JP2016146836A - ヒト多能性幹細胞から産生される心筋細胞系譜の細胞 - Google Patents
ヒト多能性幹細胞から産生される心筋細胞系譜の細胞 Download PDFInfo
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Abstract
Description
本発明は、一般に、胚細胞およびその分化の細胞生物学の分野に関する。より具体的には、本発明は、心筋細胞およびその前駆細胞を形成するための、特有の培養条件および選択技術を用いた、ヒト多能性幹細胞の制御された分化を提供する。
本出願は、2001年7月12日に出願された米国特許仮出願第60/305,087号、および2001年9月10日に出願された米国特許仮出願第60/322,695号の優先権を主張するものである。米国および許可された他の管轄権において、優先権書類は国際公開公報第01/51616号と共に本明細書によって完全に参照として本明細書に組み入れられる。
心疾患は、欧米において最も深刻な健康上の懸念の一つである。6,100万人のアメリカ人(ほぼ5人に1人)が、1つまたは複数の種類の循環器疾患を有すると推測されている(第3回全米健康栄養試験調査、1988〜94、疾病管理センターおよびアメリカ心臓協会)。広範な疾患には、冠動脈疾患(1240万人)、先天性心血管異常(100万人)、およびうっ血性心不全(470万人)が含まれる。再生医療における研究の中心的課題は、これらの疾患における心機能を再構成するのに役立ち得る細胞組成物を開発することである。
・最終段階の心筋細胞
・インビトロで増殖可能であり、かつインビトロまたはインビボで上記特徴のいずれかを有する細胞に分化可能である心臓前駆細胞
・内因性遺伝子から以下のマーカーのうちの1つまたは複数を発現するもの:心臓トロポニンI(cTnI)、心臓トロポニンT(cTnT)、および心房性ナトリウム利尿因子(ANF)
・本開示で言及する他の表現型マーカーのうちの3つまたはそれ以上を発現するもの
・霊長動物多能性幹(pPS)細胞の分化により産生されるもの
・樹立したヒト胚幹(hES)細胞株と同じゲノムを有するもの
・自発的な周期的収縮活性を発現するもの
・イオンチャネルまたは適切な電気生理等の、心筋細胞の他の特徴を表すもの
本発明は、霊長動物多能性幹細胞由来の心筋細胞およびその前駆細胞を調製し特徴づける系を提供する。
1. 未分化pPS細胞に、分化過程を開始する(胚様体を形成するかまたは直接分化するかのどちらかによる)培養パラダイムを受けさせる段階。
2. 細胞を心筋細胞系譜にするのを補助すると考えられる1つまたは複数のカーディオトロピック因子の存在下で、細胞を培養する段階。
3. 密度遠心分離法または他の適切な分離手段により、心筋細胞を他の細胞から分離する段階。
4. 所望の細胞種の優先的増殖を補助すると考えられる心筋細胞濃縮薬剤の存在下で、心筋細胞系譜の細胞を含む細胞集団を培養する段階。
本発明の技術および組成物は、pPS由来心筋細胞およびその前駆体に関する。心筋細胞の表現型特徴は、本開示の後の項で提供される。心筋細胞前駆細胞に決定的な特有の特徴は存在しないが、個体発生の通常の過程において、未分化pPS細胞がまず中胚葉細胞に分化し、次に様々な前駆細胞段階を経て機能的な(最終段階の)心筋細胞に分化することが認められている。
本発明の実施において有用な一般的技術をさらに緻密にするために、実施者は、細胞生物学、組織培養、発生学、および心臓生理学の標準的な教科書および総説を参照することができる。
本発明は、様々な種類の多能性幹細胞、特に胚組織由来あり、かつ上記のように全3胚葉の子孫を産生し得る特徴を有する幹細胞で実施することが可能である。
胚幹細胞は、霊長動物種のメンバーの胚盤胞から単離された(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5,843,780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。
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4〜8 ng/mLのレベルになるように添加する(国際公開公報第99/20741号、Geron Corp.)
本発明の細胞は、所望の表現型を有する細胞を濃縮する特殊な増殖環境において、幹細胞を培養するまたは分化させることにより(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り)得られ得る。これらの方法は、幹細胞の多くの種類、特に前項に記載した霊長動物多能性幹(pPS)細胞に適用できる。
・DNAメチル化に影響を及ぼし、かつ心筋細胞関連遺伝子の発現を変化させるヌクレオチド類似体
・(TGF-β1、TGF-β2、TGF-β3、および以下に説明するTGF-βスーパーファミリーの他のメンバーに例証される)TGF-βリガンド。TGF-β受容体に結合するリガンドはI型およびII型セリンキナーゼを活性化し、Smadエフェクターのリン酸化を引き起こす。
・アクチビンAおよびアクチビンBのようなモルフォゲン(TGF-βスーパーファミリーの他のメンバー)
・インスリン様増殖因子(IGF II等)
・骨形成タンパク質(TGF-βスーパーファミリーのメンバー、BMB-2およびBMP-4に例証される)
・(bFGF、FGF-4、およびFGF-8に例証される)線維芽細胞増殖因子、ならびに細胞質キナーゼraf-1およびマイトジェン活性化プロテインキナーゼ(MAPK)を活性化する他のリガンド
・(PDGFβに例証される)血小板由来増殖因子
・(心房性ナトリウム利尿因子(ANF)、脳ナトリウム利尿ペプチド(BNP)に例証される)ナトリウム利尿因子
・インスリン、白血病抑制因子(LIF)、上皮増殖因子(EGF)、TGFα、およびクリプト(cripto)遺伝子の産物等の関連因子
・同受容体のアゴニスト活性を有する特異的抗体
、またはDKK-1をコードするレトロウイルスを感染させることにより(Marvinら、Genes Dev. 15:316、2001)、阻害され得る。または、Wnt経路は、例えば細胞をIL-6またはグルココルチコイド等の因子と共に培養することによって、キナーゼGSK3βの活性を増加させることにより、阻害され得る。
本発明の技術により得られる細胞は、多数の表現型基準にしたがって特徴づけられ得る。pPS細胞系統由来の心筋細胞および前駆細胞は、他の供給源由来の心筋細胞の形態的特徴を有することが多い。これらは、筋節構造に特有の、免疫染色により検出可能な横紋を有する、紡錘形、円形、三角形、または多角形であってよい(実施例3)。これらは、筋管様構造を形成し得り、電子顕微鏡により試験した場合には典型的な筋節および心房顆粒を示し得る。
・横紋筋収縮の制御に対するカルシウム感受性分子スイッチを提供するトロポニン複合体のサブユニットである、心臓トロポニンI(cTnI)。
・心臓トロポニンT(cTnT)。
・発達中の心臓および胎児心筋細胞において発現されるが、成体では下方制御されるホルモンである、心房性ナトリウム利尿因子(ANF)。これは心臓細胞において非常に特異的な様式で発現されるが、骨格筋細胞では発現されないため、心筋細胞の優れたマーカーと考えられている。
・筋節ミオシン重鎖(MHC)
・タイチン、トロポミオシン、α-アクチニン、およびデスミン
・心臓中胚葉において高度に発現され、発達中の心臓において持続する転写因子である、GATA-4。これは多くの心臓遺伝子を制御し、心発生において重要な役割を果たす。
・初期のマウス胚発生中に心臓中胚葉において発現され、発達中の心臓において持続する心臓転写因子である、Nkx2.5
・心臓中胚葉において発現され、発達中の心臓において持続する転写因子である、MEF-2A、MEF-2B、MEF-2C、MEF-2D
・心臓細胞間の接着を媒介するN-カドヘリン
・心筋細胞間のギャップ結合を形成するコネキシン43
・β1-アドレナリン受容体(β1-AR)
・心筋梗塞後に血清中に増加する、クレアチンキナーゼMB(CK-MB)およびミオグロビン
細胞は、ある種の医薬スクリーニングおよび治療的応用において複製する能力、ならびに心筋細胞および心筋前駆細胞産生の蓄積を提供する能力を有することが望ましい場合もある。本発明の細胞が限定した発生系譜の細胞もしくは最終分化細胞まで発達する以前またはその後に、この細胞を選択的にテロメル化し、複製能を増加させることが可能である。テロメル化したpPS細胞は先に記載した分化経路を降りることができ、または分化細胞を直接テロメル化することも可能である。
本発明は、多数の心筋細胞系統の細胞を産生する方法を提供する。これらの細胞集団は、多くの重要な研究、開発、および商業目的に使用することが可能である。
本発明の心筋細胞を用いて、このような細胞およびその多様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、オリゴヌクレオチド等)または環境条件(培養条件または操作)をスクリーニングすることが可能である。
本発明はまた、代謝機能における先天性異常、病状の影響、または顕著な外傷の結果等の任意の明らかな必要性に対する心筋の組織維持または修復を増強する、心筋細胞およびその前駆細胞の使用法も提供する。
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。
hES細胞株、H1、H7、H9、およびH9.2(H9由来のクローン株)は、始めはフィーダー細胞上で維持し、後には実施例1のようにフィーダーを含まない条件下で維持した。培養物は、200 U/mLコラゲナーゼIV中で37℃で約5〜10分間インキュベートすることにより週に1度継代し、解離し、次にマトリゲル(登録商標)コーティングしたプレートに1:3〜1:6の比率、約90,000〜約170,000細胞/cm2で播種して、初代マウス胚性線維芽細胞により馴化した培地中で維持した。
実施例2のように調製したhES由来細胞を、心筋細胞特有の表現型マーカーの存在について解析した。
パーコール(Percoll)(商標)(コロイド性のPVPコーティングしたシリカを含む密度分離媒体)の不連続勾配上での密度分離により、心筋細胞をさらに濃縮した。心筋細胞は、懸濁液中における4日間のhES分化の誘導により産生され、ゼラチンコーティングしたプレート上で15日間さらに分化された。コラゲナーゼBで、細胞を37℃で2時間解離した。細胞を洗浄し、分化培地中に再懸濁した。5分間安定させた後、細胞懸濁液を40.5%パーコール(商標)(Pharmacia)(約1.05 g/mL)層に重層し、58.5%パーコール(商標)(約1.075 g/mL)層をさらに重層した。次に、細胞を1500 gで30分間遠心分離した。遠心分離後、パーコール(商標)の上の細胞(画分I)およびパーコール(商標)の2層の界面内の細胞層(画分II)を回収した。回収された細胞を洗浄し、分化培地中に再懸濁し、ウェル当たり104個でチャンバースライドに播種した。
心筋細胞が心臓作用性薬剤の変時性効果に適切に反応するか否かを判定することにより、hES由来心筋細胞の機能を試験した。
胚様体として培養されたH1またはH9系統のhES細胞を、分化1〜4日目、4〜6日目、6〜8日目に、DNAメチル化に影響を及ぼしそのため遺伝子発現を活性化する、シトシン類似体である5-アザ-デオキシ-シチジンで処理した。15日目に細胞を回収し、リアルタイムRT-PCR法により心筋α-MHCについて解析した。
本実施例は、ヒトES細胞の心筋細胞分化に影響を及ぼす、添加される増殖因子および5-アザ-デオキシ-シチジンの組み合わせ効果の研究である。
懸濁液中で5日間胚様体を形成させることによりhES細胞のH9株を分化させ、マトリゲル(登録商標)コーティングしたプレート上で分化培地中で12日間さらに分化させた。PBS中に200 U/mLコラゲナーゼII(Worthington)、0.2 %トリプシン(Irvine Scientific)、および0.02 %グルコースを含む溶液を用いて、細胞を解離した。細胞を分化培地中、マトリゲル(登録商標)コーティングしたプレートにプレーティングし、さらに14日間培養した。
4日間胚様体を形成させることにより、H7系統のhES細胞から心筋細胞を産生させ、ゼラチンコーティングしたプレート上で17日間増殖させた(5-アザ-デオキシ-シチジンおよび増殖因子は用いなかった)。次にコラゲナーゼBを用いて細胞を解離し、分化培地中に再懸濁して静置した。続いて、細胞懸濁液をパーコール(商標)の不連続勾配上に重層し、1500 gで30分間遠心分離した。4画分を回収した:I. 上の界面;II. 40.5%層;III. 下の界面;IV. 58.5 %層。細胞を洗浄し、分化培地中に再懸濁した。免疫染色用の細胞を、ウェル当たり104細胞でチャンバースライドに播種し、2日間または7日間培養した後、固定して染色した。
(1)集団内の少なくとも約5%の細胞が霊長動物多能性幹(pPS)細胞の系統と同じゲノムを有し、かつ内因性遺伝子から以下のマーカー:
心臓トロポニンI(cTnI)、心臓トロポニンT(cTnT)、または心房性ナトリウム利尿因子(ANF)
のうち少なくとも1つを発現することを特徴とする、単離された細胞集団。
(2)集団内の少なくとも約5%の細胞が霊長動物多能性幹(pPS)細胞の系統と同じゲノムを有し、かつ自発的な周期的収縮活性を有することを特徴とする、単離された細胞集団。
(3)少なくとも約20%の細胞が:
cTnI、cTNT、筋節ミオシン重鎖(MHC)、GATA-4、Nkx2.5、N-カドヘリン、β1-アドレナリン受容体(β1-AR)、MEF-2A、MEF-2B、MEF-2C、MEF-2D、クレアチンキナーゼMB(CK-MB)、ミオグロビン、および心房性ナトリウム利尿因子(ANF)
から選択される少なくとも3つのマーカーを発現する、(1)又は(2)のいずれかに記載の細胞集団。
(4)増殖細胞の少なくとも約60%が心臓特異的ミオシン重鎖を発現する、(1)〜(3)のいずれかに記載の細胞集団。
(5)特徴を維持すると同時に、インビトロ培養において増殖可能な、(1)〜(4)のいずれかに記載の細胞集団。
(6)テロメラーゼ逆転写酵素を発現するように遺伝的に改変された細胞を含む、(1)〜(5)のいずれかに記載の細胞集団。
(7)(1)〜(6)のいずれかに記載の細胞集団およびその取得の元となった未分化pPS細胞株からなる、2つの細胞集団のセット。
(8)(7)に記載の細胞集団のセットに属する、(1)〜(6)のいずれかに記載の細胞集団。
(9)適切な増殖環境において、pPS細胞またはその子孫を分化させることを含む、(1)から(8)のいずれかに記載の細胞集団を産生する方法。
(10)a) 本質的にフィーダー細胞を含まない環境において、pPS細胞を培養すること、
b) 培養された細胞を、心筋細胞または心筋細胞前駆細胞に分化させること、
を含む、霊長動物心筋細胞または心筋細胞前駆細胞を含む細胞組成物を産生する方法。
(11)懸濁培養においてpPS細胞の分化を開始することを含む、(9)又は(10)のいずれかに記載の方法。
(12)懸濁培養において形成された凝集塊を適切な基質上にプレーティングした後、分化を継続させることをさらに含む、(11)に記載の方法。
(13)カーディオトロピック因子を含む増殖環境においてpPS細胞を分化させることを含む、(9)〜(12)のいずれかに記載の方法。
(14)カーディオトロピック因子が、DNAメチル化に影響を及ぼすヌクレオチド類似体である、(13)に記載の方法。
(15)カーディオトロピック因子が5-アザ-デオキシ-シチジンである、(13)又は(14)のいずれかに記載の方法。
(16)モルフォゲンおよび少なくとも2つの増殖因子を含む増殖環境において、pPS細胞を分化させることを含む、(9)〜(15)のいずれかに記載の方法。
(17)モルフォゲンがアクチビンであり、かつ増殖因子がインスリン様増殖因子およびTGFβファミリーのメンバーを含む、(16)に記載の方法。
(18)MHCを発現する細胞または自発的に収縮する細胞を、集団内の他の細胞から物理的に分離することをさらに含む、(9)〜(17)のいずれかに記載の方法。
(19)分離が、密度に基づいて集団内の細胞を分配し、かつ約1.05 g/mL〜約1.075 g/mLの間の密度において細胞を回収することを含む、(18)に記載の方法。
(20)高エネルギーリン酸結合、アシル基担体分子、および心筋細胞カルシウムチャネル修飾因子を形成し得る化合物を含む培地中において、少なくとも1週間細胞を培養することをさらに含む、(9)〜(19)のいずれかに記載の方法。
(21)クレアチン、カルニチン、またはタウリンを含む培地中において、少なくとも1週間細胞を培養することをさらに含む、(9)〜(20)のいずれかに記載の方法。
(22)化合物を(1)〜(8)のいずれかに記載の細胞集団と混合し、化合物に起因する心筋細胞の任意の毒性または変調を判定することを含む、心筋細胞の毒性または変調についての化合物のスクリーニング方法。
(23)集団内の細胞の収縮活性に及ぼす化合物の任意の影響をモニタリングすることを含む、(22)に記載の方法。
(24)(1)〜(8)のいずれかに記載の細胞集団、または(9)〜(21)のいずれかに記載の方法により産生される細胞集団、およびヒト投与に適した薬理学的賦形剤を含む薬剤。
(25)心臓の疾患を治療するための薬剤の調製における、(1)〜(8)のいずれかに記載の細胞集団、または(9)〜(21)のいずれかに記載の方法により産生される細胞集団の使用。
(26)心臓の筋系内または周囲に細胞集団を投与するために適合化された装置内に、(1)〜(8)のいずれかに記載の細胞集団または(9)〜(21)のいずれかに記載の方法により産生される細胞集団を含む、心臓の疾患を治療するための生成物。
(27)(1)〜(8)のいずれかに記載の細胞集団または(9)〜(21)のいずれかに記載の方法により産生される細胞集団に組織を接触させることを含む、心臓組織において収縮活性を再構成するまたは補う方法。
(28)(1)〜(8)のいずれかに記載の細胞集団または(9)〜(21)のいずれかに記載の方法により産生される細胞集団を個人に投与することを含む、個人の心疾患を治療するための方法。
(29)pPS細胞がヒト胚盤胞から単離されたかまたはこのような細胞の子孫である、(1)〜(28)のいずれかに記載の生成物、方法、または使用。
(30)pPS細胞がヒト胚幹細胞である、(1)〜(29)のいずれかに記載の生成物、方法、または使用。
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JP2004535199A (ja) | 2004-11-25 |
JP6253689B2 (ja) | 2017-12-27 |
IL159580A (en) | 2008-08-07 |
JP2011050385A (ja) | 2011-03-17 |
AU2002313670C1 (en) | 2009-08-06 |
EP1412479A4 (en) | 2004-07-28 |
JP5758604B2 (ja) | 2015-08-05 |
CA2453438A1 (en) | 2003-01-23 |
WO2003006950A2 (en) | 2003-01-23 |
JP5917429B2 (ja) | 2016-05-11 |
CN1543500A (zh) | 2004-11-03 |
CN1543500B (zh) | 2014-04-09 |
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US7851167B2 (en) | 2010-12-14 |
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US7763464B2 (en) | 2010-07-27 |
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