JP6976939B2 - 遺伝的プログラミングによる多系統造血前駆細胞の作製 - Google Patents
遺伝的プログラミングによる多系統造血前駆細胞の作製 Download PDFInfo
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Description
本明細書で使用される、特定の成分に関する「本質的に含まない」は、本明細書では、特定の成分が組成物に意図的に全く配合されておらず、及び/又は単に汚染物質として若しくは微量で存在するという意味で用いられる。従って、あらゆる意図しない組成物の汚染に起因する特定の成分の総量は、0.05%を遥かに下回り、好ましくは0.01%未満である。最も好ましいのは、特定の成分の量を標準的な分析方法で検出することができない組成物である。
ある実施形態では、多能性幹細胞から多系統造血前駆細胞を提供するための方法及び組成物が開示される。多能性幹細胞は、限定されるものではないが、誘導多能性幹細胞及び胚性幹細胞を含む幹細胞であり得る。
ある態様では、多能性幹細胞は胚性幹細胞(ESC)である。ES細胞は、胚盤胞の内部細胞塊に由来し、高いin vitroでの分化能を有する。ES細胞は、発生中の胚の外側栄養外胚葉層を除去し、次いで非増殖細胞のフィーダー層上で内部細胞塊を培養することによって単離することができる。再プレーティングされた細胞は増殖し続け、ES細胞の新しいコロニーを生成することができ、このコロニーを取り出し、分離し、再び再プレーティングし、且つ増殖させることができる。未分化ES細胞を「継代培養」するこのプロセスを多数回繰り返して、未分化ES細胞を含む細胞株を産生することができる(米国特許第5,843,780号明細書;同第6,200,806号明細書;同第7,029,913号明細書)。ES細胞は、それらの多能性を維持しながら増殖する能力を有する。例えば、ES細胞は、細胞及び細胞分化を制御する遺伝子に関する研究に有用である。遺伝子操作及び選択と組み合わせたES細胞の多能性は、トランスジェニックマウス、キメラマウス、及びノックアウトマウスの作製によるin vivoでの遺伝子分析研究に使用することができる。
他の態様では、本明細書で使用される多能性幹細胞は、一般にiPS細胞又はiPSCと略される誘導多能性幹(iPS)細胞である。多能性の誘導は、多能性に関連した転写因子の導入による体細胞のリプログラミングにより、2006年にマウス細胞を用いて最初に達成され(Yamanaka et al.2006)、2007年にヒト細胞を用いて達成された(Yu et al.2007;Takahashi et al.2007)。iPSCの使用は、ES細胞の大規模な臨床での使用に関連した倫理的及び実際的問題の大部分を回避し、iPSC由来の自家移植された患者は、移植片拒絶反応を予防するために生涯にわたる免疫抑制治療を必要としないであろう。
造血前駆細胞を作製するための多能性幹細胞は、ドナー核が紡錘体を含まない卵母細胞に移入される体細胞核移植によって調製することもできる。核移植によって作製される幹細胞は、ドナー核と遺伝子的に同一である。1つの方法では、アカゲザル(rhesus macaque)の皮膚線維芽細胞からのドナー線維芽細胞核を、電気融合によって紡錘体を含まない成熟中期IIアカゲザル(rhesus macaque)卵母細胞の細胞質に導入する(Byrne et al.,2007)。融合した卵母細胞をイオノマイシンに暴露することにより活性化し、次いで胚盤胞期までインキュベートする。次いで、選択された胚盤胞の内部細胞塊を培養して、胚性幹細胞株を作製する。胚性幹細胞株は、正常なES細胞形態を示し、様々なES細胞マーカーを発現し、in vitro及びin vivoの両方で複数の細胞型に分化する。
A.造血前駆体(プレカーサー)プログラミング因子
本開示のある態様は、PSCを多系統造血前駆細胞にプログラミングするための造血前駆体プログラミング遺伝子をコードする構築物を提供する。本開示の多系統造血前駆細胞は、少なくとも3つの造血前駆体プログラミング遺伝子、例えば、ETS遺伝子、造血発生遺伝子、及びホメオボックス遺伝子を発現するようにPSCを改変することにより、多能性幹細胞から直接的に作製することができる。少なくとも3つの造血前駆体プログラミング遺伝子は、1つ以上の多系統構築物によってコードすることができる。
多系統構築物は、転写因子のE26形質転換特異的(ETS)ファミリー由来の少なくとも1つの遺伝子をコードする。全てのETSファミリーメンバーは、高度に保存されたDNA結合ドメイン、即ち、中央のGGA(A/T)DNA配列を有するDNA部位に結合する翼状のヘリックス−ターン−ヘリックス構造であるETSドメインによって同定される。DNA結合機能と同様に、エビデンスが、ETSドメインもタンパク質−タンパク質相互作用に関与することを示唆している。ETSファミリーは、体中に存在し、細胞分化、細胞周期制御、細胞移動、細胞増殖、アポトーシス(プログラミング細胞死)及び血管形成の調節を含む多種多様な機能に関与する。この遺伝子ファミリーのメンバーは、異なる組織の発生及び癌の進行に関与している。
多系統構築物はまた、少なくとも1つの造血発生遺伝子をコードする。造血発生遺伝子は、造血発生を誘導する任意の遺伝子であり得る。造血発生遺伝子の非限定的な例には、GFI1(増殖因子非依存性1転写抑制因子;アクセッション番号NM_001127215)、GFI1B(成長因子非依存性1B転写抑制因子;アクセッション番号NM_001135031)、TAL1(T細胞急性リンパ球性白血病;アクセッション番号NM_001287347)、LYL1(リンパ芽球性白血病由来配列1;アクセッション番号NM_005583)、LMO2(唯一のLIMドメイン2(rhombotin様1);アクセッション番号M_001142315)、GATA2(GATA結合タンパク質2;アクセッション番号NM_001145661)、又はGATA3(GATA結合タンパク質3;アクセッション番号NM_001002295)が含まれる。特定の実施形態では、造血発生遺伝子はGATA2である。
加えて、多系統構築物は、少なくとも1つのホメオボックス遺伝子をコードする。ホメオボックス遺伝子は、DNAに結合するタンパク質ドメインをコードする約180塩基対長のホメオボックスをコードする。特徴的なホメオドメインタンパク質の折り畳みは、3つのαヘリックスが短いループ領域によって連結された60のアミノ酸のヘリックス−ターン−ヘリックス(HTH)構造からなる。N末端の2つのヘリックスは、逆平行であり、より長いC末端のヘリックスが、最初の2つによって確立された軸にほぼ垂直である。この第3のへリックスが、多数の水素結合及び疎水性相互作用によってDNAと直接相互作用し、これらの結合及び相互作用は、DNAの主要な溝内で特定の側鎖と露出した塩基とチミンメチル基との間で起こる。多くのホメオドメインタンパク質が、個々の組織及び器官を生成するのに必要な共調節遺伝子のカスケードを開始することによって細胞分化を誘導する。
本開示のある態様は、長期生着能のために造血幹細胞プログラミング因子をコードする構築物を提供する。長期生着が可能な造血幹細胞は、造血幹細胞プログラミング遺伝子、特に表1に列挙された遺伝子のレベルを細胞内で増加させることによって本開示の多系統造血前駆細胞から直接的に作製することができる。本発明者らはまた、このセクションに列挙される遺伝子の全てのアイソフォーム及び変異体が本開示に含まれ、あるアイソフォーム又は変異体のアクセッション番号の非限定的な例が示されることも企図する。
ある実施形態では、プログラミング因子をコードする核酸の送達のためのベクターは、これらの因子が多能性幹細胞で発現するように構築される。このようなベクターの成分及び送達方法の詳細は以下に開示される。
当業者であれば、標準的な組換え技術(例えば、共に参照により本明細書に組み込まれるSambrook et al.,2001及びAusubel et al.,1996を参照されたい)によってベクターを構築するための十分な知識を備えているであろう。ベクターには、限定されるものではないが、プラスミド、コスミド、ウイルス(バクテリオファージ、動物ウイルス、及び植物ウイルス)、及び人工染色体(例えば、YAC)、例えば、レトロウイルスベクター(例えば、モロニーマウス白血病ウイルスベクター(MoMLV)、MSCV、SFFV、MPSV、SNVなどに由来)、レンチウイルスベクター(例えば、HIV−1、HIV−2、SIV、BIV、FIVなどに由来)、その複製可能型、複製欠損型、及び無活力(gutless)型を含むアデノウイルス(Ad)ベクター、アデノ随伴ウイルス(AAV)ベクター、シミアンウイルス40(SV−40)ベクター、ウシパピローマウイルスベクター、エプスタイン−バーウイルスベクター、ヘルペスウイルスベクター、ワクシニアウイルスベクター、ハーベイマウス肉腫ウイルスベクター、マウス乳癌ウイルスベクター、ラウス肉腫ウイルスベクターが含まれる。
ウイルスベクターは、本開示のある態様で提供することができる。組換えウイルスベクターの作製では、非必須遺伝子は、典型的には、異種(又は非天然)タンパク質の遺伝子又はコード配列で置換される。ウイルスベクターは、ウイルス配列を利用して核酸及び場合によりタンパク質を細胞に導入するある種の発現構築物である。受容体媒介性エンドサイトーシスによって細胞に感染する又は細胞に侵入し、宿主細胞のゲノムに組み込まれてウイルス遺伝子を安定且つ効率的に発現させるあるウイルスの能力により、このようなあるウイルスは、外来核酸を細胞(例えば、哺乳動物細胞)に移入するための魅力的な候補となる。本開示のある態様の核酸を送達するために使用することができるウイルスベクターの非限定的な例を以下に記載する。
プラスミド又はリポソームベースの染色体外(即ち、エピソーム)ベクターの使用も本開示のある態様で提供することができる。このようなエピソームベクターは、例えば、oriPベースのベクター、及び/又はEBNA−1の誘導体をコードするベクターを含み得る。これらのベクターにより、DNAの大きい断片を細胞に導入し、染色体外で維持し、細胞周期ごとに1回複製し、効率的に娘細胞に分裂させることができ、免疫応答を実質的に誘発しない。
ある態様では、プログラミング因子の送達は、トランスポゾン−トランスポザーゼ系を使用することができる。例えば、トランスポゾン−トランスポザーゼ系は、周知のSleeping Beauty、Frog Princeトランスポゾン−トランスポザーゼ系(後者の説明については、例えば、欧州特許第1507865号明細書を参照されたい)、又はTTAA特異的トランスポゾンPiggyBac系であり得る。
ある態様では、核酸分子を例えば相同組換えによりゲノム工学のために特定の様式で細胞に導入することができる。上述のように、細胞内で遺伝子を発現させるいくつかのアプローチは、ゲノム中にランダムに組み込まれるウイルスベクター又は導入遺伝子の使用を含む。しかしながら、これらのアプローチは、組み込まれた核酸からの発現を効果的に仲介することができない部位、又は天然遺伝子の破壊を引き起こす部位のいずれかで生じる組み込みの欠点を有する。ランダム組み込みに関連した問題は、標的ゲノム中の特定の遺伝子座、例えば、Rosa26遺伝子座に対する相同組換えによってある程度克服することができる。
本開示に有用なベクターに含まれる発現カセットは、好ましくは、(5’から3’の方向に)タンパク質コード配列、介在配列を含むスプライスシグナル、及び転写終結/ポリアデニル化配列に機能的に連結された真核生物転写プロモーターを含む。
本明細書で提供される発現構築物は、プログラミング遺伝子の発現を駆動するためのプロモーターを含む。プロモーターは、一般に、RNA合成の開始部位の位置を定めるように作用する配列を含む。最もよく知られているこの例は、TATAボックスであるが、TATAボックスが欠損した一部のプロモーター、例えば、哺乳動物の末端デオキシヌクレオチジルトランスフェラーゼ遺伝子のプロモーター及びSV40後期遺伝子のプロモーターなどでは、開始部位自体を覆う別々の要素が開始部位を固定するのに役立つ。追加的なプロモーター要素は、転写開始の頻度を調節する。典型的には、これらは、開始部位の30〜110bp上流の領域に位置するが、多数のプロモーターが開始部位の下流にも機能要素を含むように示されている。コード配列をプロモーターの制御下に置くために、選択されたプロモーターの「下流」(即ち、3’側)の転写リーディングフレームの転写開始部位の5’末端を配置する。「上流」プロモーターは、DNAの転写を刺激し、コードされたRNAの発現を促進する。
特定の開始シグナルは、コード配列の効率的な翻訳のために本方法で提供される発現構築物で使用することもできる。これらのシグナルには、ATG開始コドン又は隣接配列が含まれる。ATG開始コドンを含む外因性の翻訳調節シグナルを提供する必要があり得る。当業者であれば、容易にこれを決定して必要なシグナルを提供することができるであろう。開始コドンは、インサート全体の翻訳を確実にするために、所望のコード配列のリーディングフレームを有する「インフレーム」でなければならないことは周知である。外因性の翻訳調節シグナル及び開始コドンは、天然又は合成のいずれかであり得る。発現の効率は、適切な転写エンハンサー要素を含めることによって高めることができる。
宿主細胞内でベクターを増殖させるために、ベクターは、1つ以上の複製部位の起点(しばしば「ori」と呼ばれる)、例えば、上述したEBVのoriPに対応する核酸配列、又は複製が開始される特定の核酸配列である、プログラミングにおいて類似若しくは高い機能を有する遺伝子操作されたoriPを含み得る。別法では、上記のような他の染色体外複製ウイルスの複製起点又は自律複製配列(ARS)を使用することができる。
ある実施形態では、本開示の核酸構築物を含む細胞は、発現ベクター中にマーカーを含めることによってin vitro又はin vivoで同定することができる。このようなマーカーは、識別可能な変化を細胞に与えて発現ベクターを含む細胞の容易な同定を可能にするはずである。一般に、選択マーカーは、選択を可能にする特性を与えるマーカーである。陽性選択マーカーは、マーカーの存在がその選択を可能にするマーカーであり、陰性選択マーカーは、その存在がその選択を妨げるマーカーである。陽性選択マーカーの例は、薬剤耐性マーカーである。
本方法による造血前駆細胞にプログラミングされる多能性幹細胞への核酸、例えば、DNA又はRNAの導入は、本明細書に記載されるか又は当業者に公知であろう細胞の形質転換のための核酸送達用の任意の適切な方法を使用することができる。このような方法には、限定されるものではないが、例えば、ex vivoトランスフェクション(Wilson et al.,1989、Nabel et al.,1989)による、微量注入(Harland and Weintraub,1985;参照により本明細書に組み入れられる米国特許第5,789,215号明細書)を含む注入(それぞれ参照により本明細書に組み入れられる米国特許第5,994,624号明細書;同第5,981,274号明細書;同第5,945,100号明細書;同第5,780,448号明細書;同第5,736,524号明細書;同第5,702,932号明細書;同第5,656,610号明細書;同第5,589,466号明細書、及び同第5,580,859号明細書)による;エレクトロポレーション(参照により本明細書に組み入れられる米国特許第5,384,253号明細書;Tur−Kaspa et al.,1986;Potter et al.,1984)による;リン酸カルシウム沈殿(Graham and Van Der Eb,1973;Chen and Okayama,1987;Rippe et al.,1990)による;DEAE−デキストラン及びそれに続くポリエチレングリコールの使用(Gopal,1985)による;直接音波負荷(Fechheimer et al.,1987)による;リポソーム媒介トランスフェクション(Nicolau and Sene,1982;Fraley et al.,1979;Nicolau et al.,1987;Wong et al.,1980;Kaneda et al.,1989;Kato et al.,1991)及び受容体媒介トランスフェクション(Wu and Wu,1987、Wu and Wu,1988)による;微粒子銃(それぞれ参照により本明細書に組み入れられるPCT国際特許国際公開第94/09699号パンフレット及び同95/06128号明細書;米国特許第5,610,042号明細書;同第5,322,783号明細書、同第5,563,055号明細書、同第5,550,318号明細書、同第5,538,877号明細書、及び同第5,538,880号明細書);炭化ケイ素繊維での撹拌(それぞれ参照により本明細書に組み入れられるKaeppler et al.,1990;米国特許第5,302,523号明細書及び同第5,464,765号明細書)による;アグロバクテリウム(Agrobacterium)媒介形質転換(参照により本明細書に組み入れられる米国特許第5,591,616号明細書及び同第5,563,055号明細書)による;乾燥/阻害媒介DNA取り込み(Potrykus et al.,1985)による、並びにこのような方法の任意の組み合わせによるDNAの直接送達が含まれる。これらのような技術の適用により、細胞小器官、細胞、組織、又は生物は、安定的に又は一時的に形質転換することができる。
ある実施形態では、核酸をリポソーム媒介トランスフェクションによって多能性幹細胞に導入することができる。この方法では、核酸は、脂質複合体、例えば、リポソームなどの中に閉じ込められる。リポソームは、リン脂質二重層膜及び内部水性媒体によって特徴付けられる小胞構造である。多重膜リポソームは、水性媒体によって分離された複数の脂質層を有する。多重膜リポソームは、リン脂質が過剰の水性溶液に懸濁されたときに自然に生じる。脂質成分は、閉鎖構造の形成前に自己再編成を受け、脂質二重層間に水及び溶解溶質を閉じ込める(Ghosh and Bachhawat,1991)。また、Lipofectamine(Gibco BRL)又はSuperfect(Qiagen)と複合体化された核酸も企図される。使用されるリポソームの量は、リポソームの性質及び使用される細胞に応じて変更することができ、例えば、100万〜1000万個の細胞当たり約5〜約20μgのベクターDNAが企図され得る。
ある実施形態では、核酸は、エレクトロポレーションによって細胞小器官、細胞、組織、又は生物に導入される。エレクトロポレーションは、細胞とDNAとの懸濁液の高電圧放電への曝露を含む。レシピエント細胞は、機械的創傷により形質転換しやすくすることができる。また、使用されるベクターの量は、使用される細胞の性質に応じて変更することができ、例えば、100万〜1000万個の細胞当たり約5〜約20μgのベクターDNAが企図され得る。
A.多系統造血前駆細胞
本開示は、多能性幹細胞(PSC)から多系統造血前駆細胞を作製するための方法を提供する。PSC、例えば、ESC又はiPSCを、PSCを多系統造血前駆細胞にフォワードプログラミングする本明細書に記載される造血前駆体プログラミング遺伝子を発現するように遺伝子改変する。特に、多系統造血前駆体は、骨髄系及びリンパ系細胞へ分化する能力を有する。好ましくは、造血前駆体プログラミング遺伝子は、ETS遺伝子、造血発生遺伝子、及びホメオボックス遺伝子を含む。例示的な造血前駆体プログラミング遺伝子には、EVT2又はERG、GATA2、及びHOXA9が含まれる。
多系統造血前駆細胞は、長期生着が可能な造血幹細胞にさらにプログラミングすることができる。好ましくは、PSC又は造血前駆細胞は、その発現が多系統造血前駆体のin vivoでの安定した生着を可能にする、本明細書に記載の1つ以上の造血幹細胞プログラミング遺伝子(例えば、表1)をコードする1つ以上のさらなる発現構築物でトランスフェクトされる。1つ以上のさらなる発現構築物を多系統構築物と同時に、又はPSCが未成熟造血前駆細胞にフォワードプログラミングされた後にPSCに導入することができる。
多系統造血前駆細胞又は長期生着が可能な造血幹細胞は、当技術分野で公知の造血幹細胞培養の条件下で培養することができる。特に、造血前駆細胞は、特定の造血系統、例えば、骨髄系又はリンパ系細胞を得るための条件下で培養することもできる。
本開示の造血前駆細胞及び造血幹細胞は、多数の表現型基準に従って特徴付けることができる。この基準には、限定されるものではないが、発現細胞マーカーの検出又は定量、機能的活性、並びに形態学的特徴及び細胞間シグナル伝達の特徴付けが含まれる。他の態様では、プログラミングされる細胞は、造血細胞の同定のための造血細胞特異的プロモーターのような、組織又は細胞特異的転写調節要素を含むレポーター遺伝子発現カセットを含み得る。
本開示のある態様の方法及び組成物によって提供される造血前駆細胞及び造血幹細胞は、様々な用途に使用することができる。用途には、限定されるものではないが、少数の例を挙げると、in vivoでの造血細胞及び造血前駆体の移植又は注入;in vitroでの細胞毒性化合物、発癌物質、変異原性物質、成長/調節因子、医薬化合物などのスクリーニング;血液病及び傷害の機構の解明;薬物及び/又は成長因子が作用する機構の研究;患者における癌の診断及び監視;遺伝子治療;並びに生物学的に活性な製品の生産がある。
本開示のプログラミング由来造血前駆細胞及び造血幹細胞を使用して、本明細書で提供される造血細胞の特性に影響を及ぼす因子(例えば、溶媒、小分子薬物、ペプチド、及びポリヌクレオチド)又は環境条件(例えば、培養条件又は操作)をスクリーニングすることができる。
本開示はまた、おそらく血液病又は血液疾患、又は損傷により、そのような治療を必要とする対象にある程度の機能を回復させるための、本明細書で提供される造血幹細胞及び造血前駆細胞の使用を提供する。例えば、本明細書に開示された方法によって誘導される造血細胞及び造血前駆細胞を使用して、血液病及び障害、例えば、異常ヘモグロビン症、貧血などを処置することができる。加えて、造血幹細胞及びそれらの前駆体は、血液又は血液細胞(例えば、赤血球、血小板、及び好中性顆粒球など)を、それを必要とする対象(例えば、輸血を必要とする対象又は血液疾患を有する対象)に供給するのに有用であり得る。このような細胞は、細胞抑制療法、例えば、化学療法によって引き起こされる造血細胞欠損の処置に有用であり得る。
製造目的、分配目的、及び使用の目的で、本開示の造血前駆細胞及び造血幹細胞が、典型的には、等張性賦形剤又は培地中の細胞培養物又は懸濁物の形態で供給され、任意選択により輸送又は貯蔵を容易にするために凍結される。
以下の実施例は、本発明の好ましい実施形態を実証するために包含される。以下の実施例において開示される技術は、本発明の実施において十分に機能することが本発明者によって見出された技術を代表しており、このため、本発明の実践において好ましい方法を構成すると見なすことができることを当業者は理解するであろう。しかしながら、当業者であれば、本開示から考えて、本発明の趣旨及び範囲から逸脱することなく、開示される特定の実施形態に対する多くの変更形態が可能であり、それでもなお同様又は類似の結果が得られることを理解するであろう。
本研究は、骨髄系及びリンパ系分化能を含む多系統分化能を有する造血前駆体を作製するために行った。プログラミング遺伝子の多重構造を、多系統分化能を達成するためのプログラミング効率について試験した(表2)。導入遺伝子のコード領域をrtTET誘導性Tightプロモーター(pTight)の制御下でPiggyBac発現ベクターにクローンニングした。ETV2/ERG及びGATA2(E+G)をそれぞれ、ブラストサイジン耐性及びジェネティシン耐性を有する別々の発現ベクターにクローニングした。ブラストサイジンとジェネティシンの組み合わせ選択を用いて、トランスフェクト細胞におけるETV2/ERGとGATA2の共発現を達成した。別法では、トランスフェクトされた細胞におけるバランスのとれた均一な発現のために、ETV2/ERG及びGATA2(EG)を、1つのpTight制御発現カセットにおいてF2A切断ペプチドを介して連結した。ETV2/ERGとGATA2(EG)の連結された共発現により、プログラミング効率が有意に改善され、ETV2/ERGとGATA2(E+G)が別々のベクターで発現されたときに見られる中間内皮細胞段階を迂回するようであることが分かった(図1)。
さらなる遺伝子を、PSCの未成熟造血前駆細胞へのフォワードプログラミング効率を改善するためにスクリーニングした。未成熟CD43+CD34+及びCD43+CD34+CD133+細胞の作製の改善のための、ETV2/ERG−GATA2−HOXA9(EGH)に相補的であり得るさらなる遺伝子を検出するためにスクリーニングモデルを考案した。
造血細胞の長期生着を可能にする、EGH発現ベクターと組み合わせることができる造血幹細胞プログラミング遺伝子を検出するためにスクリーニングモデルを考案した。EGH及び様々な試験遺伝子(例えば、組み合わせ当たり最大20遺伝子)の組み合わせでトランスフェクトしたCD34+細胞を磁気活性化細胞選別(MACS)によって8日目のDOX導入培養物から精製した(図5A)。誘導注射の直後、4×106のCD34+細胞をHSC培地(例えば、SCF、FLT3L、及びTPO(それぞれ100ng/ml)を添加したStemSpanSFEM)中において106細胞/mlで回復培養物(recovery culture)にプレーティングし、18〜24時間後に回収し、6〜8週齢のNOD/SCID/IL2Rg-/c−kitW41(NBSGW)マウスに静脈内注射した。次いで、注射したマウスを、DOX含有食餌(即ち、625mg DOX/kg)を入れたケージ内で飼育し、7日間、in vivoでの連続的な導入遺伝子の発現のためにDOX供給量を与えた。HSC培養適応細胞の注射のために、0.5×106のCD34+細胞をHSC培地中のDLL4−Fc/レトロネクチン被覆プレートに0.2×106細胞/mlでプレーティングし、低酸素(例えば、5%O2)条件下において、4日目に培地の半量を交換して7日間培養した。培養後、回収した細胞を、8日目のCD34+細胞を事前に注射した同じマウスに注射し、DOX含有食餌を7日間与えた。注射後、マウスを、DOXを含まない通常の食餌に替え、6週目、12週目、及び18週目に末梢血中のヒト造血細胞、20〜24週目に骨髄中のヒト造血細胞(即ち、CD45+HLAクラス1+)の存在について試験した。
参考文献
以下の参考文献は、本明細書に記載の事項を補足する例示的な手順又はその他の詳細を提供する範囲で参照により本明細書に明確に組み入れられる。
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Claims (29)
- 多能性幹細胞から造血前駆細胞を作製するためのin vitro方法であって、
(a)共発現するETS/ERG遺伝子、GATA2、及びHOXA9遺伝子を含む造血前駆体プログラミング遺伝子をコードする少なくとも1つの発現構築物を含む多能性幹細胞(PSC)を提供すること;及び
(b)前記多能性幹細胞を、前記造血前駆体プログラミング遺伝子の発現を誘導する条件下で培養し、それにより造血前駆細胞(HPC)を作製すること;及び
(c)さらに、前記HPCを、前記造血前駆体プログラミング遺伝子の発現がもはや誘導されないような条件下で培養すること、
を含む、上記方法。 - 工程(c)が、骨髄系及びリンパ系に分化することができるCD34及びCD43の発現を有する少なくとも70%の多系統HPCを含む細胞集団を産生する、請求項1に記載の方法。
- 前記発現構築物がトランスポゾンベース又はエピソームベースの発現構築物である、請求項1に記載の方法。
- 前記造血前駆体プログラミング遺伝子が単一プロモーターの制御下にある、請求項1に記載の方法。
- 前記単一プロモーターが誘導性プロモーターである、請求項4に記載の方法。
- 前記誘導性プロモーターがテトラサイクリン誘導性プロモーターである、請求項5に記載の方法。
- 工程(b)の前記培養が4〜10日である、請求項1に記載の方法。
- 前記多能性幹細胞が胚性幹細胞(ESC)又は誘導多能性幹細胞(iPSC)である、請求項1に記載の方法。
- 前記多能性幹細胞がヒトのものである、請求項1に記載の方法。
- 前記HPCが、CD43、CD33、CD34、CD45、CD235a、及びCD41aからなる群から選択される1以上のマーカを発現する、請求項1に記載の方法。
- 前記HPCが、CD43、CD45、及びCD34からなる群から選択される1以上のマーカを発現する、請求項1に記載の方法。
- 前記HPCが未成熟HPCである、請求項1に記載の方法。
- 前記未成熟HPCがCD34及びCD43を発現する、請求項12に記載の方法。
- 前記HPCの少なくとも50%が未成熟HPCである、請求項12に記載の方法。
- 前記HPCの少なくとも70%が未成熟HPCである、請求項12に記載の方法。
- 前記HPCの少なくとも90%が未成熟HPCである、請求項12に記載の方法。
- 前記HPCが間質細胞の非存在下で培養される、請求項1に記載の方法。
- 前記HPCが無血清培地又は規定された培地で培養される、請求項1に記載の方法。
- 前記HPCが、形質細胞、ナチュラルキラー細胞、マクロファージ、肥満細胞、巨核球、赤血球、顆粒球、リンパ球、単球、白血球、及び血小板からなる群から選択される2つ以上の細胞型に分化され得る、請求項17又は18に記載の方法。
- 前記リンパ球がBリンパ球及び/又はTリンパ球である、請求項19に記載の方法。
- 前記ETS/ERG遺伝子がERG(v−ets赤芽球症ウイルスE26癌遺伝子相同体)、ETV2(ets変異体2)、FLI−1(フレンド白血病ウイルス組み込み1)、ELK3(ETSドメイン含有タンパク質)、ETS1(C−ets−1)、又はETS2(C−ets−2)である、請求項1に記載の方法。
- 前記ETS/ERG遺伝子がERG又はETV2である、請求項1に記載の方法。
- 前記造血前駆体プログラミング遺伝子がERG、GATA2、及びHOXA9を含む、請求項1に記載の方法。
- 前記造血前駆体プログラミング遺伝子がETV2、GATA2、及びHOXA9を含む、請求項1に記載の方法。
- 前記造血前駆体プログラミング遺伝子が標的配列に融合される、請求項1に記載の方法。
- 前記標的配列がNUP98又はそのホメオドメインである、請求項25に記載の方法。
- 前記造血前駆体プログラミング遺伝子がERG、GATA2、HOXA9、NUP98−HOXA9、及びNUP98−HOXA10を含む、請求項1に記載の方法。
- 前記造血前駆体プログラミング遺伝子がETV2、GATA2、HOXA9、NUP98−HOXA9、及びNUP98−HOXA10を含む、請求項1に記載の方法。
- 多能性幹細胞から造血前駆細胞を作製するためのin vitro方法であって、
(a)単一プロモーターの制御下にある、ERG、GATA2、及びHOXA9をコードする発現構築物を含む多能性幹細胞(PSC)を提供すること;
(b)前記多能性幹細胞を、ERG、GATA2、及びHOXA9が共発現されるような条件下で培養し、それにより造血前駆細胞(HPC)を作製すること、及び
(c)前記HPCを、前記ERG、GATA2、及びHOXA9の共発現なしに培養すること、
を含む、上記方法。
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