JP7407865B2 - 細胞の再プログラミングのための方法とその用途 - Google Patents
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Description
本願は、参照によりその全体が本明細書に組み込まれているものとみなす、2009年10月31日に出願された米国仮出願第61/256,967号に優先権を主張するものである。
本発明は、真核細胞再プログラミングの分野に関し、特に細胞退行分化に関する。本発明はまた、ヒト体細胞(及び他の細胞)からの安定な神経幹様細胞(NSLCs)を発生させる方法と、そのように発生された細胞のヒトの治療における用途に関する。
従来より、医療、科学、及び診断分野において、卵母細胞又は他の幹細胞と融合又は交換されることなく、容易に取得可能な細胞を一般的に取得が困難である細胞へと再プログラムする、或いは細胞が新しい又は異なる機能性を有するように細胞を再プログラムするための要望がある。
神経幹様細胞(NSLC)
本方法は、NSLC中への第1の型の細胞の形質転換を直接的又は間接的に操作可能であるような、少なくとも1つの神経幹細胞特異的ポリペプチドの細胞内レベルを増加させることを含む。収量又はNSLCの型を増加させるために、方法は、第1の型の細胞のクロマチン及び/又はDNAを、ヒストンアセチル化剤、ヒストン脱アセチル化の阻害剤、DNA脱メチル化剤、及び/又はDNAメチル化の阻害剤と接触させること、及び/又はNSLC中への第1の型の細胞の直接的又は間接的な形質転換を操作することが可能であるような少なくとも1つの他の神経幹細胞特異的ポリペプチドの細胞内レベルを増加させることを更に含んでもよい。
用語の意味
する。
再プログラム化細胞は、細胞特異的マ-カ-又はマ-カ-のセット、形態、及び/又は元の細胞の特性ではなかった生物学的機能を発現する。「再プログラム化体細胞」は、体細胞の分化状態を変更または逆転させる工程を指し、これは、劣った分化状態又は新しい分化状態のいずれかへの分化した状態の完全的又は部分的のいずれかの変換であり得る。
細胞形質転換
DNAメチル化阻害剤は、抑制された遺伝子発現を回復する能力が立証されている。DNAメチル化を阻害するために好適な薬剤としては、限定されるものではないが、5-アザシチジン、5-アザ-2-デオキシシチジン、1-β-D-アラビノフラノシル-5-アザシトシン、及びジヒドロ-5-アザシチジン、及びゼブラリン(ZEB)、BIX(ヒストンリジンメチルトランスフェラ-ゼ阻害剤)、並びにRG108が挙げられる。
したがって、用語「細胞骨格構造攪乱物質」は、細胞を不安定化するために細胞骨格構造を阻害し得、並びに引き続き細胞の形状と細胞及び核機能との間のフィ-ドバック機構を排除し得るような任意の分子を指す。本発明による適切な細胞骨格構造攪乱物質としては、限定されるものではないが、サイトカラシンB又はDのようなアクチン細胞骨格構造阻害物質のサイトカラシン族、及び2,3-ブタンジオンモノオキシムなどのようなミオシン阻害物質が挙げられる。このような前処理は、再プログラミングを増進させる。好適な実施形態では、神経原性転写因子の導入前、導入中、又は導入後に、少なくとも1つの細胞骨格構造阻害物質の存在下で1日、細胞が培養される。
神経幹様細胞(NSLCs)の取得
トランスフェクション過程中で導入されたDNAは、核内ゲノム中には挿入されないために、細胞が有糸分裂を行う際に、外部DNAは経時的に減少する。非複製型を維持する非ウィルスベクタ-は、低い免疫原性を有し、並びに調製かつ使用するために容易かつ安全である。更に、プラスミドはDNAの大きな断片に対応可能である。
したがって、本発明の細胞及び方法は、アルツハイマ-病、パ-キンソン病、多発性硬化症、又は脊髄損傷などのような神経的疾患を治療、予防、又は安定化するために有用であり得る。本技術は、インヴィヴォでのNSLCsの移植又はインヴィトロでの分化の誘導、並びにインヴィヴォでの神経プロジェニタ-細胞又は特異的なニュ-ロン又はグリア細胞の移植によって実行され得る、臨床治療のための神経幹細胞、神経プロジェニタ-細胞、ニュ-ロン及びグリア細胞の十分なソ-スを提供する。
ポリヌクレオチドの送達
ポリペプチドの送達
細胞及び細胞系
組織
スクリ-ニング法
(i)実施例1のように、繊維芽細胞のセッティングを行い、培養し、NSLCに形質転換し、
(ii)別個のウェル中で、Msi1、Ngn2及び/又はMBD2をそれぞれの候補化合物と置き換えることによって、化合物のライブラリをスクリ-ングし、
(iii)候補化合物が繊維芽細胞をNSLCsに形質転換することが、置き換えられたMsi1、Ngn2及び/又はMBD2と同程度に可能である場合、化合物「ヒット」を同定し、
(iv)(iii)部分からの化合物が全てのMsi1、Ngn2及びMBD2を置換せず、並びにそれ自体によって繊維芽細胞をNSLCsへ形質転換することができない場合、次に(iii)からの化合物をそれぞれのウェルに入れることによって、(ii)部分では除去されていなかったMsi1、Ngn2及び/又はMBD2を、異なるウェル中のそれぞれの候補化合物で置き換えることによって化合物のライブラリを測定すること、
(v)(iii)部分からの化合物と一緒に、候補化合物が、置換されたMsi1、Ngn2及び/又はMBD2とほぼ同程度に繊維芽細胞をNSLCsへと形質転換させることが可能な場合、化合物「ヒット」を同定し、
(vi)(v)部分からの化合物がMsi1、Ngn2及び/又はMBD2の全てを置換せず、並びに(iii)部分からの化合物と一緒に繊維芽細胞をNSLCsへと形質転換することができない場合、次いで(iii)及び(v)部分からの化合物をそれぞれのウェルに入れることによって、(ii)部分では除去されていなかったMsi1、Ngn2又はMBD2を異なるウェルにて、それぞれの候補化合物で置き換えることによって、化合物のライブラリをスクリ-ニングし、
(vii)(iii)及び(v)部分からの化合物と共に、置換されたMsi1、Ngn2及び/又はMBD2とほぼ同程度に、候補化合物が繊維芽細胞をNSLCsへと形質転換できる場合、化合物「ヒット」を同定し、
(viii)(iii)、(v)及び(vii)部分からの化合物の組み合わせが繊維芽細胞をNSLCへ形質転換させることができるような場合、これらの化合物に対する修正が行われ得、これらの化合物のより有効かつ安全な変型を更にスクリ-ニングする。
神経栄養因子の送達
実施例
実施例I
ヒト繊維芽細胞の調製
(3.3×10-5M)の成分で補充され、L-アスコルビン酸が存在しないHamのF-12培地との3:1の比からなる。
で補充されたHamのF-12培地との3:1の比からなる。
構築されたベクタ-を使用するリポフェクタミンによるHFFの一過性トランスフェクション
遺伝子アレイ解析
サイクル閾値(CT)は、増幅された標的の量が設定された閾値に到達するサイクル数を示す。CT値は、0~40の範囲である(後者は、信号の検出の不成立を定義する初期上限PCRサイクル数を表している)。ΔCT値[ΔCT=CT(標的遺伝子)-CT(3つのハウスキ-ピング遺伝子の平均)]がHFF Ctrlについて計算され、続いて、それぞれのサンプルの標準物質として使用された。すべての遺伝子発現値は、基準物質に関する1.00の相対値に振り分けられ、これが、ΔΔCT=ΔCT(処理された)-ΔCT(HFF Ctrl)であるように、比較遺伝子発現を決定するために用いられる。
相対的発現は、式2-ΔΔCTを用いて計算される。
免疫組織化学アッセイ
実施例II
3つの異なる神経原性遺伝子の再プログラミング効率の比較
遺伝子発現解析
免疫組織化学アッセイ
実施例III
ベクタ-の種々の組み合わせによるHFFのトランスフェクション及び細胞骨格の崩壊
遺伝子発現解析
免疫組織化学アッセイ
遺伝子アレイ解析
接着及び浮遊条件中のNSLCへのHFFの再プログラミングにおけるNucleofector II DeviceとNucleofector 96-well Shuttle Deviceの比較
神経増殖培地の比率が4日目までに100%に増加され、並びにサイトカラシンBの比率が5日目までに完全に削除されて、培地が毎日交換された。ホルスコリン(10μM)が、4日目以降に培地に添加された。浮遊状態にある細胞が、遠心分離によってペレット化され、それらの培地が、接着状態に関して記載されたように、毎日交換された。細胞が、3、7、12日に回収され、免疫組織化学アッセイが行われた。
神経球形成アッセイ及び細胞分化アッセイ
培養を、37℃、5%CO2、5%O2にてインキュベ-トして、少なくとも2か月間、供給した。
これら球体の20日目の免疫組織化学解析(表12及び図4)は、神経幹細胞マ-カ-Sox2、Musashi、CD133、ネスチン、及びGFAPに関する免疫陽性染色を示した。細胞はまた、両細胞のセット(NSLC及びhNPC)の三分化能潜在能力を示唆している、βIII-チュ-ブリン(ニュ-ロンに対するマ-カ-)、O4(希突起膠細胞に対するマ-カ-)、及びGFAP(星状細胞に対するマ-カ-)に関して陽性に染色され、並びに、細胞が最終的には分化されなかったことを示している、NGFrec及びNeuN(分化されたニュ-ロンに対するマ-カ-)に関して陰性であった。
これらのデ-タは、NSLCsがhNPCsと同様ではあるが、同一ではないことを裏付けている。
有用な基準としては、形態学的特徴(長い突起又は神経突起)、ニュ-ロン特異的マ-カ-又は抗原のセットの発現などのような生理学的及び/又は免疫学的特徴が挙げられる。更に、NSLCsは、ニュ-ロン細胞、星状細胞の高パ-センテ-ジ並びに希突起神経膠細胞群のより低いパ-センテ-ジへの分化潜在能力を備えた三分化能性様前駆体細胞へと容易に戻る。
実施例VI
HFFsの再プログラミングにおけるBMP信号伝達経路の意味
HFF細胞から産生されたNSLCsは皮膚由来前駆体(SKPs)ではない
実施例VIII
神経様細胞(NLCs)からのBDNF放出
実施例IX
NSLCsに向かう異なる細胞型の再プログラミング
ヒトCD34+細胞、ヒトADSC及びヒト角化細胞の調製
1500rpmで5分間の遠心分離が行われたのちに、上記のように、細胞がCellStartコ-ティングされたフラスコに播種された。
実施例X
3D細胞外マトリックス(CDM)の組立て
3M)、グルタチオン(3.3×10-6M)、及び1%ペニシリン/ストレプトマイシン/アンフォテリシンB)の3:1比を備える。この完全に化学的に限定された培地中で繊維芽細胞を超集密的密度にて培養することによって、増殖速度が低減された高合成期へとそれら細胞が移行することを引き起こし繊維芽細胞それ自体によって完全に合成される新生3D細胞外マトリックス(CDM)内の繊維芽細胞の多重層からなる生きた組織等価物(LTE)の生産へと誘導する。
CDM内における細胞の分化形質転換及び再プログラミング
実施例XI
CDM内の再プログラムされた細胞遺伝子発現解析
遺伝子発現アレイ
IGF-1、IGF-2、NPY及びCSF-3などの成長因子の遺伝子発現は、Msi1又はNgn2によるトランスフェクションに続いて増強された。VEGFとGDNFの発現は、Msi1とNgn2によって、それぞれほぼ5倍と7倍に増加された。しかし、トランスフェクトされた細胞の中で、BDNF、EGF、及びbFGFの発現は活性化されず、トランスフェクトされていない細胞と比べてダウンレギュレ-トもされた。神経突起伸張の成長関連マ-カ-及び再生関連マ-カ-である成長関連蛋白質(GAP-43)の発現、並びにニュ-ロンの発達及び誘導に関与するネトリンの発現は、トランスフェクトされた細胞中で高度に発現された(表26)。III型受容体チロシンキナ-ゼ、神経親和性チロシンキナ-ゼ受容体、及び神経親和性チロシンキナ-ゼのような、成長因子及び神経原性因子のための受容体の発現は増加された。繊維芽細胞特異的マ-カ-のビメンチン及びフィブロネクチンは、再プログラムされた細胞中でダウンレギュレ-トされえた。
実施例XII
リポフェクタミン及びヌクレオフェクチンによるCDM内の細胞の再プログラミング
遺伝子発現解析
免疫組織化学解析
実施例XIII
NSLCsのテロメラ-ゼ活性
実施例XIV
腫瘍形成アッセイ
実施例XVI
一過性トランスフェクションからのNSLCs中におけるプラスミドDNAの非ゲノム組込み
実施例XVII
移植されたhNSLCsの神経保護的効果
1)多発性硬化症の動物モデルにおける効果
種々のCNS抗原(ミエリン希突起神経膠細胞糖蛋白質(MOG)、プロテオリピド蛋白質(PLP)及びミエリン塩基性蛋白質(MBP))を使用して、EAEは動物の種々の種及び系統(マウス、ラット、キヌザル、アカゲザル)で誘導され得る。
細胞の有無でのEAE動物モデルの処置
2)片麻痺性動物モデル(成人ラットの左感覚運動皮質の片側性アブレ-ション)における効果
実施例XVIII
Shuttle装置及び内胚葉系中胚葉への再プログラミングのための異なる小分子を使用した遺伝子の種々の組み合わせによるHFFのトランスフェクション
トランスフェクション後、細胞が0.1%ゼラチンでコ-ティングされたプレ-ト上に播種され、37℃、5%CO2、5%O2にてインキュベ-トされた。表30に従って、培地が一日おきに交換された。4日目に、定量的リアルタイムPCRによって、細胞が解析された。
膵臓プロジェニタ-様細胞へのHFFsの再プログラミング
実施例XIX
多分可能様幹細胞(PLSC)へのヒト脂肪細胞由来幹細胞(ADSC)の再プログラミング
表34:プラスミド及び1日~14日の培地構成成分
Matrigel(BD Biosciences)でコ-ティングされた6-ウェルプレ-トに細胞を播種し、37℃、5%CO2にてインキュベ-トされた。1日目及び2日目に、VPA及び5-AZAを補充された又は補充されていない100%mTwSR1培地(StemCell Technologies)に交換された。3日目及び6日目に、それぞれの条件からの細胞が、TrypLE中で5分間インキュベ-トすることによって脱着され、計測並びに遠心分離が行われた。細胞が上記のように再トランスフェクトされて、VPA及び5-AZA有無のmTeSR1培地中、Matrigelコ-ティングプレ-トに播種された。1日~2日に記載されたように、培地が交換された。潜在能力を持つ再プログラムされた細胞の生存及びクロ-ン増殖を推進するために、Y27632(Stemgent、10μM)が7日~14日に補充された。20日目に、アルカリフォスファタ-ゼ検出キット(Millipore)を使用して並びに免疫組織化学解析によって、細胞が解析された。
多分可能性へのNSLCsの再プログラミング
NSLCsの有用性は、多分可能様細胞へと向かう再プログラミングのための多くの利点を提供することができた。例えば、c-Mycのような腫瘍発生性遺伝子の必要条件を排除することで、癌性細胞を誘導する危険性を低減する。神経再生的及び神経変性的用途に関しては、これら細胞は、更なるヒト多分化能細胞誘導を検討するための貴重な細胞源を確立し、並びに人の疾患をモデル化するために患者に特異的な多能性及び多分可能性幹細胞を誘導するための潜在的能力を有する細胞源も確立する。
実施例XX
SCIDマウスにおける奇形腫アッセイ
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Claims (8)
- 繊維芽細胞、角化細胞、血液細胞、骨髄細胞、および脂肪細胞由来幹細胞から選択される第1の型の細胞を、多能性または単分化能性である神経系細胞へと再プログラミングする方法であって、
(1)前記第1の型の細胞のクロマチン及び/又はDNAを再構築するために、前記細胞にヒストンアセチル化剤、ヒストン脱アセチル化の阻害剤、DNA脱メチル化剤、及び/又は、DNAメチル化の化学的阻害剤を導入し、
(2)前記第1の型の細胞に対して、少なくとも1種の再プログラミング剤を一過的に適用し、ここで前記再プログラミング剤が、少なくとも1種の遺伝子調節因子の内因性発現を直接又は間接的に増加させる物質であり、ここで前記少なくとも1種の遺伝子調節因子の内因性発現は前記多能性または単分化能性である神経系細胞の存在に必要であり、ここで前記再プログラミング剤は、MSI1及びNEUROG2(NGN2)から選択されるポリペプチド、又は、当該ポリペプチドをコードするポリヌクレオチドであり、
(3)前記細胞を、神経系多能性又は単分化能性細胞への転換を支持する培養条件下に、再プログラミング剤の不在下で転換遺伝子調節因子の安定な発現を生じさせるのに十分な期間に亘って保持し、
(4)前記細胞を、神経系多能性又は単分化能性細胞への転換を支持する培養条件下に、1種又は2種以上の第2の遺伝子を安定して発現させるのに十分な期間に亘って維持し、ここで前記1種又は2種以上の第2の遺伝子は、ネスチン、Sox2、GFAP、Msi1、Soc1、及びCD133から選択され、ここで前記1種又は2種以上の第2の遺伝子の安定な発現は前記遺伝子調節因子が安定に発現した結果であり、ここで
(i)前記1種又は2種以上の第2の遺伝子の安定な発現は、前記多能性または単分化能性である神経系細胞の表現型的及び/又は機能的特性の特徴であり、かつ
(ii)前記1種又は2種以上の第2の遺伝子のうちの少なくとも1種の安定な発現は、胚幹細胞の表現型的及び機能的特性の特徴ではないことを含み、
ここで、前記期間の終了時に、前記第1の型の細胞は、神経系多能性又は単分化能性細胞に転換され、
ここで、前記少なくとも1種の遺伝子調節因子がそれぞれ、Musashi1(Msi1)及びNeurogenin2(Ngn2)から選択される、方法。 - 前記DNAメチル化の化学的阻害剤が、5-アザシチジン、5-アザ-2-デオキシシチジン、1-β-D-アラビノフラノシル-5-アザシトシン、ジヒドロ-5-アザシチジン、ゼブラリン、及びRG108からなる群から選択され、
前記ヒストン脱アセチル化の阻害剤が、バルプロン酸、フェニルブチレート、トリコスタチンA、Na-ブチレート、5ベンズアミド、及び環式テトラペプチドからなる群から選択され、及び/又は、前記DNA脱メチル化剤が、メチル-CpG結合ドメインタンパク質2(MBD2)である、請求項1に記載の方法。 - 前記神経系細胞が、後に神経体細胞に分化する多能性細胞である、請求項1または2に記載の方法。
- 前記神経体細胞が、βIII-チューブリン、Map2b、シナプシンおよびACHEのうちの1種以上を発現する、請求項3に記載の方法。
- 前記神経系細胞が、前記第1の型の細胞中で発現される複数種の遺伝子の安定した抑制によって特徴付けられる、請求項1~4のいずれか1項に記載の方法。
- 前記再プログラミング剤が細胞内に送達される、請求項1~5のいずれか一項に記載の方法。
- 前記神経系細胞が、ネスチン、Sox2、GFAPおよびMsi1のうちの1種以上を発現する神経幹様細胞である、請求項1、2、5、又は6に記載の方法。
- 神経系多能性又は単分化能性細胞への転換を支持する培養条件が、レチノイド化合物、神経栄養因子、bFGF、EGF、SHH、Wnt3a、神経ペプチドY、エストロゲン、リチウム及びL-アスコルビン酸からなる群より選択される1種又は2種以上の因子を含む、請求項1~7のいずれか1項に記載の方法。
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