JP4823689B2 - 再ミエリン化および脊髄損傷の治療のためのヒト胚性幹細胞に由来するオリゴデンドロサイト - Google Patents
再ミエリン化および脊髄損傷の治療のためのヒト胚性幹細胞に由来するオリゴデンドロサイト Download PDFInfo
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Description
本発明は、一般に、胚細胞および神経系前駆細胞の細胞生物学の分野に関する。より具体的には、本発明は、生物学的研究、薬剤スクリーニング、およびヒトの治療に使用するのに適した、オリゴデンドロサイトおよびその前駆細胞の濃縮された集団を提供する。
本出願は、2002年7月11日に出願された米国仮出願第60/395,382号、および2003年4月4日に出願された米国実用出願第10/406,817号の利益を主張する。優先権出願は、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。
オリゴデンドロサイトは、中枢神経系の支持において重要な生理的役割を担う。ヒトの治療にオリゴデンドロサイトが利用できれば、神経細胞を絶縁するミエリン鞘の欠陥によって生じる障害状態の治癒が促進され得る。
本発明は、研究および薬学的組成物の調製に用いるための、グリア系譜の霊長動物細胞を効率的に産生する系を提供する。
本発明は、多能性幹細胞からオリゴデンドロサイトおよびその前駆細胞を効率的に産生することにより、それらの細胞の大きな集団を作製する問題を解決する。
オリゴデンドロサイトとは、中枢神経系の外膜構造(神経膠)の一部を形成する外胚葉起源の神経系細胞である。この細胞は、個々の軸索の周りを覆いCNSのミエリン鞘を形成する、不定数のベール様またはシート様突起を有する。この細胞は、本開示で後に説明する形態学的基準、表現型基準、または機能的基準によって同定することができる。
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、および抗体技法は、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することができる。本発明の使用に特に適しているのは、胚盤胞等の妊娠後に形成される組織または妊娠期間の任意の時期に採取した胎児組織もしくは胚組織等に由来する霊長動物多能性幹(pPS)細胞である。限定されない例は、以下に記載するような胚性幹細胞もしくは胚性生殖細胞の初代培養または樹立株である。本発明の技法を初代胚組織または胎児組織に直接実行し、最初に未分化細胞株を樹立することなく初代胚性細胞から神経系細胞を直接導出することも可能である。
胚性幹細胞は、霊長動物組織から単離することができる(米国特許第5,843,780号;Thomsonら、Proc. Natl. Acad. Sci. USA 92:7844、1995)。ヒト胚性幹(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の記載する技法により、ヒト割球から調製することが可能である。hES細胞に相当する細胞型には、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。
ヒト胚性生殖(hEG)細胞は、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ように、始原生殖細胞から調製することができる。
オリゴデンドロサイトを作製するための出発材料として有用なpPSまたは胚性幹細胞を産生するために、本発明の実施はヒト胚または胚盤胞を脱凝集することを決して必要としない。hES細胞は、公共の受託所(例えば、WiCell Research Institute、米国、ウィスコンシン州、マディソン、またはAmerican Type Culture Collection、米国、バージニア州、マナッサス)から入手可能な樹立株から得ることができる。米国特許公報第2003-0113910A1号は、胚または胎児組織を用いずに導出された多能性幹細胞について報告している。多能性表現型を誘導する因子を使用することにより、臍帯血または他の前駆細胞をpPS細胞に再プログラミングすることも可能であると考えられる(Chambersら、Cell 113:643、2003;Mitsuiら、Cell 113:631、2003)。適切な条件下において、別の方法でpPSまたはhES細胞の定義に見合う任意の細胞を、本発明によりオリゴデンドロサイト系譜細胞の導出に用いることができる。
pPS細胞は、分化を促進せずに増殖を促進する培養条件を用いて培養し、連続して増殖させることが可能である。血清を含む例示的な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)のいずれか、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.)
本発明のオリゴデンドロサイト系譜細胞は、所望の表現型を有する細胞を濃縮および拡大する特殊な成長環境において幹細胞を培養することによって得られる。成長環境によって、オリゴデンドロサイト系譜への分化が特異的に方向づけられ得る、所望の細胞の成長が促進され得る、他の細胞型の成長が阻害され得る、またはこれらの活性の任意の組み合わせが起こり得る。
オリゴデンドロサイトを産生する過程は、典型的に2つの局面、起源幹細胞集団に分化を引き起こす段階;およびオリゴデンドロサイト系譜細胞を主要細胞型にする段階を含む。これらの事象は、経時的にまたは同時に起こり得る。
所望の目的のために細胞を用いる以前の任意の段階として、本発明の使用者は、オリゴデンドロサイト系譜細胞を培養において増殖させることによりこの細胞の数を増やしてもよい。
必要に応じて、本発明の細胞を、複製段階を超えて機能的表現型にさらに成熟させることができる。これを行うことで、前駆細胞の可能性を特徴付ける、または治療目的もしくは薬剤スクリーニング目的のために最終段階の細胞を得ることができる。
多くの表現型基準に従って、細胞を特徴付けることができる。基準には、形態学的特徴の顕微鏡観察、発現した細胞マーカーの検出または定量、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反応が含まれるが、これらに限定されない。
オリゴデンドロサイトに特有の表現型マーカーを発現するかどうかに従って、本発明の分化細胞を特徴付けることができる。細胞集団の成熟度に従って存在し得るオリゴデンドロサイト細胞の古典的な免疫細胞化学的マーカーは、以下の通りである:
・NG2、マクロファージおよびオリゴデンドロサイト前駆細胞によって発現されるコンドロイチン硫酸プロテオグリカン
・ガラクトセレブロシド(GalC)、拘束されたオリゴデンドロサイトのマーカー
・ミエリン塩基性タンパク質(MBP)、成熟ミエリンおよびミエリン産生細胞のマーカー。
・PDGFRα、オリゴ前駆細胞、オリゴデンドロサイト、および他の細胞型によって発現されるPDGFの膜受容体
・TRα1、オリゴ前駆細胞、オリゴデンドロサイト、ニューロン、および他の細胞型によって発現される甲状腺ホルモンの核受容体
・ミエリンプロテオリピドタンパク質、オリゴデンドロサイトおよびグリア前駆細胞で発現されるミエリンの成分
・O4抗体によって規定されるエピトープ、オリゴデンドロサイト、アストロサイト、およびそれらの前駆細胞のマーカー
・ビメンチン、アストロサイト前駆細胞を特徴付ける線維芽細胞型フィラメントタンパク質(オリゴデンドロサイトでは陰性である場合が多い)
・神経膠繊維酸性タンパク質(GFAP)、アストロサイトのマーカー(オリゴデンドロサイトでは陰性)
・A2B5、II型アストロサイト、グリア前駆細胞、オリゴデンドロサイト前駆細胞、および膵臓β細胞で発現されるエピトープ
・オリゴデンドロサイトおよびその突起を染色し、脊髄および小脳両方の有髄化軸索と一致する、RIP抗体によって認識されるエピトープ。
・Olig1、オリゴ前駆細胞、運動ニューロン前駆細胞、および腎細胞によって発現されるヘリックス・ループ・ヘリックス(HLH)ファミリー転写因子
・Olig2、オリゴ前駆細胞、運動ニューロン前駆細胞、および松果体によって発現される別のHLHファミリー転写因子
・Sox10、オリゴ前駆細胞、オリゴデンドロサイト、シュワン細胞、神経堤、蝸牛、前立腺、およびメラノサイトによって発現されるSoxファミリー転写因子
・Nkx2.2、オリゴ前駆細胞、オリゴデンドロサイト、ニューロン前駆細胞、膵臓α細胞および膵臓β細胞によって発現されるHoxファミリー転写因子
・Pax6、オリゴ前駆細胞、ニューロン前駆細胞、膵αおよびβ細胞、水晶体網膜、下垂体、肝臓、および脾臓によって発現されるHLHファミリー転写因子。
・ニューロン核抗原(NeuN)、ニューロン成熟のマーカー(通常、オリゴデンドロサイト系譜細胞では陰性)
・クラスIIIβチューブリン(TuJ1)、神経細胞の別のマーカー
・微小管関連タンパク質2(MAP-2)、CNS細胞のマーカー(おそらく陽性)
・SSEA-4、Oct-4、およびテロメラーゼ逆転写酵素(TERT)、未分化pPS細胞のマーカー(オリゴデンドロサイトおよびその前駆細胞では陰性)。
単離したpPS細胞またはpPS細胞の樹立株に由来する場合、本発明のオリゴデンドロサイトは起源細胞または細胞株の子孫であると特徴付けられ得る。したがって、オリゴデンドロサイトはその由来の元となった細胞と同じゲノムを有することになる。このことは、任意の核型変化のほかに、pPS細胞とオリゴデンドロサイトとの間で染色体DNAが90%を超えて同一であることを意味する。導入遺伝子を導入する、または内因性遺伝子をノックアウトするために組換え法により処理したオリゴデンドロサイトは、未操作の遺伝子要素はすべて保存されているため、依然として由来の元となった株と同じゲノムを有すると見なされる。
品質管理の目的で、本発明の分化細胞の特性を機能的基準によって特徴付けることが望ましい場合が多い。目的とする最終的な用途により、異なる機能が異なる相対的関心となり得る。例えば、組織培養において神経組織を再ミエリン化する能力、インビボで脱髄が誘導された部位を修復する能力、または損傷した対象において神経機能を回復する能力について、細胞を評価することができる。これらの特性を判定するための、以下の限定されない例証を含む多くの実験モデルが存在する。
2〜3ヶ月齢雌ラットから腰椎および頚椎後根神経節(DRG)ニューロンを回収することにより、成体DRG培養物を調製する。細胞を粉砕し、遠心分離し、mL当たり約100,000個の生存ニューロンでDMEM F12培地に再懸濁し、ラミニンコーティングした皿にプレーティングして4週間培養する。約2.5 x 104個のオリゴデンドロサイト系譜細胞を添加し、毎日フィードしながらさらに4週間培養することにより、インビトロ髄鞘形成を行う。ヒトオリゴデンドロサイトによるげっ歯類軸索の髄鞘形成は、TargetおよびBlakemore、Eye 8(part2):238、1994に例証されている。
成体ラット脊柱において、慢性脱髄の領域を誘導することができる(Keirsteadら、J Neurosci. 19:7529、1999)。鉛遮蔽を用いてT9を中心に、2 cmを超える距離で脊髄を40 GのX線照射に曝露するが、これにより曝露細胞のDNAにニックが導入され、細胞分裂している細胞が死滅する。2日後に、T9においてエチジウムブロマイドを脊髄内に直接注入する。エチジウムブロマイドはこれに曝露した細胞を死滅させるインターカレート剤であり、これによって慢性脱髄の無細胞領域ならびに脊柱領域の約60%を通して生存オリゴデンドロサイトおよびアストロサイトがない状態が提供される。
SCIモデルは、挫傷および背側片側切断を含む。挫傷では、適切な脊髄損傷装置を用いて、脊髄層を23ミリ秒を上回る時間をかけて約0.9 mm除去する(中程度の損傷)。片側切断損傷では、定位的なマニピュレーターを用いて先のとがった手術用メスで脊髄の背側の半分を切断する。どちらの手順とも、その後適切な術後処置を行う。
本発明の特定のオリゴデンドロサイト前駆細胞集団は、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、細胞内の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亢進することができる。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。
本発明は、様々な重要な研究、開発、および商業目的のために、多数のオリゴデンドロサイトを産生する方法を提供する。
本発明の細胞を用いて、オリゴデンドロサイト前駆細胞および成熟オリゴデンドロサイト両方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(培養環境または操作等)をスクリーニングすることができる。
本発明は、治療を必要とする患者において神経機能を保持または回復するための、オリゴデンドロサイト前駆細胞およびその派生物の使用を提供する。特に、神経組織を再ミエリン化するため、またはさもなければ神経ネットワークの維持もしくは再生を支持するために、本発明の細胞を投与することができる。いかなる限定も意味することなく、投与した細胞は、すでに所定の位置にあるニューロンの機能を安定化するもしくは改善する効果を有する、またはニューロンが相互にもしくはそれが制御する組織と新たな連結を形成するのを支持する可能性がある。
実施例1:hES細胞のオリゴデンドロサイトへの分化
H7株およびH1株のヒト胚性幹(hES)細胞を、初代マウスフィーダー細胞により馴化しbFGFを添加したノックアウト(無血清)培地中、マトリゲル(登録商標)基層上で無フィーダー条件において未分化状態で増殖させた(国際公開公報第99/20741号; 国際公開公報第01/51616号、Geron Corp)。
GRMはグリア制限培地である(表2を参照のこと)。
移行培地(TR)は、GRMおよびhES細胞を作製するための馴化培地の1:1混合物として作製する。
・1日目:コラゲナーゼIV(Gibco 17101-015)を用いて接着基層からESコロニーを解離し、コロニーを4 ng/mL bFGF(Gibco 13256-029)を有するTR中で低接着性6ウェルプレート(Corning 3471)に入れた。分化手順の最初の3日間のみ、ペニシリン-ストレプトマイシン(Gibco 10378-016)を用いた。
・2〜10日目:細胞をレチノイン酸(RA;オールトランス-レチノイン酸、Sigma 223018)、10μMと共に培養し、合計8日間毎日フィードした。RA保存液は、6 mg/mLの濃度で(約0.02 M)DMSOに溶解して調製した。
・3日目から:培地をGRMに置換し、それ以上はbFGFを添加しなかった。培地は毎日交換した。RAは光感受性であるため、フィード中は照明を最小限に落とした。ES細胞凝集体を含むウェルの培地を、15 mLチューブに回収した。低速で短時間遠心分離した後(800 rpm、1分間)、上清を吸引除去し、新鮮培地を添加した。穏やかに上下にピペッティングし(2〜3回)、6ウェルプレートの各ウェルに4 mLずつ確実に均一に分配した。
・10〜15日目:10日目以後は、毎日フィードする際に、20 ng/mL濃度のEGF(Sigma E9644)および2 ng/mL濃度のbFGFを添加した。
・15〜21日目:EGFは20 ng/mL濃度で添加し続けたが、bFGFは培地から除去した。
・21日目以後:20 ng/mL EGFを有するGRM培地を維持することにより、42日目以降でも神経の特徴を有する新たな凝集体/凝集塊が産生され得た。
・これらの神経球を選択するため、分化手順の28日目に、マトリゲル(登録商標)をコーティングした6ウェルプレート(マトリゲル(登録商標)1:30、BD Bioscience 356231)に、培養物全体を解離手順を行うことなく、12〜20時間(一晩)移した。翌日、培養物を穏やかに振盪すると、神経球のみが接着したままであるので、培養物の残りを新鮮なGRM培地で置換した。
・35日目:ポリ-L-リジン(Sigma P2636)およびラミニンでコーティングした4チャンバー・イメージングスライド(Nalgene-Nunc International 154917)に、神経凝集体をプレーティングした。トリプシン-EDTAで短時間(5分)処理し、細胞の凝集を解離させた。PLL-ラミニン上で細胞を7日間培養し、その間一日おきに培養物にフィードした。
・42日目:培養物をパラフォルムアルデヒドで固定し、免疫組織化学法により細胞を特徴付けした。使用したマーカー:NeuN、ガラクトセレブロシド(GalC)、Map2、O4、ビメンチン、GFAP。
本実施例では、実施例1と同様の戦略にいくつかの改良点を加え、H7株由来のhES細胞を移植用のオリゴデンドロサイト前駆細胞に分化させた。GRMの処方は、プロゲステロン濃度を65 ng/mLに再検討する点以外は同様とした。EGFを初めから添加し、2日後にbFGFを除いた。
本実施例では、表4に示す手順に従ったhES株H7からのオリゴデンドロサイトの産生過程におけるマーカー発現を追跡する。
を再ミエリン化する
これらの細胞によってインビボで起こった髄鞘形成が(内因性オリゴデンドロサイトの誘導によるのではなく)直接的な効果であることを実証するため、分化手順の28日目の細胞を脱髄のシバラーマウスモデルに移植した。シバラーマウスは、染色体18に位置するミエリン塩基性タンパク質遺伝子の変異に関してホモ接合性である(Mbpshi/Mbpshi)。この遺伝子は重複しており、重複遺伝子の大部分が反転し、アンチセンスRNAの形成を引き起こす。これにより、CNSを通じて重篤なミエリン欠損が生じる。
ES由来オリゴデンドロサイト系譜細胞が神経活性を回復する能力を、脊髄損傷のラット挫傷モデルで判定した。
Claims (8)
- 塩基性線維芽細胞成長因子、甲状腺ホルモン受容体のリガンド、およびレチノイン酸受容体のリガンドを含む培地中で未分化ヒト胚性幹(hES)細胞を培養する段階を含む、未分化ヒト胚性幹(hES)細胞からグリア細胞を製造する方法。
- 前記ヒト胚性幹(hES)細胞が甲状腺ホルモンT3及びレチノイン酸を含む培地で培養される、請求項1記載の方法。
- 前記ヒト胚性幹(hES)細胞が甲状腺ホルモンT3及びセレンを含む培地で培養される、請求項1記載の方法。
- 細胞が懸濁状態で培養される、請求項1記載の方法。
- 細胞を固相表面にプレーティングし、表面に接着する細胞を回収することによって分離を行う、グリア細胞を非グリア細胞から分離する段階をさらに含む、請求項1から4のいずれか一項記載の方法。
- グリア細胞をマイトジェンの非存在下で培養することを更に含む、請求項1から5のいずれか一項記載の方法。
- 請求項1から6のいずれか一項記載の方法に従ってグリア細胞を製造する段階;
製造されたグリア細胞と化合物とを混合する段階;
前記化合物と混合したことに起因する、グリア細胞またはその活性の任意の変化を判定する段階;および
前記変化と化合物のグリア細胞に対する影響とを関連づける段階
を含む、グリア細胞に対する影響に関して化合物をスクリーニングする方法。 - 請求項1から6のいずれか一項記載の方法に従ってグリア細胞を製造する段階を含む、
中枢神経系の機能を改善するため、または脊髄損傷を治療するための薬物を製造する方法。
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GB2407822B (en) | 2006-02-22 |
JP2005532079A (ja) | 2005-10-27 |
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CA2489203A1 (en) | 2004-01-22 |
CN1852971B (zh) | 2013-06-12 |
GB2407822A (en) | 2005-05-11 |
HK1093219A1 (en) | 2007-02-23 |
JP5514756B2 (ja) | 2014-06-04 |
CN1852971A (zh) | 2006-10-25 |
CA2489203C (en) | 2014-03-11 |
AU2003250477A1 (en) | 2004-02-02 |
CN103396993A (zh) | 2013-11-20 |
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WO2004007696A2 (en) | 2004-01-22 |
US20040009593A1 (en) | 2004-01-15 |
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CN103396993B (zh) | 2018-12-07 |
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