JP7420860B2 - 前駆細胞を指向性分化によって胃組織に変換するための方法及びシステム - Google Patents
前駆細胞を指向性分化によって胃組織に変換するための方法及びシステム Download PDFInfo
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Description
本発明は、国立衛生研究所(National Institutes of Health)の助成によるDK080823、DK092456、及びGM063483に基づく連邦政府の支援を受けて行われた。政府は本発明に一定の権利を有する。
本願は、あらゆる目的から、2014年5月28日に出願された“Methods and Systems for Converting Precursor Cells into Gastric Tissues through Directed Differentiation”と題されるWells et alに対する米国仮特許出願第62/003,719号明細書に対する優先権及びその利益を主張する。
一態様において、本方法は、多能性であるか、又は多能性になるよう誘導することのできる幹細胞を入手するステップを含み得る。一部の実施形態において、多能性幹細胞は胚性幹細胞に由来し、一方で胚性幹細胞は初期哺乳類胚の全能性細胞に由来するもので、インビトロで無制限の未分化増殖が可能である。胚性幹細胞は、初期胚である胚盤胞の内部細胞塊に由来する多能性幹細胞である。未分化胚芽細胞から胚性幹細胞を得る方法は、当該技術分野において周知である。例えば、本明細書にある種の細胞型が例示されるが、当業者であれば、本明細書に記載される方法及びシステムを任意の幹細胞に適用可能であることを理解するであろう。
一部の実施形態において、iPSCは、ある種の幹細胞関連遺伝子を非多能性細胞、例えば成体線維芽細胞にトランスフェクトすることによって得られる。トランスフェクションは、典型的にはレトロウイルスなどのウイルスベクターを用いて達成される。トランスフェクトされる遺伝子としては、マスター転写調節因子Oct-3/4(Pouf51)及びSox2が挙げられるが、他の遺伝子が誘導効率を増進させることも考えられる。3~4週間後、少数のトランスフェクト細胞が形態学的及び生化学的に多能性幹細胞と類似したものになり始め、典型的には、形態学的選択、倍加時間によるか、又はレポーター遺伝子及び抗生物質選択によって単離される。本明細書で使用されるとき、iPSCとしては、限定はされないが、マウスにおける第1代iPSC、第2代iPSC、及びヒト人工多能性幹細胞を挙げることができる。一部の実施形態では、レトロウイルス系を使用して、4つの中心的遺伝子:Oct3/4、Sox2、Klf4、及びc-Mycを使用してヒト線維芽細胞を多能性幹細胞に形質転換し得る。代替的実施形態では、レンチウイルス系を使用して、OCT4、SOX2、NANOG、及びLIN28で体細胞を形質転換する。iPSCにおいてその発現を誘導し得る遺伝子としては、限定はされないが、Oct-3/4(例えば、Pou5fl);Sox遺伝子ファミリーの特定のメンバー(例えば、Sox1、Sox2、Sox3、及びSox15);Klfファミリーの特定のメンバー(例えば、Klf1、Klf2、Klf4、及びKlf5)、Mycファミリーの特定のメンバー(例えば、C-myc、L-myc、及びN-myc)、Nanog、及びLIN28が挙げられる。
本出願人の発明以前には、胚性幹細胞及び/又はiPSCなどの前駆細胞を胃組織に変換するために利用可能なシステムはなかった。
胃の上皮は、胚体内胚葉(DE)と呼ばれる単層の細胞に由来する。前方DEは前腸並びに肺、食道、胃、肝臓及び膵臓を含めたその関連器官を形成し、後方DEは中腸及び後腸を形成して、これは小腸及び大腸並びに泌尿生殖器系の部位を形成する。DEはインビボで消化管及び気道の上皮を生じる。マウス、ヒヨコ及びカエルの胚を使用した研究からは、原腸胚期におけるDEの前後パターンの確立が、続く前腸及び後腸発生に必須であることが示唆される。一部の実施形態において、ESC及びiPSCなどのPSCは、初めに胚体内胚葉(DE)、次に前方/前腸上皮(例えば、前腸スフェロイド)、その次に胃組織へと、段階的な形で指向性分化を経る。この過程には、BMP、Wnt及びFGFシグナル伝達経路が決定的に重要であると考えられている。WNT及びFGFの活性化は腸管形態形成を促進する働きをし、及びBMPシグナル伝達の阻害は前腸運命を促進する。前腸の単層立方上皮は初めに多列円柱上皮、次に胃上皮を含む腺及び小窩並びに絨毛の基部にある増殖帯(これは予定プロジェニタードメイン(presumptive progenitor domain)に対応する)へと発生する。
一部の実施形態では、アクチビン誘導性胚体内胚葉(DE)がFGF/Wnt/ノギン誘導性前方内胚葉パターン形成、前腸特異化及び形態形成、並びに最後にプロガストリック培養系をさらに経ることにより、表層粘液細胞、粘液腺細胞、内分泌、及びプロジェニター細胞を含めた機能性の胃細胞型への胃組織成長、形態形成及び細胞分化が促進され得る。一部の実施形態では、ヒトPSCを、粘液、内分泌、及びプロジェニター細胞型を含む胃上皮にインビトロで分化するように効率的に指向させる。特定のタイプの胃組織形成を促進するため、任意の発生段階で成長因子などの分子を加え得ることは理解されるであろう。
一部の実施形態では、多能性幹細胞は「ワンステップ」プロセスによって胃細胞型に変換される。例えば、多能性幹細胞をDE培養物に分化させることのできる1つ以上の分子(例えばアクチビンA)が、DE培養物の指向性分化を促進することのできる追加的な分子(例えば、Wnt3a/FGF4アクチベーター及びBMP阻害薬)と組み合わされることにより、多能性幹細胞が直接処理される。
一部の実施形態では、本明細書に記載される胃組織又は関連細胞型を使用して、ピロリ菌(H.Pylori)の胃取り込み及び/又は輸送及び/又は処理機構に関して薬物をスクリーニングすることができる。例えば、これは、最も容易に吸収される又は有効な薬物をスクリーニングするためハイスループット方式で行うことができ、薬物の胃取り込み及び胃毒性を試験するために行われる第1相臨床試験を増強することができる。これには、小分子、ペプチド、代謝産物、塩の細胞周囲及び細胞内輸送機構が含まれ得る。本明細書に開示される胃組織はさらに、生体適合性を評価するための、胃組織との接触が意図される任意の薬剤及び/又は装置との適合性の評価に使用され得る。
ヒト胚性幹細胞株WA01(H1)及びWA09(H9)をWiCellから入手した。ESC株及びiPSC株は、mTesR1培地(Stem Cell Technologies)においてHESC適格Matrigel(BD Biosciences)上でフィーダーフリー条件でコロニーとして維持した。細胞は4日毎にdispase(Invitrogen)を用いて常法で継代した。
(図14に要約する)Matrigel(BD Biosciences)で被覆した24ウェルプレートのmTesR1培地+ROCK阻害薬Y27632(10μM;Stemgent)においてヒトES及びiPS細胞を単一細胞としてウェル当たり150,000細胞でプレーティングした。ROCK阻害薬は、分化のためのプレーティング後の幹細胞の生存を増強する。翌日から開始して、漸増濃度の0%、0.2%、及び2.0%既知組成ウシ胎仔血清(dFBS;Invitrogen)を含有するRPMI 1640(Invitrogen)において細胞をアクチビンA(100ng ml-1;Cell Guidance Systems)で3日間処理した。
PSCを分化させるため、Matrigel(マトリゲル)で被覆した24ウェルディッシュにおいて、ROCK阻害薬Y-27632(10μM;Stemgent)を含むmTesR1にウェル当たり150,000細胞の密度でaccutase(Stem Cell Technologies)を使用して単一細胞としてプレーティングした。翌日、以前記載されているとおりPSCはDEに分化した11、35。漸増濃度の0%、0.2%、及び2.0%既知組成ウシ胎仔血清(dFBS;Invitrogen)を含有するRPMI 1640培地(Invitrogen)において細胞をアクチビンA(100ng ml-1;Cell Guidance Systems)に3日間曝露した。加えて、DE誘導の初日にBMP4(50ng ml-1;R&D Systems)を添加した。
DE誘導に続き、2.0%dFBSを含むRPMI 1640において細胞を成長因子/拮抗薬で3日間処理した。後方前腸スフェロイドを作成するため、ノギン(200ng ml-1;R&D Systems)と、FGF4(500ng ml-1;R&D Systems)と、WNT3A(500ng ml-1;R&D Systems)又はCHIR99021(2μM;Stemgent)のいずれかとでDEを3日間処理した。CHIR99021は、Wntシグナル伝達経路を刺激する小分子である。最終日にRA(2μM;Sigma Aldrich)を添加する。三次元成長及び前庭部の特異化。後方前腸スフェロイドを以前記載されているとおりMatrigel(BD Biosciences)に包埋し10、12、続いて、N2(Invitrogen)、B27(Invitrogen)、L-グルタミン、10μM HEPES、ペニシリン/ストレプトマイシン、及びEGF(100ng ml-1;R&D Systems)を補足したアドバンストDMEM/F12(Invitrogen)において成長させた。前庭部の特異化のため、三次元成長の最初の3日間にRA及びノギンを添加した。内分泌細胞の特異化のため、30日目にEGF濃度を10ng ml-1に下げる。
DE誘導に続き、2.0%dFBS及び成長因子:WNT3A(500ng ml-1;R&D Systems)、CHIR99021(2μM;Stemgent);FGF4(500ng ml-1;R&D Systems)、及びノギン(200ng ml-1;R&D Systems)を含むRPMI 1640培地において細胞を培養した。培地は毎日交換した。3日後、WNT3A(又はCHIR99021)、FGF4、及びノギンの組み合わせにより、培養ウェルに浮遊前腸スフェロイドがもたらされた。前腸内胚葉の後方化のため、WNT/FGF/ノギン処理の3日目にRA(2μM;Sigma Aldrich)を添加した。
スフェロイドを以前記載されているとおりの三次元インビトロ培養系に移した5、10、12。簡潔に言えば、スフェロイドを回収し、50μl Matrigel(BD Biosciences)に再懸濁し、及び三次元ドロップレットでプレーティングした。組織培養インキュベーターにおいてMatrigelを10~15分間固化させた後、腸培地:N2(Invitrogen)、B27(Invitrogen)、L-グルタミン、10μM HEPES、ペニシリン/ストレプトマイシン、及びEGF(100ng ml-1;R&D Systems)を含むアドバンストDMEM/F12でスフェロイドをオーバーレイした。最初の3日間、この腸培地にRA及びノギンを添加した。培地は必要に応じて3~4日毎に取り替えた。20日目、オルガノイドを回収し、約1:12希釈で新鮮なMatrigelにリプレーティングした。
過剰発現コンストラクトを作成するため、Gateway Cloning(Invitrogen)法を用いてhNEUROG3 cDNA(ダナ・ファーバー/ハーバード癌センターDNAリソースコア(Dana-Farber/Harvard Cancer Center DNA Resource Core;クローンHsCD00345898)をpInducer20レンチウイルスベクター(T.Westbrookから供与された36)にクローニングした。高力価レンチウイルス粒子はCCHMCウイルスベクターコアによって作製された。AccutaseでH1 hESCを分離し、10μM Y-27632を含むmTesR1に単一細胞懸濁液としてプレーティングし、レンチウイルスに4時間曝露した。mTesR1は毎日取り替え、2日後、培地にG418(200μg ml-1)を添加して組み込みクローンを選択した。G418耐性細胞は抗生物質において無限に維持したが、他の場合には通常どおり培養して継代した。
初代ヒト包皮線維芽細胞(HFF)は新生児ヒト包皮組織から培養し、シンシナティ大学皮膚科学科(Department of Dermatology,University of Cincinnati)を通じて2人のドナーから入手し、及びSusanne Wells PhDから供与いただいた。10%FCS(Hyclone)を補足したDMEM(Invitrogen)からなる線維芽細胞培地においてHFFを培養し、継代第5代と第8代との間の再プログラム化に使用した。本研究に使用したEBNA1/OriPベースのエピソームプラスミドpCLXE-hOct3/4-shp53、pCLXE-hSox2-Klf4、pCLXE-hLmyc-Lin28、及びpCLXE-GFPは以前記載されており37、Addgeneから入手した(ID番号:それぞれ27077、27078、27080、及び27082)。最適化されたヒト皮膚線維芽細胞Nucleofectorキット(VPD-1001;Lonza)をエピソームプラスミドによるHFFのトランスフェクションに使用した。簡潔に言えば、各トランスフェクションについて、室温において200×gで10分間遠心して1×106個のHFFをペレット化し、100μlの室温Nucleofector溶液に再懸濁し、1.25μgの各エピソームプラスミドをヌクレオフェクトした(プログラムU20)。2回のトランスフェクションからの細胞(合計2×106細胞)を、10cm組織培養プレートの線維芽細胞培地にリプレーティングし、37℃/5%CO2で培養した。トランスフェクションの6日後、1.07×106個の照射マウス胚線維芽細胞(MEF)が入ったゼラチン被覆10cmディッシュの線維芽細胞培地に4.5×105個のHFFをリプレーティングした。トランスフェクション後7日目に開始して、細胞に毎日、20%ノックアウト血清代替物、1mM L-グルタミン、0.1mM β-メルカプトエタノール、0.1mM 非必須アミノ酸、及び4ng ml-1塩基性FGF(全てInvitrogenから)を補足したDMEM/F12培地を供給した。約2週間後、hESC様の形態を有する孤立したコロニーを手動で切り出し、hESC適格matrigel(Becton Dickinson)で被覆された組織培養ディッシュのmTesR1培地(Stem Cell Technologies)にリプレーティングした。mTeSR1/matrigel培養に適応させた後、自発的分化が最小限の、ロバストな増殖及びhESC様の形態を維持したiPSCを、凍結保存及び特徴付けのため拡大した。
以下の表は、前駆細胞から胃オルガノイドを発生させるための例示的処理プロトコルを示す。
本出願人は、初めに、胎生期において胃底部で特異的に発現するが前庭部では発現しない遺伝子を同定しようとした。E14.5マウス胚の消化管を顕微解剖し、4つの領域に分けた:前胃(食道を含む)、胃底部、前庭部、及び十二指腸。図15を参照のこと。次にこれらの領域の領域形成マーカーをqPCRによって分析した。図15は、種々の領域で発現することが知られる対照遺伝子の発現を示す。胃底部及び前庭部は、そのSox2及びGata4の高発現、並びにP63及びCdx2の欠如によって前胃及び十二指腸と区別することができる。重要なことに、Pdx1(前庭部のマーカー)は胃底部と比べて前庭部組織においてはるかに高いレベルで発現し、正確な解剖を指示するものである。
ピロリ菌(H.pylori)株G2738及びCagAが欠損している突然変異体G27株(ΔCagA)39を、以前記載されているとおり40、コロンビア寒天基礎培地(Fisher Scientific)、5%ウマ血液(Colorado Serum Company)、5μg ml-1、バンコマイシン及び10μg ml-1トリメトプリムからなる血液寒天プレートで成長させた。オルガノイド注入のため、ピロリ菌(H.pylori)をブルセラブロスに1×109細菌ml-1の濃度で再懸濁し、Nanoject II(Drummond)微量注入器装置にロードした。約200nl(2×105細菌を含有する)を各オルガノイドの管腔に直接注入し、注射を受けたオルガノイドを24時間培養した。陰性対照としてはブルセラブロスを注入した。
免疫蛍光染色
全ての組織を4%パラホルムアルデヒドに、凍結処理用には室温で1時間又はパラフィン処理用には4℃で一晩のいずれかで固定した。凍結切片については、組織を30%スクロース中に4℃で一晩保護し、次OCT(Tissue-Tek)に包埋し、10μmに切り出した。パラフィン切片については、組織を段階的エタノール系列、続いてキシレンで処理し、次にパラフィン包埋し、7μmに切り出した。組織培養細胞は室温で15分間固定し、直接染色した。染色については、凍結スライドを室温に解凍し、PBS中に再水和させる一方で、パラフィンスライドを脱パラフィン化して抗原回復に供した。スライドをPBS+0.5%Triton-X中の5%正常ロバ血清(Jackson Immuno Research)において室温で30分間ブロックした。一次抗体(「方法」の表1に掲載)をブロッキング緩衝液中に希釈し、4℃で一晩インキュベートした。スライドをPBSで洗浄し、二次抗体と共に室温で1時間インキュベートし、Fluoromount-G(Southern Biotech)を使用してカバースリップをマウントした。Nikon A1Rsi倒立共焦点顕微鏡で共焦点像を取得した。
Nucleospin RNA IIキット(Machery-Nagel)を使用して組織から全RNAを単離した。Superscript VILO cDNA合成キット(Invitrogen)を製造者のプロトコルに従い使用して、100ng RNAから逆転写を実施した。CFX-96リアルタイムPCR検出システム(BioRad)でQuantitect SybrGreen Master Mix(Qiagen)を使用してqPCRを行った。ΔΔCT法を用いて分析を実施した。PCRプライマーはqPrimerDepot(http://primerdepot.nci.nih.gov)の配列を使用して設計しており、表2に掲載する。
ピロリ菌(H.pylori)に感染させたオルガノイドを氷冷PBS中においてMatrigelから回収し、150gで5分間遠心した。プロテアーゼ阻害薬(Roche)を補足したM-PER哺乳類タンパク質抽出試薬(Thermo Scientific)中に組織を溶解させた。細胞溶解物からの10μg全タンパク質を抗c-Met抗体(2μg;Cell Signaling 4560)によって4℃で16時間免疫沈降させた。次にプロテインA/Gアガロースビーズ(20μl;Santa Cruz Biotechnology)を添加し、試料を4℃で16時間インキュベートした。免疫沈降物をPBSで3回洗浄し、次に、β-メルカプトエタノール(40μl;BioRad)を含有するLaemmliローディング緩衝液に再懸濁した。試料を4~20%トリス-グリシン勾配ゲル(Invitrogen)上で泳動させ、80Vで3.5時間泳動させた。ゲルをニトロセルロース膜(Whatman Protran、0.45μm)に105Vで1.5時間転写した。膜をKPL Detectorブロック溶液(Kirkeaard&Perry Laboratories)において室温で1時間ブロックし、次に一次抗体と共に4℃で一晩インキュベートした。使用した一次抗体:抗ホスホチロシン(Santa Cruz、sc-7020;1:100)、抗c-Met(Abcam、ab59884;1:100)、及び抗ピロリ菌(H.pylori)CagA(Abcam、ab90490;1:100)。膜を洗浄し、Alexa Fluor抗マウス680(Invitrogen;1:1000)二次抗体においてインキュベートした。Odyssey赤外線イメージングソフトウェアシステム(Licor)を使用してブロットを画像化した。
hPSCは胚体内胚葉(DE)に分化した11。DEはインビボで胃腸管及び気道の上皮を生じる。全ての内胚葉器官の発生における次の2つの重要なイベントは、前後(A-P)軸に沿ったDEのパターン形成及び腸管形態形成であり、前方におけるSox2+前腸及び後方におけるCdx2+中・後腸の形成がもたらされる(E8.5、14体節期マウス胚、図1Aにおいて強調表示されるとおり)。この形態形成及び内胚葉と中胚葉との間の組織相互作用は、インビボ及びインビトロの両方で適切な器官形成にとって決定的に重要であるものと思われる。WNT3AとFGF4とは、以下の3つのことを行うため相乗作用することが以前実証されている:hPSC由来のDEを後方化し、間葉の拡大を促進し、及び中・後腸マーカーCDX2を発現する腸管様構造の構築を誘導する10、12。図1Aは、e8.5(14体節期)マウス胚においてSox2タンパク質が前腸内胚葉を特徴付け、及びCdx2タンパク質が中/後腸内胚葉を特徴付けることを示す。図1Bは、BMPを阻害すると中/後腸運命が抑制され、前腸マーカーSOX2の発現が促進されたことを示す。培地単独(対照)又は指示される成長因子/拮抗薬を含む培地において3日間曝露したhPSC-DE培養物におけるパターン形成マーカーのPCR解析。WNTとFGFとを合わせた活性は、既報告のとおりCdx2発現を誘導し10、一方、BMP拮抗薬ノギンはCdx2発現を抑制し、高レベルの前腸マーカーSOX2を誘導するのに十分であった。*、対照と比較してp<0.05。**、WNT/FGFと比較してp<0.005。図1Cは、Wnt/FGF/ノギンを用いて作成された前腸スフェロイドが、高レベルのCDX2を有するWnt及びFGF単独で作成したスフェロイドと比較したとき、ホールマウント免疫蛍光染色及びmRNAによって高レベルのSOX2タンパク質を有することを示す。*、p<1.0×10-6。図1Dは、e8.5、14体節期マウス胚における後方前腸が胃及び膵臓を生じ、高レベルのHnf1βタンパク質を有することを示す。図1Eは、スフェロイド作成ステップの最終日に培養物をRAに曝露すると、SOX2発現上皮においてHNF1βの発現が誘導され、後方前腸スフェロイドの形成がもたらされることを示す。*、p<0.005。図1Fは、前方及び後方前腸内胚葉の両方の形成におけるノギン及びRAのパターン形成効果を要約する系統図を示す。スケールバー、100μm。エラーバーは標準偏差を表す。
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Claims (21)
- a)FGF4と、WNTシグナル伝達経路の活性剤と、ドルソモルフィン、LDN189、DMH-1、及びノギンからなる群から選択されるBMPシグナル伝達経路の阻害剤を、胚体内胚葉細胞に接触させることにより、前記胚体内胚葉細胞を前腸スフェロイドに分化させるステップと、
b)ステップa)の前腸スフェロイドにレチノイン酸を接触させて、後方前腸スフェロイドを形成するステップと、
c1)ステップb)の後方前腸スフェロイドにEGF、レチノイン酸、及びドルソモルフィン、LDN189、DMH-1、及びノギンからなる群から選択されるBMPシグナル伝達経路の阻害剤を接触させて前庭部組織を含む胃オルガノイドを形成するステップ、又は、
c2)ステップb)の後方前腸スフェロイドにEGF、レチノイン酸、ドルソモルフィン、LDN189、DMH-1、及びノギンからなる群から選択されるBMPシグナル伝達経路の阻害剤、及びWNTシグナル伝達経路の活性剤を接触させて胃底部組織を含む胃オルガノイドを形成するステップのいずれか一方と、を含む、
インビトロで、胃オルガノイドを形成する方法。 - 前記胚体内胚葉細胞が、多能性幹細胞に由来する、請求項1に記載の方法。
- 前記多能性幹細胞が、胚性幹細胞又は人工多能性幹細胞である、請求項2に記載の方法。
- ステップa)の前記胚体内胚葉細胞を、24~120時間接触させる、請求項1~3のいずれか一項に記載の方法。
- ステップa)の前記胚体内胚葉細胞を、2日間接触させる、請求項1~4のいずれか一項に記載の方法。
- ステップb)の前記前腸スフェロイドを、1日間接触させる、請求項1~5のいずれか一項に記載の方法。
- ステップc1)又はステップc2)の前記後方前腸スフェロイドを、3日間接触させる、請求項1~6のいずれか一項に記載の方法。
- 前記FGF4が50ng/ml~1500ng/mlの濃度で提供される、請求項1~7のいずれか一項に記載の方法。
- 前記FGF4が500ng/mlの濃度で提供される、請求項8に記載の方法。
- 前記WNTシグナル伝達経路の活性剤がWnt3a又はCHIR99021である、請求項1~9のいずれか一項に記載の方法。
- 前記WNTシグナル伝達経路の活性剤がWnt3aであり、Wnt3aが50ng/ml~1500ng/mlの濃度で提供される、請求項10に記載の方法。
- 前記Wnt3aが500ng/mlの濃度で提供される、請求項11に記載の方法。
- 前記WNTシグナル伝達経路の活性剤がCHIR99021である、請求項12に記載の方法。
- 前記CHIR99021が2μMの濃度で提供される、請求項13に記載の方法。
- ステップa)、ステップc1)、ステップc2)又はこれらの任意の組み合わせのBMPシグナル伝達経路の阻害剤がノギンである、請求項1~14のいずれか一項に記載の方法。
- 前記ノギンが、50ng/ml~1500ng/mlの濃度で提供される、請求項15に記載の方法。
- 前記ノギンが、200ng/mlの濃度で提供される、請求項16に記載の方法。
- a)請求項1~17のいずれか一項に記載の方法により、インビトロで形成される胃オルガノイドを、化合物と接触させるステップ;及び
b)胃オルガノイドによる化合物の吸収レベルを検出するステップと、を含む、
インビトロで、胃オルガノイドの吸収効果を同定する方法。 - a)請求項1~17のいずれか一項に記載の方法により、インビトロで形成される胃オルガノイドを、化合物と接触させるステップ;及び
b)胃オルガノイドによる化合物の吸収レベルを検出するステップと、を含む、
インビトロで、胃オルガノイドに対する化合物の毒性を同定する方法。 - 請求項1~17のいずれか一項に記載の方法により胃オルガノイドを形成することを含む、インビトロで、胃疾患の治療に用いるための代替胃組織を作成する方法。
- 前記胃疾患が、胃遺伝性疾患、消化性潰瘍疾患、メネトリエ病及び胃癌からなる群から選択される、請求項20に記載の方法。
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