JP5460677B2 - ヒト胚幹細胞由来の膵島細胞 - Google Patents
ヒト胚幹細胞由来の膵島細胞 Download PDFInfo
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- JP5460677B2 JP5460677B2 JP2011258931A JP2011258931A JP5460677B2 JP 5460677 B2 JP5460677 B2 JP 5460677B2 JP 2011258931 A JP2011258931 A JP 2011258931A JP 2011258931 A JP2011258931 A JP 2011258931A JP 5460677 B2 JP5460677 B2 JP 5460677B2
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- cells
- cell
- islet
- differentiation
- insulin
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Description
本発明は、一般に、細胞生物学、胚幹細胞、および細胞分化の分野に関する。より具体的には、本発明は、膵内分泌機能を有する分化細胞を提供する。
本願は、2001年12月7日に出願された米国特許仮出願第60/338,885号の優先権を主張する。
米国糖尿病協会では、現在、米国には糖尿病であると確認された人が500万人おり、1,000万人を上回る人が糖尿病の危険性があると推定している。
本発明は、多能性細胞から膵島細胞系譜の細胞に分化した霊長動物細胞を効率的に産生する系を提供する。膵島前駆細胞が大幅に濃縮された細胞集団について記載する。次には、膵島前駆細胞は、インスリン、グルカゴン、ソマトスタチン、またはこれら全3種類の組み合わせを分泌する細胞を含むコロニーにさらに分化され得る。
本発明は、多能性幹細胞からヒト膵島細胞を効率的に分化させる方法を示すことにより、それらの細胞の大きな集団を産生するという問題を解決する。
本開示の目的上、「膵島細胞」という用語は、最終分化膵内分泌細胞、および通常膵内分泌として分類される子孫を形成するように拘束された任意の前駆細胞を意味する。細胞は、いくつかの一般的に認められる形態学的特徴および膵島細胞系譜に特有の表現型マーカー(以下に例示する)を表す。成熟α細胞はグルカゴンを、成熟β細胞はインスリンを、成熟δ細胞はソマトスタチンを、PP細胞は膵ポリペプチドを分泌する。
最終的分化細胞を含む)を産生するために、本発明の培養系に用いる一群の化合物の1つを指す。化合物の作用形態に関しては限定しない。例えば、薬剤は、表現型の変化を誘導または補助することにより、特定の表現型により細胞の増殖を促進することによりもしくは他の増殖を遅延させることにより、分化過程を補助する可能性がある。それはまた、培地中に存在する、または、そうでなければ望まれない細胞種への経路に分化させる細胞集団によって合成される可能性がある他の因子に対する阻害剤として作用することができる。
分子遺伝学および遺伝子工学における一般的な方法は、Molecular Cloning: A Laboratory Manual (Sambrookら、Cold Spring Harbor);Gene Transfer Vectors for Mammalian Cells (MillerおよびCalos編);およびCurrent Protocols in Molecular Biology(F.M. Ausubelら編、Wiley & Sons) の現行版に記載されている。分子生物学、タンパク質化学、および抗体技術は、Current Protocols in Protein Science(J.E. Colliganら編、Wiley & Sons);Current Protocols in Cell Biology(J.S. Bonifacinoら、Wiley & Sons)、およびCurrent Protocols in Immunology(J.E. Colliganら編、Wiley & Sons)に見出すことができる。本開示で引用する遺伝子操作用の試薬、クローニングベクター、およびキットは、BioRad、Stratagene、Invitrogen、ClonTech、およびSigma-Aldrich Co.等の市販業者から入手可能である。
本発明は、様々な種類の幹細胞を用いて実施され得る。幹細胞のうち本発明での使用に適した細胞は、胚盤胞または妊娠中の任意の時点で採取される胎児組織もしくは胚組織等の、妊娠後に形成される組織由来の霊長動物幹(pPS)細胞である。限定されない例は、以下に例示するような、胚幹細胞または胚生殖細胞の初代培養または樹立株である。
胚幹細胞は、霊長動物種のメンバーの胚盤胞から単離できる(米国特許第5,843,780号、Thomsonら、Proc. Natl. Acad. Sci. USA 92:7844、1995)。ヒト胚幹(hES)細胞は、Thomsonら(米国特許第6,200,806号;Science 282:1145、1998;Curr. Top. Dev. Biol. 38:133 ページ以降、1998)およびReubinoffら、Nature Biotech. 18:399、2000の記載する技術により、ヒト胚盤胞細胞から調製することが可能である。hES細胞に相当する細胞種には、国際公開公報第01/51610号(Bresagen)に概説されるような、原始外胚葉様(EPL)細胞等のその多能性派生物が含まれる。
ヒト胚生殖(hEG)細胞は、最終月経期から約8〜11週間後に得られるヒト胎児物質中に存在する始原生殖細胞から調製することができる。適切な調製方法は、Shamblottら、Proc. Natl. Acad. Sci. USA 95:13726、1998および米国特許第6,090,622号に記載されている。
pPS細胞は、分化を促進せずに増加を促進する培養条件を用いて培養し、連続的に増殖させることが可能である。血清を含む代表的なES培地は、80% DMEM(ノックアウトDMEM、Gibco等)、20%の既知組成ウシ胎仔血清(FBS、Hyclone)または血清代替品(国際公開公報第98/30679号)のどちらか、1%非必須アミノ酸、1 mM L-グルタミン、および0.1 mMβ-メルカプトエタノールから作製する。使用する直前に、ヒトbFGFを4 ng/mLになるように添加する(国際公開公報第99/20741号、Geron Corp.)。従来通り、ES細胞は、典型的には胚または胎児組織由来の線維芽細胞であるフィーダー細胞層上で培養する。
本発明の膵島細胞は、所望の表現型を有する細胞を濃縮する特殊な増殖環境で幹細胞を培養、分化、または再プログラミングすることにより得られる(所望の細胞の増殖によるか、または他の細胞種の阻害もしくは死滅による)。これらの方法は、前項に記載した霊長類多能性幹(pPS)細胞を含む多くの種類の幹細胞に適用可能である。
pPS細胞からの膵島細胞の産生および濃縮は、膵細胞および他の細胞種の形成について多能性である初期段階の前駆細胞を形成することによって促進され得ることが、本発明の仮説である。一般的な意味では、本ストラテジーは、関連性のある拘束された共通前駆細胞について濃縮された細胞集団を形成する最初の段階、および膵島の形成に向けてますます特殊化したより成熟した細胞にさらに分化させる次の段階を含む。このストラテジーに従い、いくつかの計画的段階において、成熟膵島に向けたpPS細胞の分化が行われる。
内胚葉細胞に向けてpPS細胞の分化を開始するには、2つのアプローチが存在する。1つは、細胞を新しい基層上にプレーティングすること、または培地を交換して細胞外基質または分化を阻害する可溶性因子を除去することである。これは「直接分化法」と称される場合があり、国際公開公報第01/51616号および米国特許公報第20020019046号において一般用語として記載されている。通常、直接分化法では、分化過程における残りのフィーダー細胞に起因して起こりうる問題を回避するために、pPS細胞の無フィーダー培養から開始することが好ましい。実施例4は、初期分化因子を含む培地を導入することにより、消化管内胚葉が直接分化によって産生される例を提供する。
培養物を膵島経路のさらに下流の段階に向けて駆動するため、pPS細胞またはその分化した子孫を膵島分化因子の混合物中で培養してもよい。それぞれの因子は、単独でまたは組み合わせで、所望の細胞種への変換頻度を増加させ、膵島表現型を有する細胞の増殖をもたらし、他の細胞種の増殖を阻害し、または別の様式で膵島細胞を濃縮する可能性がある。本発明を実施するために、膵島細胞が濃縮される機構を理解する必要はない。以下は候補分化因子の限定されないリストである。
分化または分離のストラテジーを最適化する上で、組織特異的プロモーターがレポーター遺伝子の発現を駆動する、ベクターで遺伝子改変した細胞を用いることが役立つ場合がある。
細胞は、形態学的特徴の顕微鏡観察、発現された細胞マーカーの検出または定量等の表現型基準、インビトロで測定可能な機能的基準、および宿主動物に注入した際の挙動に従い、特徴づけされ得る。
本発明の細胞は、それらが様々な種類の膵島細胞に特有の表現型マーカーを発現するか否かに従って特徴づけされ得る。有用なマーカーには、表2に示すマーカーが含まれる。
臨床応用における膵島細胞の目的に対して持たれる多大な関心は、細胞集団が宿主動物の膵島系を再構成する能力である。再構成は、いくつかの確立した動物モデルを用いて試験され得る。
本発明の膵島前駆細胞は、実質的な増殖能を有する。必要に応じて、内因性遺伝子からの転写を増加させることによって、または導入遺伝子を導入することによって、細胞中のテロメラーゼ逆転写酵素(TERT)のレベルを増加させることにより複製能をさらに増強することができる。特に適切なのは、国際公開公報第98/14592号に提供されているヒトテロメラーゼ(hTERT)の触媒成分である。ヒト細胞におけるテロメラーゼのトランスフェクションおよび発現は、Bodnarら、Science 279:349、1998およびJiangら、Nat. Genet. 21:111、1999に記載されている。遺伝子改変細胞は、標準的な方法に従って、RT-PCR法、テロメラーゼ活性(TRAPアッセイ法)、hTERTの免疫細胞化学染色、または複製能により、hTERTの発現について評価することができる。myc、SV40ラージT抗原、またはMOT-2をコードするDNAで細胞を形質転換する等の、細胞を不死化する他の方法もまた意図している(米国特許第5,869,243号、国際公開公報第97/32972号、および国際公開公報第01/23555号)。
本発明は、多数の膵島前駆細胞および成熟膵島細胞を産生する方法を提供する。これらの細胞集団は、様々な重要な研究、開発、および商業目的に使用することができる。
本発明の膵島細胞を用いて、膵島前駆細胞およびその様々な子孫の特徴に影響を及ぼす因子(溶媒、小分子薬剤、ペプチド、ポリヌクレオチド等)または環境条件(培養条件または操作等)をスクリーニングすることができる。
本発明はまた、そのような療法を必要とする患者において膵島機能を回復するための、膵島前駆細胞またはその派生物の使用を提供する。膵内分泌(インスリン、グルカゴン、またはソマトスタチン)の不適切な産生、または適切に分泌を制御できないことに関する任意の病態には、必要に応じて本発明に従って調製される細胞による治療が考慮され得る。特に関心が持たれるのは、1型(インスリン依存型)糖尿病の治療である。
本発明の細胞はまた、膵島細胞の1つまたは複数の内分泌ポリペプチドを産生させるように設計された機械装置中の機能的組成物としても使用され得る。
実施例1:胚幹細胞の無フィーダー増殖
未分化ヒト胚幹(hES)細胞の樹立株は、基本的にフィーダー細胞を含まない培養環境で維持した。
サブコンフルエントな培養物中でDMSOを用いる全体的な分化過程を開始するストラテジーにより、未分化hES細胞をヒト肝細胞の特徴を有する細胞に分化させた。次にNa-ブチラートを添加することにより、細胞を誘導して肝細胞用様細胞を形成させる。
インスリン分泌細胞は、先の実施例に記載する肝細胞分化手順を改変して用い、H9株のhES細胞から導出した。
本実施例では、子宮で起こる通常の発達を模倣した、pPS細胞からの膵島の段階的誘導の例を提供する。
・さらなる添加物なし(培地対照)
・4 nMアクチビンA(R&D Systems)
・0.5 mMブチラートナトリウム(Sigma)
・アクチビンAおよびブチラートの両方。
全部で8日間の処理日数の期間、培地を毎日交換した(1日を除いて)。
hES細胞のH7株を、実施例1のようにmEF培地中で未分化形態で増殖させた。次に、1:1のmEF馴化培地とDFB+からなる混合培地中で、これらの細胞を懸濁培養で(胚様体を形成する)増殖させた。DFB+培地とは、B27添加物(1x)、インスリン(25μg/ml)、プロゲステロン(6.3 ng/ml)、プトレシン(10μg/ml)、セレン(セレナイトの形態、100 ng/ml)、トランスフェリン(50μg/ml)、および甲状腺ホルモン受容体リガンドT3(40 ng/ml)を添加したDMEM/F12培地である。翌日、10μMオールトランスレチノイン酸を添加した。3日目に培地を10μMオールトランスレチノイン酸を添加したDFB+に交換し、その後7日間1日おきに培地を添加した(段階1)。
本実験は、分化の段階IIIの期間中に膵島細胞系譜に特有の遺伝子発現プロファイルを補充する上での、膵島関連遺伝子の過剰発現の有効性を実証する。
1. 少なくとも5%の細胞が内因性遺伝子由来の以下のタンパク質の1つまたは複数を分泌する、霊長動物多能性幹(pPS)細胞を分化させることによって得られる単離された細胞集団:インスリン、グルカゴン、ソマトスタチン、または膵ポリペプチド。
2.インスリン分泌細胞、グルカゴン分泌細胞、およびソマトスタチン分泌細胞を含む、霊長動物多能性幹(pPS)細胞を分化させることによって得られる単離された細胞塊。
3. 少なくとも5%の細胞が以下のマーカーの少なくとも2つを発現する、前記請求項のいずれか一項記載の細胞集団:Pdx1、Ngn3、インスリン、IAPP、およびNkx6.1。
4. 含んでいる未分化pPS細胞が1%未満である、前記請求項のいずれか一項記載の細胞集団。
5. 高血糖NODマウスに移植した場合に、空腹時グルコースレベルを200 mg/dL未満に低下させる、前記請求項のいずれか一項記載の細胞集団。
6. テロメラーゼ逆転写酵素(TERT)を高レベルで発現するように遺伝子改変した、前記請求項のいずれか一項記載の細胞集団。
7. 霊長動物胚幹細胞の樹立株と同じゲノムを有する、前記請求項のいずれか一項記載の細胞集団。
8. 前記請求項のいずれか一項記載の分化細胞集団、およびそれが得られる元となった未分化pPS細胞株を含む、2つの細胞集団。
9. 膵島細胞分化因子の混合物中でpPS細胞またはその子孫を培養し、それによって少なくとも5%の細胞が内因性遺伝子由来の以下のタンパク質の少なくとも1つを分泌する細胞集団を取得する段階を含む、ポリペプチド分泌細胞を取得するための方法:インスリン、グルカゴン、ソマトスタチン、または膵ポリペプチド。
10. pPS細胞が分化して、胚様体、または肝細胞もしくは腸管内皮の特徴を有する細胞を形成する、請求項9記載の方法。
11. 膵島細胞分化因子の混合物が以下の少なくとも1つを含む、請求項9〜10記載の方法:アクチビンA、ニコチンアミド、シクロパミン、ベータセルリン、およびIGF-1。
12. 膵島細胞分化因子の混合物がTGF-βアンタゴニストおよび1つまたは複数のマイトジェンを含む、請求項9〜10記載の方法。
13. 細胞を遺伝子改変してニューロゲニン3等の膵転写因子の発現をもたらす段階をさらに含む、請求項9〜12記載の方法。
14. 請求項9〜13のいずれか一項記載の方法に従って得られる、請求項1〜8記載の分化細胞集団。
15.
a) 請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団を培養する段階、および
b) 培養細胞によって分泌されるインスリン、グルカゴン、またはソマトスタチンを回収する段階
を含む、インスリン、グルカゴン、またはソマトスタチンを産生する方法。
16.
a) 請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団、および
b) 細胞集団の通過を妨げるが、細胞集団によって分泌されるインスリン、グルカゴン、またはソマトスタチンの通過を可能にする半透膜
を含む、インスリン、グルカゴン、またはソマトスタチンを産生する装置。
17. 請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団を含む、薬学的組成物。
18. 化合物を請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団と混合する段階、化合物と混合したことに起因する細胞集団における任意の表現型変化または代謝変化を判定する段階、およびその変化を化合物がインスリン、グルカゴン、またはソマトスタチンの分泌を調節する能力と関係づける段階を含む、膵島細胞機能を調節する能力について化合物をスクリーニングする方法。
19. 被験者に請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団を投与する段階を含む、被験者において膵島細胞機能を再構成する方法。
20. 被験者に請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団を投与する段階を含む、被験者において1型糖尿病を治療する方法。
21. インスリン、グルカゴン、またはソマトスタチンの欠損に関連する病態を治療する医薬品の調製における、請求項1〜8記載の分化細胞集団または請求項9〜13記載の方法によって得られる分化細胞集団の使用。
22. 病態が1型糖尿病である、請求項18記載の使用。
23. pPS細胞がヒト胚盤胞から得られる細胞の子孫である、前記請求項のいずれか一項記載の細胞集団、装置、方法、または使用。
24. pPS細胞がヒト胚幹細胞である、前記請求項のいずれか一項記載の細胞集団、装置、方法、または使用。
Claims (4)
- アクチビンA及びヒト胚性幹細胞のインビトロ子孫である内胚葉細胞の集団を含み、前記内胚葉細胞の集団が、Sox17を発現する細胞、HNF3βを発現する細胞およびHNF4αを発現する細胞を含み、前記内胚葉細胞がアクチビンAを含む培地中で霊長類多能性(pPS)細胞を培養することによって作製された細胞である、細胞培地。
- ナトリウムブチラートをさらに含む、請求項1に記載の細胞培地。
- Sox17が、未分化細胞におけるSox17発現の100倍を超えて発現される、請求項2に記載の細胞培地。
- HNF3βが、未分化細胞におけるHNF3β発現の10倍を超えて発現される、請求項2に記載の細胞培地。
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