JP2022501045A - ヒト多能性成人幹細胞 - Google Patents
ヒト多能性成人幹細胞 Download PDFInfo
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Abstract
Description
本出願は、米国特許法に基づく利益を主張するものである。2018年9月21日に出願された米国仮出願シリアル番号62/734,740の§119(e)の内容は、参照により全体として本開示に組み込まれている。
Sambrook and Russell eds. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition;
the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology;
the series Methods in Enzymology (Academic Press, Inc., N.Y.);
MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press);
MacPherson et al. (1995) PCR 2: A Practical Approach;
Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual;
Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition;
Gait ed. (1984) Oligonucleotide Synthesis;
U.S. Patent NO. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization;
Anderson (1999) Nucleic Acid Hybridization;
Hames and Higgins eds. (1984) Transcription and Translation;
Immobilized Cells and Enzymes (IRL Press (1986));
Perbal (1984) A Practical Guide to Molecular Cloning;
Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory);
Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London);
Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edition (Cold Spring Harbor Laboratory Press (2002));
Current Protocols In Molecular Biology (F. M. Ausubel, et al. eds., (1987));
the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995));
Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual;
Harlow and Lane, eds. (1999) Using Antibodies, A Laboratory Manual;
Animal Cell Culture (R.I. Freshney, ed. (1987));
Zigova, Sanberg and Sanchez-Ramos, eds. (2002) Neural Stem Cells.
別途定義されない限り、本明細書において使用されるすべての技術的および科学的用語は、本開示が属する技術分野の当業者により一般に理解されるのと同一の意味を有する。本明細書において使用されるように、以下の用語は、以下の意味を有する。
研究者たちは長い間、臨床応用の可能性を秘めた多能性幹細胞の供給源を、ヒト成人組織から探している。本発明は、比較的小さなサイズの初期段階の前駆体の集団を、ヒト成人組織から単離できることを示すものである。これらの初期段階の前駆体は、活性化/発達を経て、ヒト多能性幹細胞になることができる。細胞の多能性は、3つの胚葉すべてに分化する能力によって実証されている。さらに、本明細書で開発された新たな活性化/発達システムにより、ヒト多能性幹細胞を取得して、in vitroで拡張することができる。さらに、ヒト成人組織から由来する多能性幹細胞は、倫理的・政治的に問題視されることもなく、遺伝子操作も必要としない。さらに、本技術のもう一つの利点は、ヒト多能性幹細胞が非腫瘍化であることが実証されたことである。従って、本開示の技術は、組織損傷や慢性疾患、加齢関連疾患を治療するための実用的な細胞ベースの治療への道を開くものである。
初期段階の前駆体の単離した集団をin vitroでの活性化/発達を促進するために、活性化/発達システムが確立されている。
活性化された幹細胞集団および/またはその様々な分集団は、本明細書で開示された初期段階の前駆体に由来し、その多能性、例えば、適切な培養条件および培地を用いて3つの胚葉(外胚葉、中胚葉および内胚葉)のすべての細胞型に分化する能力によって識別することができる。細胞の分化状態の確認は、当業者に知られているように、細胞型特定マーカの同定によって行うことができる。
本開示は、本明細書に開示された初期段階の前駆体に由来する活性化された幹細胞を用いて、それを必要とする被験者の疾患を治療する方法を提供する。いくつかの実施形態において、本明細書に開示されている初期段階の前駆体に由来する、活性化された幹細胞集団における1または複数の分集団を用いて、それを必要とする被験者の疾患を治療する方法が提供される。いくつかの実施形態において、本明細書に開示されている初期段階の前駆体に由来する活性化された幹細胞に由来する、分化した細胞を用いて、それを必要とする被験者の疾患を治療する方法が提供される。再生医療は、損傷細胞、組織または臓器の修復、置換または再生を助けるために設計された治療法治療法を含む。本明細書で開示されている方法は、再生医療における細胞ベースの治療に使用する可能性がある。
実施例1:ヒト成人組織からの初期段階の前駆体の単離
ヒト成人組織から初期段階の前駆体を単離するために、以下の方法が使用された。試験されたヒト成人組織には、ヒト末梢血、臍帯血、骨髄および臍帯などが含まれる。一実験では、ヒト末梢血は、カリフォルニア州スタンフォードのスタンフォード血液センタで採取された。すべての献血者は、書面によるインフォームド・コンセントを提供した。ヒト末梢血5−10mlをリチウムヘパリンチューブ(BD diagnostics社)に採取し、4℃で保存した。別の実験では、産科で分娩時に臍帯血を採取し、4℃で保存した。臍帯組織も採取し、4℃で保存した。別の実験では、ヒト初期段階の前駆体を単離するために骨髄を採取した。他のヒト組織サンプルもうまく利用できた。
上記の実施例1に記載されているように、ヒト成人組織から得られた初期段階の前駆体の活性化/発達を促進するために、以下の方法を用いた。ヒト初期段階の前駆体をin vitroで活性化・培養するための活性化/発達システムを開発した。
ヒト成人組織から得られた初期段階の前駆体を含む比較的小さな細胞の集団を培養すると、細胞融合が観察された。ヒト初期段階の前駆体を含む細胞ペレットを、1mlの50%PEG1500に穏やかに再懸濁し、室温で2分間インキュベートした。次に1mlの無血清α−MEMを緩慢に加え、室温で細胞を30分間インキュベートした。次に、懸濁液を3,000〜15,000xgで4℃で10分間遠心分離した。上清液を除去し、細胞ペレットを穏やかに再懸濁し、活性化/発達システムで培養した。
細胞培養で初期段階の前駆体の活性化/発達を促進するために、活性化/発達システムを調製した。このシステムでは、初代肝細胞および/または肝細胞株の細胞、またはそれらの細胞混合物、およびその他の試薬および因子を含む培地が採用された。活性化/発達システムは、トランスウェルを用いた共培養システムであってもよく、後述の馴化培地を用いてもよい。
上記実施例2に記載した活性化された幹細胞における増殖マーカ、成長因子およびサイトカインの発現レベルを以下の方法を用いて評価した。RT−PCRを用いて、Cyclin D−1およびc−Mycを含む増殖マーカ、トランスフォーミング成長因子β(TGF−β)、血管内皮成長因子(VEGF)、肝細胞成長因子(HGF)、IL−6およびIL10を含む成長因子およびサイトカインの発現レベルを検出した。内部対照としてGAPDHを用いた。また、成長因子およびサイトカインのレベルをIFなどの方法で評価した。その結果、活性化された幹細胞の集団は、増殖マーカであるCyclin D1やc−Myc、VEGF、TGF−β、HGF、IL−6、IL10などの成長因子およびサイトカインを発現した。活性化された幹細胞はHLA−ILow/HLA−II−であり、免疫原性が低いことを示している。その結果、活性化された幹細胞の集団は、アルブミンとAFP(内胚葉特定マーカ)、オステオカルシンとデスミン(中胚葉特定マーカ)、ネスチン(外胚葉特定マーカ)を発現しており、活性化された幹細胞が多能性を持つ可能性をさらに示した。
実施例2で調製した活性化された幹細胞の集団を用いて、以下の方法で皮膚傷を治療した。
フィブリノゲンとトロンビンのストック溶液を解凍し、最終濃度12.5mg/mlのフィブリノゲンと2.5U/mlのトロンビンにCaCl2(最終濃度45mM)を加えて1.5mlチューブに入れて一緒に混合し、フィブリンゲルを作製した。混合物の200μlを24ウェルプレートに穏やかにピペッティングした。このフィブリノゲン含有物を、37℃で2時間かけてフィブリンゲルスカフォールドを形成させた。実施例2で調製した活性化された幹細胞を、24ウェルプレートまたは48ウェルプレートの1ウェルあたりフィブリンゲルスカフォールドの上に2.5×105個播種し、1ウェルあたり0.5mlまたは1mlの馴化培地で一晩培養した。このようにして作られた細胞/スキャフォールドの3次元構造体は、次の移植の準備が整った。別の方法では、活性化された幹細胞をフィブリノゲン、トロンビンおよび馴化培地と予め混合した後、24ウェルプレートまたは48ウェルプレートに播種した。フィブリンゲルが形成された後(例えば、約2時間後)、0.5または1mlの馴化培地を各ウェルに加え、細胞/スキャフォールドの3次元構造体を一晩培養すると、移植の準備が整う。また、実験の前にフローサイトメトリを行い、細胞/スキャフォールドの3次元構造体の中で培養された細胞の特徴を調べた。
皮膚を準備した後、10−12週齢の免疫不全(ヌード)オスマウス(Simonsen Labs)10匹に、イソフルラン麻酔下で中背皮に直径6mmの全層パンチバイオプシ傷をつけた。傷口の収縮を抑制するために,厚さ1.6mmのシリコーンシート(Press−to−Seal Silicone Sheet JTR−S−2.0,Grace Bio−Labs,Bend,OR)で作製したドーナツ型のスプリント(内径10mm、外径14mm)を創傷部の周囲に配置し,6−0ナイロン縫合糸(6−0 Ethilon Nylon Suture,Ethicon LLC.,Cornelia,GA)を用いて8本の断続的な縫合糸で固定した。次に、上述の細胞/スキャフォールドの3次元構造体(約250,000細胞/構造体)を創傷床に移植した(n=5)。また、幹細胞を含まないフィブリンゲル(スキャフォールドのみ)を対照として創傷床に移植した(n=5)。傷口を覆うために、トリミングされた無菌Tegaderm透明フィルムドレッシング(3M)をスプリントの上部に貼り付けた。
傷口の写真画像を、傷口ができてから毎日、一定の距離からデジタルカメラで撮影した。傷口面積を総体的に評価するために、元の傷口面積に対する現在の傷口の割合を計算して、傷口面積を解析した。傷口が完全に閉じたと考えられるのは、傷口面積が総じてゼロになったときである。
糖尿病マウス(db/db、Jackson Labs)を用いて、上述の細胞/スキャフォールドの3次元構造体の創傷治癒効果を研究した。皮膚の準備後、6ヶ月以上の糖尿病マウス10匹(体重60〜80g)を用いて、イソフルラン麻酔下で中背皮に慢性創傷を生成させた。次に、上述の細胞/スキャフォールドの3次元構造体(約250,000細胞/構造体)を創傷床に移植した(n=5)。また、幹細胞を含まないフィブリンゲル(スキャフォールドのみ)を対照として創傷床に移植した(n=5)。傷口の写真画像は、傷口ができてから毎日撮影し、上述のように評価した。治療後65日目(D65)に糖尿病マウスをCO2で安楽死させた。前述のとおり、皮膚の創傷部分と周辺組織を採取し、組織学的分析と治療効果の評価を行った。
実施例2で調製した活性化された幹細胞の創傷治癒においての治癒可能性を研究するために、3次元細胞/スキャフォールドの構造体を作製し、免疫不全マウスの全層皮膚創傷に適用した。活性化された幹細胞を予めフィブリンゲルに播種し(またはフィブリンゲルに予め混合し)、移植前に一晩培養したところ、細胞はしっかりと成長し、フィブリンゲル上でコンフルエントな状態を示した。
Claims (20)
- (1)少なくとも一部分の赤血球を血液サンプルから除去することと、
(2)3,000xg−15,000xgでサンプルを遠心分離してペレットを取得することと、
(3)ペレット内の細胞を溶液に懸濁させることと、
(4)CD49f+細胞を溶液中で濃縮することと
を備えて、前記溶液中の前記細胞の少なくとも40%が、CD49fを発現し、6μm未満の直径を有するCD49f+細胞である
細胞集団を調製する方法。 - 前記サンプルを5,000xg超で遠心分離する、請求項1に記載の方法。
- 前記サンプルを7,000xg超で遠心分離する、請求項1に記載の方法。
- 前記CD49f+細胞が、さらにSSEA4に陽性である、請求項1から3のいずれか一項に記載の方法。
- 前記CD49f+細胞が、さらにABCG2およびLinに陰性である、請求項1から4のいずれか一項に記載の方法。
- 前記CD49f+細胞が、さらにCD73およびCD45に陽性であって、CD4およびLin28に陰性である、請求項1から4のいずれか一項に記載の方法。
- 前記CD49f+細胞が、Oct4、Nanog、CD31、CD117、およびCD105からなる群から選択される1または複数のマーカをさらに発現する、請求項1から6のいずれか一項に記載の方法。
- 前記CD49f+細胞が、CD3、CD4、CD8、CD11b、およびCD41からなる群から選択される1または複数のマーカを発現しない、請求項1から7のいずれか一項に記載の方法。
- 前記溶液中の前記細胞の20%未満が、赤血球である、請求項1から8のいずれか一項に記載の方法。
- 前記CD49f+細胞の直径が5μm未満である、請求項1から9のいずれか一項に記載の方法。
- 前記CD49f+細胞は、核と細胞質の比率(v/v)が、少なくとも約9:1である、請求項1から10のいずれか一項に記載の方法。
- 細胞の少なくとも40%が、CD49fを発現し、6μm未満の直径を有するCD49f+細胞である、
少なくとも1000個の前記細胞を含む、組成物。 - 前記CD49f+細胞は、さらにSSEA4に陽性である、請求項12に記載の組成物。
- 前記CD49f+細胞は、さらにABCG2およびLinに陰性である、請求項12または13に記載の組成物。
- 前記CD49f+細胞は、さらにCD73およびCD45に陽性であって、CD4およびLin28に陰性である、請求項12から14のいずれか一項に記載の組成物。
- 前記CD49f+細胞が、Oct4、Nanog、CD31、CD117、およびCD105からなる群から選択される1または複数のマーカをさらに発現する、請求項12から15のいずれか一項に記載の組成物。
- 前記CD49f+細胞が、CD3、CD4、CD8、CD11b、およびCD41からなる群から選択される1または複数のマーカを発現しない、請求項12から16のいずれか一項に記載の組成物。
- 前記CD49f+細胞は、核と細胞質の比率(v/v)が、少なくとも約9:1である、請求項12から17のいずれか一項に記載の組成物。
- 前記CD49f+細胞が、1または複数の因子を含む培地によって活性化され、活性化された細胞がABCG2を発現する、請求項12から18のいずれか一項に記載の組成物。
- (a)直径が6μm未満であり、(b)CD49fを発現し、および(c)ABCG2を発現しないヒト細胞の集団に由来する幹細胞の集団であって、前記幹細胞の集団が、ABCG2を発現し、異種細胞の集団である、幹細胞の集団。
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AU (2) | AU2019345279B2 (ja) |
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US20210380937A1 (en) * | 2017-04-04 | 2021-12-09 | The Board Of Trustees Of The Leland Stanford Junior University | Preparation , expansion, and uses of adult pluripotent stem cells |
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CN112739208A (zh) | 2021-04-30 |
AU2023200406A1 (en) | 2023-02-23 |
IL281574A (en) | 2021-05-31 |
AU2019345279B2 (en) | 2022-10-27 |
EP3852527A1 (en) | 2021-07-28 |
US11845956B2 (en) | 2023-12-19 |
US20240076610A1 (en) | 2024-03-07 |
AU2019345279A1 (en) | 2021-04-15 |
EP3852527A4 (en) | 2022-11-02 |
JP7329265B2 (ja) | 2023-08-18 |
WO2020061557A1 (en) | 2020-03-26 |
JP2023129719A (ja) | 2023-09-14 |
CA3113255A1 (en) | 2020-03-26 |
US20200095545A1 (en) | 2020-03-26 |
SG11202102737XA (en) | 2021-04-29 |
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