JP2022115925A - 結腸オルガノイドならびにその作製方法および使用方法 - Google Patents
結腸オルガノイドならびにその作製方法および使用方法 Download PDFInfo
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Abstract
Description
本出願は、その全体がすべての目的のために参照により本明細書に組み込まれる2016年12月5日に出願された米国仮特許出願番号第62/429,948号の利益を主張する。
特に明記しない限り、用語は当業者による従来の使用法に従って理解されるべきである。
いくつかの態様において、iPSCは、成体線維芽細胞のような非多能性細胞へのある特定の幹細胞関連遺伝子のトランスフェクションによって誘導される。トランスフェクションは、レトロウイルスのようなウイルスベクターを介して達成され得る。トランスフェクトされた遺伝子はマスター転写調節因子Oct-3/4(Pouf51)およびSox2を含むが、他の遺伝子が誘導の効率を高めることが示唆されている。3~4週間後、少数のトランスフェクトされた細胞が多能性幹細胞と形態学的および生化学的に類似するようになり、通常は形態学的選択、倍加時間、またはレポーター遺伝子および抗生物質選択を通じて単離される。本明細書中で使用されるとき、iPSCには、第一世代iPSC、マウスにおける第二世代iPSC、およびヒト人工多能性幹細胞が含まれるが、これらに限定されない。
本開示のHCOは、胚体内胚葉(DE)と呼ばれる単純な細胞シートに由来し得る。前駆細胞から胚体内胚葉を誘導する方法は、D’Armour etら2005およびSpenceらによって教示されているように、当該技術分野において周知である。前側DEは前腸ならびに肝臓および膵臓を含むその関連器官を形成し、後側DEは、小腸および大腸、ならびに腎尿路生殖器系の一部を形成する中腸ならびに後腸を形成する。マウス、ニワトリおよびカエルの胚を用いた研究は、原腸胚期のDEにおいて前後パターンを確立することがその後の前腸および後腸の発達の前提条件であることを示唆している。Wntシグナル伝達経路およびFGFシグナル伝達経路は、このプロセスにとって重要であると考えられており、後部内胚葉および後腸運命を促進するように、ならびに前部内胚葉および前腸運命を抑制するように作用する。後腸の単純な立方体上皮は、最初に擬似層状柱状上皮に発達し、次いで、極性のある柱状上皮と増殖性領域とを絨毛の基部に含有する絨毛に発達し、これは推定前駆細胞ドメインに対応する。
いくつかの態様において、DEの後側化した内胚葉細胞はさらに1つ以上の特化細胞型に発達する。アクチビン誘導胚体内胚葉(DE)はさらに、FGF/Wnt誘導後側内胚葉早口、後腸の規格および形態形成、ならびに最終的には腸管成長、腸細胞、杯細胞、パネート細胞および腸内分泌細胞を含む機能的腸細胞型への細胞分化を促進した前腸培養系を受けることができる。いくつかの態様において、ヒトPSCは、分泌細胞型、内分泌細胞型および吸収性細胞型を含み得る腸管上皮へと試験管内で分化するように効率的に定方向化される。成長因子のような分子は、特定の種類の腸管組織形成を促進するために何らかの発達期に添加され得ることは理解されるであろう。
FGFおよびWNTシグナル伝達に加えて、骨形成タンパク質(BMP)、具体的にはBMP2およびBMP4は、後側/後腸の運命を促進し、前腸の運命を抑制することができることは同定されてきた。加えて、BMPシグナル伝達は、腸管の異なる部域型の形成を調節する。後腸期後のノギンによるBMPの阻害は、近位腸管の運命(十二指腸/空腸)を促進する。後腸期後のBMPシグナル伝達の活性化は、より遠位の腸管細胞運命(盲腸/結腸)を促進する。
SATB2発現は、胚および成体の後部の腸の腸内胚葉を標識する。
HIOおよびHCOの部域的同一性および成熟を広範に調べるために、本発明者らは、生体内で成長したHIOおよびHCOのRNA配列分析を実施し、それらをヒト胎児および成体の小腸および大腸の公表データセットと比較した。主成分分析は、成体および胎児の腸から単離された初代組織が主成分1(PC1)軸に沿ってまとまって密集することを明らかにし、これは試料間の累積的な変動の36.5%を占めた(図14A)。GO分析は、この変動が初代組織においてのみ存在し、PSC由来移植片には存在しない細胞型によるものであることを明らかにした。例えば、ヒトの初代組織には存在し、移植片には非存在である上位10の生物学的過程のうち6つは免疫細胞と関連していた(図14B~C)。第2の主成分(PC2)は、累積変動の17.7%を占め、成熟により試料を分離する(図7A)。この成分は、移植されたオルガノイドがヒト胎児腸管および胎児結腸よりも成熟しているが、成体の結腸および腸管ほど成熟していないことを明らかにした。第3の主成分(PC3)は累積変動の6.7%を占め、部域的同一性により試料を分離し、HCOが結腸により類似しているのに対し、HIOは小腸と密集していることを示す(図7A)。興味深いことに、ヒト胎児試料は部域同一性(小腸対結腸)に基づいて密集しておらず、これらの試料が消化管の指示された領域からはっきりと分離されていなかったかもしれないことを示唆した。
歴史的に、前腸、中腸、および後腸の分類は、前後の腸門脈の発達および腸間膜の血液供給源に基づいている(Uppal et al.,2011)。中腸および後腸の代替的な定義が提案されてきており、中腸は臍よりも前側の部分に由来する腸の部分であり、後腸は臍よりも後側に由来する(Johnston,1913、Savin et al.,2011)。いずれの場合においても、解剖学的ランドマークへの歴史的な依存、ならびに前部、中部および後腸を区別するためのより精確な分子マーカーの欠如は、PSCからこれらの細胞/組織を試験管内で作製する方法を開発することを困難にしてきた。それゆえ、発達中の中腸部域と後腸部域を明確に区別するマーカーの同定が不可欠である。
動物。8~16週齢の免疫不全NOD-SCID IL-2Rynu"(NSG)マウスを移植実験に用いた(オハイオ州シンシナティ市のComprehensive Mouse and Cancer Core Facilityから入手)。野生型マウスをマウス胎児腸管に関する研究に使用した。すべてのマウスは、シンシナティ子供病院医療センター(CCHMC)の動物施設において飼育した。すべての実験は、CCHMCの施設内動物管理使用委員会の承認を得て行った。
大腸のマーカーを同定するために、本発明者らはまず、GNCPro http://gncpro.sabiosciences.comigncpro/expression_grapherphpを使用して、東京大学データベースに基づいて(他の組織と比較して)結腸において上方調節された転写因子を同定した。この検索に基づいて、SATB2は結腸において6番目にランク付けされた遺伝子であった。SATB2が結腸において実際に上方調節されていることを検証するために、本発明者らはTiGERデータベース(hftp://bioinfo.wilmer.ihu.edu/tiger/db gene/SATB2-index.html)を用いてSATB2発現を検索した。結腸におけるSATB2の発現をさらに確認するため、および多数の組織にわたるタンパク質発現を検討するために、本発明者らはHuman Protein Atlas(http://www.proteinatlas.org/search/satb2)を使用した。同様の手法を用いて大腸/結腸の他のマーカーを同定した。
すべてのプロットと統計分析はRバージョン3.3.1(2016-06-21)で行った。プロットはRパッケージ’ggplot2’(Ginestet、2011)を用いて作成した。Rパッケージ’SeqRetriever’’SeqRetriever’バージョン0.6 https://github.com/hilldr/SeqRetrieyerを使用して、Cufflinks出力の差次的発現分析および統計的検定を完了した。超幾何平均検定を用いて、Rパッケージ’GeneOverlap’http://shenlab-sinai.cithub.io/shenlab-sinai/を使用して、群間で共有遺伝子発現シグネチャの相対量を評価した。完全なRNA配列FASTQ加工パイプラインおよび解析スクリプトは、https://qithub.com/hilldr/Munera2016で入手可能である。
Aronson,B.E.,Aronson,S.R.,Berkhout,R.P.,Chavoushi,S.F.,He,A.,Pu,W.T.,Verzi,M.P.,and Krasinski,S.D.(2014).GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3,lysine 27.Bba-Gene Regul Mech 1839,1273-1282.
この出願の発明に関連する先行技術文献情報としては、以下のものがある(国際出願日以降国際段階で引用された文献及び他国に国内移行した際に引用された文献を含む)。
(先行技術文献)
(特許文献)
(特許文献1) 米国特許出願公開第2013/0137130号明細書
(特許文献2) 国際公開第2015/183920号
(特許文献3) 国際公開第20151173425号
(非特許文献)
(非特許文献1) LI et al."SATB2 is a sensitive marker for lower gastrointestinal well-differentiated neuroendocrine tumors," International Journal of Clinical & Experimental Pathology,01 June 2015 (01.06.2015),Vol.8,No.6,Pgs.7072-7082.entire document
(非特許文献2) EBERHARD et al."A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer," British Journal of Cancer,28 February 2012 (26.02.2012),Vol.106,No.5,Pgs.931-938.entire document
(非特許文献3) ZACHOS et al."Human Enteroids/Colonnids and Intestinal Organoids Functionally Recapitulate Normal Intestinal Physiology and Pathophysiology," Journal of Biological Chemistry,16 December 2015 (16.12.2015),Vol.291,No.8,Pgs.3759-3766.entire document
Claims (18)
- ヒト結腸オルガノイドの形成を誘導する方法であって、
a.胚体内胚葉(DE)をFGFシグナル伝達経路活性化因子およびWNTシグナル伝達経路活性化因子(例えば、CHIRON/GSK2阻害因子)と、前記DEが中後腸スフェロイドを形成するのに十分な期間、接触させるステップと、
b.ステップ(a)の前記中後腸スフェロイドをBMP活性化因子およびEGFシグナル伝達経路活性化因子と、前記ヒト結腸オルガノイドを形成するのに十分な期間、接触させるステップとを含み、前記ヒト結腸オルガノイドがSATB2を発現する、方法。 - 前記DEが、胚性幹細胞、胚性生殖細胞、人工多能性幹細胞、中胚葉細胞、胚体内胚葉細胞、後部内胚葉細胞、後腸細胞またはこれらの組み合わせから選択される前駆細胞に由来する、請求項1に記載の方法。
- 前記FGFシグナル伝達経路活性化因子が、小分子FGFシグナル伝達経路活性化因子、タンパク質ベースのFGFシグナル伝達経路活性化因子、FGF1、FGF2、FGF3、FGF4、FGF10、FGF11、FGF12、FGF13、FGF14、FGF15、FGF16、FGF17、FGF18、FGF19、FGF20、FGF21、FGF22、FGF23、またはこれらの組み合わせから選択される、請求項1または2に記載の方法。
- 前記WNTシグナル伝達経路活性化因子が、タンパク質Wntシグナル伝達経路活性化因子、小分子Wntシグナル伝達経路活性化因子、好ましくは塩化リチウム、2-アミノ-4,6-二置換ピリミジン(ヘテロ)アリールピリミジン、IQ1、QS11、NSC668036、DCAベータ-カテニン、2-アミノ-4-[3,4-(メチレンジオキシ)-ベンジル-アミノ]-6-(3-メトキシフェニル)ピリミジン、Wnt1、Wnt2、Wnt2b、Wnt3、Wnt3a、Wnt4、Wnt5a、Wnt5b、Wnt6、Wnt7a、Wnt7b、Wnt8a、Wnt8b、Wnt9a、Wnt9b、Wnt10a、Wnt10b、Wnt11、Wnt16、GSK3阻害剤、好ましくはCHIRON、またはこれらの組み合わせから選択される、請求項1~3のいずれか1項に記載の方法。
- 前記BMP活性化因子が、BMP2、BMP4、BMP7、BMP9、BMP経路を活性化する小分子、BMP経路を活性化するタンパク質、ノギン、ドルソモルフィン、LDN189、DMH-1、ベントロモフィン(ventromophin)、およびこれらの組み合わせから選択される、請求項1~4のいずれか1項に記載の方法。
- 前記DEが中後腸スフェロイドを形成するのに十分な前記期間が、ステップ(a)の前記中後腸スフェロイドによるCDX2の発現によって決定される、請求項1~5のいずれか1項に記載の方法。
- 前記中後腸スフェロイドが、前記ヒト結腸オルガノイドを形成するのに十分な前記期間、前記ヒト結腸オルガノイドの細胞によるSATB2およびCDX2の発現による、請求項1~6のいずれか1項に記載の方法。
- 前記HCOが結腸腸内分泌細胞(EEC)の存在を特徴とする、請求項1~7のいずれか1項に記載の方法。
- 前記HCOが陰窩の存在を特徴とし、絨毛を実質的に含まない、請求項1~8のいずれか1項に記載の方法。
- 前記HCOが結腸特異的杯細胞を含む、請求項1~9のいずれか1項に記載の方法。
- 前記HCOが、パネート細胞を実質的に含まない、請求項1~10のいずれか1項に記載の方法。
- 前記HCOが結腸特異的ホルモンINSL5を分泌する、請求項1~11のいずれか1項に記載の方法。
- 請求項1~7のいずれか1項に記載の方法によって得られるHCO。
- 請求項1~7のいずれか1項に記載のHCOを、哺乳類、好ましくはげっ歯類、好ましくは免疫無防備状態のげっ歯類、好ましくは免疫無防備状態のマウスの腎被膜下に生着させることを含む、結腸組織を形成する方法。
- 大腸炎、結腸癌、ポリポーシス症候群、および/または過敏性腸症候群から選択される疾患に対して有望な治療薬の有効性および/または毒性を決定する方法であって、前記有望な治療薬を請求項1~12のいずれか1項に記載のHCOと、前記有望な治療薬の有効性および/または毒性を決定するのに十分な期間、接触させることを含む、方法。
- 請求項1~15のいずれか1項に記載のHCOを含む免疫無防備状態のげっ歯類。
- 請求項1~16のいずれか1項に記載のHCOに由来する腸管結腸オルガノイド。
- 前記腸管オルガノイドが、免疫機能、神経支配、血管、絨毛、およびパネート細胞のうちの1つ以上を含まない、請求項17に記載の腸管オルガノイド。
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WO2018106628A1 (en) | 2018-06-14 |
JP7068305B2 (ja) | 2022-05-16 |
AU2021286289B2 (en) | 2023-12-14 |
CN110062764A (zh) | 2019-07-26 |
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AU2021286289A1 (en) | 2022-01-06 |
AU2017373767B2 (en) | 2021-09-16 |
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