
- 調整することにより、非調整微小組織に比して、細胞生存率を上昇させる請求項39に記載の方法。
- 前記細胞生存率は、ATPの測定によって定量化される請求項43に記載の方法。
- 前記PSC由来肝細胞は、無血清培地又は血清限定培地において培養される請求項1に記載の方法。
- 前記微小組織は、少なくとも50μmの直径を有する請求項1に記載の方法。
- 3D微小組織であって、1つ以上の細胞外基質たんぱく質又はそのフラグメントを補給されたPSC由来肝細胞の凝集物を含有する3D微小組織。
- 前記微小組織は、請求項1〜46のいずれか一項に記載の方法によって作成される請求項47に記載の3D微小組織。
- 前記微小組織は、約100μm〜約800μmの直径を有する請求項47に記載の3D微小組織。
- 前記微小組織は、安定的誘導の可能なCYP発現を有する請求項47に記載の3D微小組織。
- 医薬品組成であって、請求項47に記載の機能性微小組織を含有する医薬品組成。
- キットであって、1つ以上の細胞外基質たんぱく質又はそのフラグメントを補給されたPSC由来肝細胞の凝集物を含有する3D微小組織を含有するキット。
- 前記微小組織は、請求項1〜46のいずれか一項に記載の方法によって作成される請求項52に記載のキット。
- 前記微小組織は、培養容器上に提供される請求項52に記載のキット。
- 前記培養容器は、超低接着(ULA)プレートである請求項54に記載のキット。
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