JP2017046702A - 体性幹細胞 - Google Patents
体性幹細胞 Download PDFInfo
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- JP2017046702A JP2017046702A JP2016197477A JP2016197477A JP2017046702A JP 2017046702 A JP2017046702 A JP 2017046702A JP 2016197477 A JP2016197477 A JP 2016197477A JP 2016197477 A JP2016197477 A JP 2016197477A JP 2017046702 A JP2017046702 A JP 2017046702A
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Abstract
Description
本願は、2010年8月4日に出願された米国仮特許出願第61/370,600号;2010年9月17日に出願された米国仮特許出願第61/383,842号;および2011年2月25日に出願された米国仮特許出願第61/446,669号の優先権を主張する。これらの先の出願は、全体を参考で本明細書中に引用される。
幹細胞は、多くのまたは全ての細胞系にインビボでまたはインビトロで分化できる多能性または全能性細胞である。これらの多能性により、胚性幹(ES)細胞は、変性または遺伝性疾患を治療するのにかなり有望であると考えられる。しかし、倫理的配慮がヒトのES細胞の使用を妨げている。非胚起源の幹細胞がこの障害を回避するであろう。ゆえに、非胚性幹細胞の必要性が存在する。
本発明は、多能性または全能性である、体性幹細胞、および関連方法に関する。
本発明は、少なくとも一部は、(i)多能性または全能性幹細胞集団、即ち、SB細胞集団が、細胞を含まないと考えられていたサンプルから単離できること、(ii)2価カチオンキレート剤(例えば、EDTA)がこの集団の多能性または全能性幹細胞を活性化し、これらの分化能を失わせることなく増殖させること;および(iii)この多能性または全能性幹細胞の集団が外胚葉、内胚葉、及び中胚葉に分化できるという予想できない知見に基づくものである。この集団のSB−1細胞はCD9に関して陽性に染色され、この集団のSB−2細胞はSSEA1+、SSEA4+、CD13+、及びStro1+の1以上について陽性に染色される。SB細胞集団、SB−1細胞、及びSB−2細胞は、ヒトからまたは非ヒトのいずれから単離されてもよい。上記体性幹細胞が得られる、非ヒトの例としては下記がある:霊長類、イヌ、齧歯動物、モルモット、ネコ、ウマ、ウシ、ヒツジ、及びブタ。換言すると、これらは、以下に制限されないが、ペット動物、家畜動物、実験動物、及び疾患モデル動物が挙げられる。
本発明は、SB細胞集団、非胚起源から調製される多能性または全能性幹細胞の集団に関する。ES細胞と同様、この集団の細胞は、全能性または多能性である。より重要なことでは、この集団は、非常に高い収率で容易に得られる。したがって、これを用いて、様々な変性疾患または組織損傷を治療する際の分化、機能性細胞を再生できる。下記実施例に示されるように、上記集団は、インビトロで容易に調製、維持及び拡張でき、さらに通常の技術的アプローチを用いて分化するように誘導できる。加えて、上記集団の幹細胞を動物被検者(例えば、マウス)に移植した後には、悪性腫瘍の証拠はない。正常な染色体対を含むと、これらの幹細胞は細胞系中立(lineage-uncommitted)であり、体の全ての体(非生殖)細胞を形成できる。上記幹細胞はまた、生殖配偶子である精子および/または卵子、ならびに胎盤の胚及び胎児部分の細胞や組織を形成できる。これらの幹細胞は、系統誘導剤(lineage-induction agent)、増殖剤(proliferation agent)、および分化抑制剤(differentiation inhibitory agent)に応答性である。これらの利点により、上記幹細胞は、他の幹細胞の代わりになる。
例えば、SB−1細胞を含む、上記SB細胞集団は、様々な様式で使用できる。
SB細胞集団における上記幹細胞は、薬剤が細胞タイプに関連する疾患を治療するのに有用であることを示す形で特定の細胞タイプに影響を及ぼすことができる薬剤を同定するためのスクリーニングアッセイに使用することができる。例えば、病気(例えば、変性疾患)を治療するための薬剤候補を同定する方法に幹細胞を使用することができる。本方法は、試験化合物を幹細胞を接触させ、その病気でダウンレギュレートするポリペプチドの発現レベルを測定する工程を含む。試験化合物の存在下での発現レベルが、その化合物の不存在下でのレベルに比べて高ければ、その化合物はその病気を治療するための候補であることが示される。このような病気の例としては、糖尿病、神経変性疾患、関節炎、癌、または自己免疫疾患がある。発現レベルは、mRNAレベルでまたはタンパク質レベルでのいずれかで測定されうる。
または、試験物質は、受動的にまたは活性トランスポーターメカニズムによりのいずれかで、細胞膜を通過して、機能を変化させるように細胞内で作用するものであってもよい。
本明細書に開示されるSB細胞集団の幹細胞を、ヒト胚操作の道徳的配慮をさけて、変性または遺伝性疾患の治療に使用できる。
本明細書に記載される幹細胞は、外来の、組み換えポリペプチドを発現させるために使用できる。したがって、組換核酸を含むこのような幹細胞は、本発明の範囲に含まれる。組換核酸は、ポリペプチドをコード化してもよく、幹細胞は上記ポリペプチドをコード化するmRNAを含んでもよい。
本発明は、異なる幹細胞系に簡便に系統的にアクセスするための幹細胞バンクまたはライブラリーを特徴とする。バンクまたはライブラリーのSB細胞集団は、健常な被検者または利用者、例えば、研究者に有益であろう既知の病態または病気の症状を有する被検者由来である。また、上記幹細胞から分化した細胞を有する細胞バンクまたはライブラリーもまた、本発明の範囲に含まれる。幹細胞から分化した細胞の例としては、脳細胞、神経、星状膠細胞、グリア細胞、T細胞、B細胞、軟骨細胞、骨細胞、膵島細胞、脂肪細胞、心臓細胞、肝細胞、腎細胞、肺細胞、筋細胞、および眼細胞が挙げられる。被検者は、ヒトまたは非ヒト脊椎動物であってもよい。幹細胞は、ヒト、マウス、ウサギ、ウシ、ブタ等の、いずれの哺乳動物器官由来であってもよい。
特定の実施形態では、本発明は、幹細胞集団が病気の症状を有する被検者から得られる幹細胞を含む幹細胞バンク化システムを特徴とする。上記病気の症状としては、上記変性疾患がある。SB細胞集団を異なる病気を有する異なる被検者から集め、幹細胞の特性を明らかにする。特性(複数の特性)をデータベースコンピューターに入力する。加えて、または代わりに、細胞の特徴を、病気の症状に必ずしも関連しない特定の表現型に基づいて明らかにする。例えば、肝臓胞の特性は、異なる代謝能の遺伝的基礎、またはこれに関連する基本的な生理機能を研究するために、カフェイン、アルコール、薬剤等の特定の化合物の代謝能に基づいて明らかにすることができる。他の細胞型は、機能的および/または形態学的表現型に基づいて特徴付けることができる。
上記幹細胞は、遺伝子操作して、移植を目的とした組織適合性ドナー細胞または組織を作製してもよい。移植及び細胞治療の目的は、機能不全の(failing)組織または器官を機能性ドナー組織または器官にうまく置換することである。しかしながら、移植を成功させるためには、以下の2つの主要な障壁を克服する必要がある:適切なドナー組織または器官の入手可能性及び免疫拒絶。機能不全の組織または器官の置換および拒絶の治療は、限られた数の許容できるドナーおよび毒性のある免疫抑制剤及び長期間の免疫抑制プロトコールを組み合わせて一緒に投与する必要があることによって、限定される。現在の実験的な移植プロトコールは、主に、同胞ドナー、他の少数の(small pools of)同種異系ドナー、及び異種ドナーに依存している。上記遺伝子操作された幹細胞を用いれば、これらの限定を克服できる。
本発明は、上記細胞または活性薬剤/化合物を含む薬剤組成物を提供する。薬剤組成物は、治療上有効な量の細胞または活性薬剤/化合物、および、必要であれば他の活性物質を、製薬上許容できる担体と混合することによって調製できる。担体は、投与経路によって、様々な形態を有しうる。他の活性物質の例としては、既知のまたは上記のスクリーニング方法によって同定される活性化合物が挙げられる。
本明細書に開示される幹細胞及び方法は、被検者を評価するのに使用できる。通常、若い健常な被検者は、幹細胞(SSEA4+細胞、CD66e+/BLSCs、またはCD9+/SB−1細胞)の割合(%)が比較的より高い。下記実施例4で討論されるように、これらの細胞の数または割合(%)は、被検者の年齢に比例してまたは遺伝子異常若しくは望ましくない環境因子への暴露により減少する。この減少により、損傷後の組織の修復能等の、被検者の幹細胞が関連する能力が低下する。
血液サンプルまたは骨髄サンプルをヒトから採取し、抗凝固EDTAチューブまたはヘパリンチューブに入れた。チューブを4℃で6〜48時間攪拌した後、サンプルは2層に分かれた。上層は、SB細胞集団を含み、これをさらにC6 accuriフローサイトメトリー、免疫細胞化学、及びRNA抽出/RT−PCRによって分析した。下層は、6.0μm以上の大きさである、赤血球及び白血球を含んだ。
アッセイを行ったところ、上記指摘されるように、増殖するSB細胞は異なる細胞系に分化できる幹細胞であることが示された。
SB−1細胞を含む、SB細胞集団の幹細胞への2価カチオンキレート剤であるEDTAの役割を試験するために、アッセイを行った。
以下で述べるように、SB細胞集団の細胞数を測定することを用いることによって、加齢に関連する疾患または癌を有する被検者の危険性を評価できる。
In vivoでの細胞追跡アッセイにおいて、ヒト骨髄サンプルから単離された、SB細胞集団由来の106個の細胞を、SCIDマウスの尾静脈に注射した(実験SCIDマウス)。コントロールとして、PBSをSCIDマウスの尾静脈に注射した(コントロールSCIDマウス)。30、60、及び90日後、骨髄、血液、及び筋肉を実験及びコントロールSCIDマウス双方から集めた。マウスの骨髄サンプルをフローサイトメトリーを用いて分析した。結果から、MSCマーカー(即ち、ヒトCD105、EGFレセプター、Stro1、及びCXCR1)、BLSCマーカー(即ち、CEA)、および微小胚性様幹細胞(VSEL)マーカー(即ち、CD133)が実験SCIDマウスでは検出されたが、コントロールSCIDマウスでは検出されなかったことが示される。これらの結果から、BLSC、VSEL、及びMSCがSB細胞集団の幹細胞の下流にあることが示唆される。加えて、マウスの筋肉サンプルから抽出されたRNAをRT−PCRによって分析した。ヒト筋原因子4(myogenic factor 4)、SM22、Pax7、及びGAPDHがリアルタイムRT−PCRによって検出された。リアルタイムRT−PCRで筋肉マーカーを検出するのに使用された全てのプライマーを以下に列挙する。
本明細書に開示されるすべての特徴は、いずれの組み合わせで組み合わされてもよい。本明細書に開示される各特徴は、同じ、等価の、または同様の目的に適う別の特徴に置換されてもよい。ゆえに、特記しない限り、開示される各特徴は、一連の等価のまたは同様の特徴の一例であるのみである。
Claims (34)
- 0.3〜6.0μmの大きさを有し、CD9+である、単離された体性幹細胞。
- 該単離された体性幹細胞が多能性であるまたは全能性である、請求項1に記載の単離された体性幹細胞。
- 前記細胞がヒト細胞である、請求項1または2に記載の単離された体性幹細胞。
- 前記細胞が非接着性である、請求項1〜3のいずれか1項に記載の単離された体性幹細胞。
- 前記細胞がCD9+CD349+である、請求項1〜4のいずれか1項に記載の単離された体性幹細胞。
- 0.3〜6.0μmの大きさを有し、SSEA1+、SSEA4+、CD13+、またはStro1+である、単離された体性幹細胞。
- 該単離された体性幹細胞が多能性であるまたは全能性である、請求項6に記載の単離された体性幹細胞。
- 前記細胞がヒト細胞である、請求項6または7に記載の単離された体性幹細胞。
- 前記細胞が非接着性である、請求項6〜8のいずれか1項に記載の単離された体性幹細胞。
- 被検者から複数の細胞を含む体液サンプルを得、
前記サンプルが上層及び下層に分かれるまで前記サンプルを容器中でEDTAまたはヘパリンとインキュベートし、
上層を収集し、さらに
前記上層から0.3〜6.0μmの大きさを有する体性幹細胞の集団を単離することを有する、体性幹細胞の集団の調製方法。 - 前記体液サンプルが血液または骨髄サンプルである、請求項10に記載の方法。
- 前記被検者がヒトである、請求項10または11に記載の方法。
- 前記単離が遠心、フローサイトメトリー、または濾過によって行われる、請求項10〜12のいずれか1項に記載の方法。
- 前記収集後、前記収集後前記上層をADPとインキュベートすることをさらに有する、請求項10〜13のいずれか1項に記載の方法。
- 前記インキュベートが、前記サンプルをヘパリンとインキュベートし、前記収集後であって前記単離前に、収集された上層をさらにEDTAとインキュベートすることによって、行われる、請求項10〜14のいずれか1項に記載の方法。
- 請求項10〜15のいずれか1項に記載の方法によって調製される体性幹細胞の集団。
- 前記体性幹細胞がCD9+である、請求項16に記載の集団。
- 前記体性幹細胞がCD9+CD349+である、請求項17に記載の集団。
- 前記体性幹細胞がSSEA1+、SSEA4+、CD13+、またはStro1+である、請求項16に記載の集団。
- 前記集団が被検者から得られた血液または骨髄サンプル中に存在する、請求項16〜19のいずれか1項に記載の集団。
- 前記被検者がヒトである、請求項16〜20のいずれか1項に記載の集団。
- 前記体性幹細胞が非接着性である、請求項16〜21のいずれか1項に記載の集団。
- 請求項10〜15のいずれか1項に記載の方法によって異なる被検者の血液または骨髄サンプルから調製される複数の体性幹細胞の集団を有する細胞バンク。
- 2価カチオンキレート剤をサンプルに添加し、さらに
サンプル中の幹細胞を前記2価カチオンキレート剤とインキュベートすることを有する、サンプルに含まれる幹細胞の数の増加方法。 - 前記2価カチオンキレート剤がEDTAまたはEGTAである、請求項24に記載の方法。
- 前記幹細胞が0.3〜6.0μmの大きさを有する、請求項24または25に記載の方法。
- 前記幹細胞がCD9+である、請求項26に記載の方法。
- 請求項10〜15のいずれか1項に記載の方法によって、被検者から、それぞれが0.3〜6.0μmの大きさを有する、体性幹細胞の集団を得、さらに
前記体性幹細胞の数を測定することを有する、加齢に関連する疾患(ageing-related disorder)または癌を有する危険性に関する被検者の評価方法であって、
前記被検者は、前記数が第一の所定の値未満であると前記疾患を有する危険性があるとまたは前記数が第二の所定の値を超えると癌を有する危険性があると決定される、方法。 - 前記体性幹細胞がCD9+、CD349+、SSEA1+、SSEA4+、CD13+、またはStro1+である、請求項28に記載の方法。
- ヘパリンをインキュベート工程で使用して、体性幹細胞の集団を得る、請求項28または29に記載の方法。
- 前記加齢に関連する疾患が、自己修復欠損症(self-repair defect)、変性疾患、自己免疫疾患、心血管疾患、または糖尿病である、請求項28〜30のいずれか1項に記載の方法。
- 請求項10〜15のいずれか1項に記載の方法によって調製される体性幹細胞を含む、被検者における体性幹細胞の数の増加のための薬剤。
- 請求項10〜15のいずれか1項に記載の方法によって調製される体性幹細胞を含む、筋損傷疾患(muscle injury disease)または筋肉変性疾患(muscle-degenerative disease)の治療のための薬剤。
- 前記筋肉変性疾患(muscle-degenerative disease)が、筋ジストロフィー、線維筋痛、ミオパシー、皮膚筋炎、多発性筋炎、横紋筋融解症、または心筋炎である、請求項33に記載の薬剤。
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