JP7372910B2 - ヒト多能性幹細胞由来の胸腺オルガノイドのインビトロ生成 - Google Patents
ヒト多能性幹細胞由来の胸腺オルガノイドのインビトロ生成 Download PDFInfo
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Description
本特許出願は、その開示全体が参照により本明細書に組み入れられる、2017年9月20日出願の米国仮出願第62/560,908号の利益を主張する。
本発明は、米国国立衛生研究所、国立がん研究所、外科部門によって、プロジェクト番号Z01BC010763の下、政府の支援を受けて成された。政府は、本発明において一定の権利を有する。
ヒト人工多能性幹細胞(hiPSC)(NL5-GFP)をESSENTIAL8培地(Gibco,Waltham,MA)で維持した。hiPSCを増幅及び維持するために、培地を毎日交換し、2~3日間ごとに1:3又は1:6の比でMATRIGELマトリクス(BD Biosciences,Franklin Lakes,NJ)コーティングされた皿に細胞を機械的に継代した後、該細胞は胸腺上皮細胞に分化し始める(1日目の前)。hiPSCのTEPLCへの分化については、Sun et al.,Cell Stem Cell,13:230-236(2013)に教示されているプロトコルを改変した。要約すると、ゼノフリー条件で培養された細胞の生存を改善するために、ESSENTIAL8培地+RhoK阻害剤の入ったMATRIGELマトリクスでコーティングされた皿にhiPSCを播種した(図1、0~1日目)。以下の分化工程は、hiPSCに3D構造を形成させ、胸腺上皮細胞への分化を継続させるために、解離せずに、3日目に再プレーティング工程を加えたこと以外は、Sun et al.に記載の通りである。
誘導前に、リン酸緩衝生理食塩水(PBS)で細胞を軽く洗浄した。100ng/mL ACTIVIN Aタンパク質(PeproTech,Rocky Hill,NJ)を補給した既知組成の無血清X-VIVO10培地(Lonza,Basel,Switzerland)でhiPSCを3日間培養した。次いで、0.25%トリプシンで細胞を解離させ、5000~10,000細胞/cm2の密度でMATRIGELコーティングされた皿に再プレーティングした。更に2日間、細胞を同じ分化培地で培養した(図1、1~6日目)。分化した細胞を1μM 全trans型RA(Sigma,St.Louis,MO)及び25μM IWR1(Tocris,Bristol,UK)で4日間処理した(図1、6~10日目)。次いで、10ng/mL BMP4及び50ng/mL WNT3a(R&D Systems,Minneapolis,MN)をTEPCの誘導のために使用した(図1、10~15日目)。X-VIVO10培地を基本培地として使用した。全ての培地及び添加剤は、特に断りのない限り、Invitrogen(Waltham,MA)から購入した。
位相差顕微鏡下で顕微鏡下手術用ハサミを使用して、15日間インビトロで分化させた後の3D胸腺構造を機械的にピッキングした。2D培養物を3mm×3mmの正方形に切り出し、37℃で超低接着V字底96ウェルプレートにおけるTEC増幅培地(MEBM(Lonza,Basel,Switzerland)+10% B27(Gibco,Waltham,MA)+GLUTAMAX(X1)補給剤(Thermo Fisher Scientific,Waltham,MA)+20ng/mL hEGF+0.1pM コレラ毒素B+0.4ng/mL ヒドロコルチゾン+2.5μg/mL インスリン)中で一晩懸濁培養した。オルガノイドを形成するために、15日目に多層の分化したhiPSCからハサミを使用して3D構造をピッキングし、TEC増幅+100ng/mL Wnt3a+100ng/mL FGF7+50ng/mL BMP4中で培養した。間葉因子を同定するために、以下の試薬を前述の培地に添加した:100mg/mL FGF8、100ng/mL FGF10、100ng/mL IGF-1、KAAD-シクロパミン0.5μM、及びTGFb RIキナーゼ阻害剤5μM。MSCが再集合した場合、3回継代したヒト間葉系幹細胞を20,000細胞/オルガノイドで超低接着V字底96ウェルプレートに播種した。
一次抗体、二次抗体、及びIgGアイソタイプは、Abcam(Cambridge,UK)から入手した。60℃で1時間加熱し、続いて、10分間キシレンで洗浄し、次いで、漸減エタノール系列に再水和することによって、ホルマリン固定パラフィン包埋組織切片を脱脂した。脱脂後、マイクロ波を使用して、1×Antigen Retrieval CITRA PLUSバッファ(カタログ番号HK086,BioGeneX,Fremont,CA)中で15分間スライドを煮沸した。脱イオン水で激しく洗浄した後、該スライドを1×PBSに浸漬した。染色前に、細胞及び組織切片の両方をブロッキングし、PBS+1% FBS+0.1% TRITON X-100界面活性剤(T-FBS)によって4℃で2時間透過処理した。T-FBSバッファで1:100希釈した一次抗体を4℃で一晩インキュベートした。T-FBSで3回洗浄した後、T-FBSバッファで1:200希釈したALEXA FLUORコンジュゲート二次抗体と共にサンプルを4℃で一晩インキュベートし、続いて、T-FBSで激しく洗浄した。据え付ける前に、DAPI(Vectorshield,Burlingame,CA)で核を対比染色した。オルガノイド全体を免疫蛍光染色するために、オルガノイド全体を一晩固定し、ブロッキングし、PBS+1% FBS+0.1% TritonX-100(T-FBS)によって4℃で一晩透過処理した。T-FBSバッファで1:1000希釈した一次抗体を4℃で一晩インキュベートした。T-FBSで3回洗浄した後、T-FBSバッファで1:1000希釈したAlexa Fluorコンジュゲート二次抗体と共にサンプルを4℃で一晩インキュベートし、続いて、T-FBSで激しく洗浄した。据え付ける前に、DAPI(Vectorshield,Burlingame,CA)で核を対比染色した。20×Plan-アポクロマート(開口数0.8)対物レンズを備えるZEISS LSM880レーザー走査顕微鏡(Carl Zeiss,Inc.,Thornwood,NY)で蛍光画像を収集した。
この実施例は、ゼノフリー培養でヒトiPSCから初期胸腺上皮前駆様細胞(TEPLC)が生成されることを立証する。
この実施例は、FOXN1発現がTEPLCの拡大培養によって誘導され得ることを立証する。
この実施例は、TEPLCから3Dスフェロイドが発生することを立証する。
この実施例は、3Dスフェロイドの胸腺オルガノイドへの分化、及びhiPS由来のオルガノイドが42日間でケラチン5及びケラチン8を生成する三次元網目構造を形成したことを立証する。
この実施例は、特定の培地を添加することによって、iPS由来の胸腺オルガノイドのエクスビボ成長の継続が可能になったことを立証する。
この実施例は、あまり分化していない胸腺上皮前駆体に取り囲まれているスフェロイドが、該スフェロイドのより長い成長期間にわたる成長を可能にすることを立証する。実施例5に記載の通り、スフェロイドを成長させた。1週間超にわたって成長させたスフェロイドの3D培養によって、図6に示す通り、崩壊するオルガノイドが生成されることが見出された。球形構造を形成する細胞(「初期TEPC」)は、より低いレベルの細胞(TEPLC)よりも分化しており、該初期TEPCは、連続増幅によって疲弊していると仮定した。更に、下層の細胞はあまり分化していないので、この層は、後期のオルガノイド成長に寄与し得ると仮定した。これら仮説を検証するために、図6に示す通り、多層構造の14日目の胸腺上皮前駆様細胞を手術用ハサミで正方形に切り出し、TEC培地+BMP4、Wnt3a、及びFGF7中で42日間3D培養した。該正方形は、図6のより分化した細胞(A)及びあまり分化していない細胞(B)を含んでいた。42日目に、切片を切り出し、DAPIで染色し、免疫組織化学的検査に供した。得られたオルガノイドの染色から、胸腺オルガノイドが3D構造のケラチン5+/ケラチン8+細胞を生成することが明らかになった。また、切り出し領域の一部がK5又はK8のシングルポジティグ細胞になり始めることも明らかになった。特定の理論又は仮説に縛られるものではないが、TEPCは成長し、胸腺に主に機能を与える細胞である髄質及び皮質のTECに分化すると仮定される。皮質(シングルポジティブK8)及び髄質(シングルポジティブK5)は、通常、発生の後期に胸腺組織へと発生する。
この実施例は、胸腺オルガノイドが、ヒトTEC前駆体領域に類似しているK5+K8+集団を生成することを立証する。
この実施例は、間葉系幹細胞(MSC)因子の添加によって、β5t発現細胞の領域を有する胸腺オルガノイドが生成できることを立証する。
この実施例は、MSC因子の添加がオルガノイド形成の再現性を改善することを立証する。
この実施例は、hiPSC由来のオルガノイドがFOXN1を発現することを立証する。
この実施例は、hiTO細胞がケラチン5、ケラチン8、及び胸腺プロテオソームβ5tを発現することを立証する。
この実施例は、hiTO細胞がMHCクラスII細胞表面受容体HLA-DRを発現することを立証する。
この実施例は、hiTO細胞がDLL4及びIL-7を発現することを立証する。
この比較例は、失敗した胸腺オルガノイドを生成する試みを示すものである。
この比較例は、失敗した胸腺オルガノイドを生成する試みを示すものである。
Claims (19)
- インビトロで胸腺オルガノイドを調製する方法であって、
(i)インビトロで多能性幹細胞を内胚葉細胞に分化させることと;
(ii)インビトロで前記内胚葉細胞を第3咽頭嚢内胚葉(PPE)細胞に分化させることと;
(iii)インビトロで前記第3PPE細胞を胸腺上皮前駆様細胞(TEPLC)に分化させることと;
(iv)インビトロ三次元培養で前記TEPLCを胸腺上皮前駆細胞(TEPC)に分化させることと;
(v)骨形成タンパク質4(BMP4)の存在下においてインビトロ三次元培養で前記TEPCを胸腺上皮細胞(TEC)に分化させることと;
(vi)インビトロ三次元培養で前記TECから胸腺オルガノイドを形成させることとを含み、
前記胸腺オルガノイドが、β5t、DLL4、及びインターロイキン7のうちのいずれか1つ以上を発現し、
前記方法が、前記細胞を間葉又は間質細胞と共培養することを含まない方法。 - (v)が、Wnt3a及び線維芽細胞成長因子7(FGF7)の一方又は両方の存在下においてインビトロ三次元培養で前記TEPCをTECに分化させることを含む、請求項1に記載の方法。
- (i)の前に少なくとも1日間、哺乳類細胞基底マトリクスにおいて前記多能性幹細胞を培養することを含む、請求項1又は2に記載の方法。
- 前記TEPLCが、ケラチン5+/ケラチン8+/FOXN1-である、請求項1~3のいずれか一項に記載の方法。
- 前記細胞を継代することを含まない、請求項1~4のいずれか一項に記載の方法。
- (iii)が、前記細胞を解離させることなく前記第3PPE細胞をTEPLCに分化させることを含む、請求項1~5のいずれか一項に記載の方法。
- 前記胸腺オルガノイドが、ケラチン5+/ケラチン8+/FOXN1+細胞を含む、請求項1~6のいずれか一項に記載の方法。
- 前記胸腺オルガノイドが、ケラチン5+/ケラチン8+/胸腺プロテオソームβ5t+細胞を含む、請求項1~7のいずれか一項に記載の方法。
- 前記胸腺オルガノイドが、ケラチン5高/ケラチン8低細胞を含む、請求項1~6のいずれか一項に記載の方法。
- 前記胸腺オルガノイドが、ケラチン5低/ケラチン8高細胞を含む、請求項1~6のいずれか一項に記載の方法。
- (i)~(vi)のうちのいずれか1つ以上がゼノフリー培地で実施される、請求項1~10のいずれか一項に記載の方法。
- 前記胸腺オルガノイドを培養して、T細胞の分化を促進する1つ以上の自己タンパク質を過剰発現させることを更に含む、請求項1~11のいずれか一項に記載の方法。
- T細胞の分化を促進する1つ以上の前記自己タンパク質が、DLL4及びIL-7のうちの1つ以上を含む、請求項12に記載の方法。
- (iv)が、1つ以上の間葉系幹細胞(MSC)因子の存在下で前記TEPLCをTEPCに分化させることを含む、請求項1~13のいずれか一項に記載の方法。
- 前記1つ以上のMSC因子が、FGF7、BMP4、Wnt3a、線維芽細胞成長因子10(FGF10)、インスリン様成長因子-1(IGF-1)、線維芽細胞成長因子8(FGF8)、トランスフォーミング成長因子β阻害剤(TGFβinh)、及びシクロパミンのうちの1つ以上を含む、請求項14に記載の方法。
- 前記MSC因子のうちの1つ以上が、FGF10、IGF-1、FGF8、TGFβinh、及びシクロパミンを含む、請求項15に記載の方法。
- インビトロで胸腺移出T細胞を調製する方法であって:
胸腺オルガノイドを請求項1~16のいずれか一項に記載の方法によりインビトロで調製することと;
前記細胞を前記胸腺オルガノイドから放出させることであって、前記胸腺オルガノイドから放出される前記細胞が、胸腺移出T細胞であることと;
前記胸腺オルガノイドから前記胸腺移出T細胞を単離することとを含む方法。 - 哺乳類における病態の治療又は予防のための剤を製造する方法であって:
請求項1~16のいずれか一項に記載の方法により胸腺オルガノイドを調製することと;
前駆細胞を前記胸腺オルガノイドに遊走させることと;
前記胸腺オルガノイドに遊走した細胞を前記胸腺オルガノイドから放出させることであって、前記胸腺オルガノイドから放出される細胞が、胸腺移出T細胞であることと;
前記胸腺オルガノイドから前記胸腺移出T細胞を単離することとを含み、
前記胸腺移出T細胞が前記剤に製剤化される、方法。 - 前記病態が、がん、免疫不全、自己免疫病態、感染症、又は血液病態である、請求項18に記載の方法。
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