JP5732011B2 - 非骨軟骨性の間葉組織由来の多能性細胞の同定および単離 - Google Patents
非骨軟骨性の間葉組織由来の多能性細胞の同定および単離 Download PDFInfo
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Description
本発明は、非骨軟骨性の間葉組織から単離され、および一連の細胞表面マーカーの有無を特徴とする、単離された多能性成体細胞に関する。本発明は、このような細胞の集団を同定および単離する方法、ならびにこの応用、例えば組織の修復および再生用の薬学的組成物の製造における適用にも関する。
幹細胞は、自身を維持すること、および1種類または複数の細胞のタイプに分化することが可能なために、差次的な特徴を示す。幹細胞、およびこの応用に関する研究は未だ初期段階にあるが、骨髄に含まれる成体幹細胞は30年以上にわたって移植に使用されている。このような状況であるにもかかわらず近年では、幹細胞技術は大きな進歩を遂げており、幹細胞は現在、組織の修復および再生のための治療における重要な可能性を秘めた、組織および器官の有望な供給源と見なされている。
ある局面では、本発明は、(a)非骨軟骨性の間葉組織から単離され;(b)CD9<+>、CD10<+>、CD13<+>、CD29<+>、CD44<+>、CD49a<+>、CD51<+>、CD54<+>、CD55<+>、CD58<+>、CD59<+>、CD90<+>、およびCD105<+>を発現し;ならびに(c)CD11b、CD14、CD15、CD16、CD31、CD34、CD45、CD49f、CD102、CD104、CD106、およびCD133の発現を欠く、以下、本発明の多能性成体細胞と記載する、単離された多能性成体細胞に関する。本発明の多能性成体細胞は、増殖する能力、およびさまざまな細胞系列に分化する能力を示す。特定の態様では、本発明の多能性成体細胞は、骨表現型細胞、筋肉表現型細胞、およびニューロン表現型細胞に分化可能である。
(a)非骨軟骨性の間葉組織を採取する段階;
(b)酵素による消化によって細胞懸濁物を得る段階;
(c)細胞を沈降させ、細胞を適切な培地に再懸濁する段階;ならびに
(d)細胞を培養し、結合を示さない細胞を除去する段階。
(a)細胞を、対象集団に特徴的な1つもしくは複数の特徴的なマーカーに特異的に結合する標識化合物と共にインキュベートする段階;および
(b)細胞と特異的に結合する化合物間の結合の有無を検出する段階。
(a)非骨軟骨性の間葉組織を採取する段階;
(b)酵素による消化で組織から細胞懸濁物を得る段階;
(c)細胞懸濁物を、対象集団に特徴的な1つもしくは複数の表面マーカーに特異的に結合する標識化合物と共にインキュベートする段階;および
(d)マーカーの発現プロファイルを有する細胞を選択する段階。
(a)ほぼ均質である、本発明の多能性成体細胞の細胞集団を単離する段階;
(b)細胞集団を培養して増殖させる段階;
(c)生物学的薬剤もしくは薬学的薬剤、またはこれらの薬剤のコンビナトリアルライブラリーを対象細胞集団に供し、およびこれらの薬剤の、培養細胞に対する効果を評価する段階。
非骨軟骨性の間葉組織(「軟部組織」)から、多能性成体細胞の限定的な集団を得るのに有用な同定法および単離法を設計する目的で、皮下脂肪組織から得られた、単離されて間もないヒト間葉細胞の表現型を解析し、および表面マーカーの変化を細胞増殖中にインビトロで、ならびにさまざまな細胞系列に分化する能力も検討した。
(a)非骨軟骨性の間葉組織を採取する段階;
(b)酵素による消化で細胞懸濁物を得る段階;
(c)細胞を沈降させ、細胞を適切な培地に再懸濁する段階;ならびに
(d)細胞を固体表面で培養し、固体表面への結合を示さない細胞を除去する段階。
(a)細胞を、対象集団の1つもしくは複数の特徴的なマーカーに特異的に結合する標識化合物と共にインキュベートする段階;および
(b)細胞と特異的に結合する化合物の結合の有無を検出する段階。
(a)非骨軟骨性の間葉組織を採取する段階;
(b)酵素による消化で組織から細胞懸濁物を得る段階;
(c)細胞懸濁物を、対象集団に特徴的な1つもしくは複数の表面マーカーに特異的に結合する標識化合物と共にインキュベートする段階;および
(d)マーカーの発現プロファイルを有する細胞を選択する段階。
(a)ほぼ均質である、本発明の多能性成体細胞の細胞集団を単離する段階;
(b)細胞集団を培養して増やす段階;
(c)生物学的薬剤もしくは薬学的薬剤、またはこれらの薬剤のコンビナトリアルライブラリーを、細胞集団に供し、および薬剤の培養細胞に対する作用を評価する段階。
軟部組織からの多能性成体細胞の単離、および表面マーカーの解析
軟部組織からの多能性成体細胞の単離を、細胞培養用のプラスチック容器に対する結合を示すことを特徴とする、増殖および分化の能力を有する細胞を選択することで実施した。次に細胞の特性を、単離されて間もない細胞、および培養発生中の細胞における一連の表面マーカーの発現をフローサイトメトリーでインビトロでモニタリングすることで解析した。
- インテグリン:CD11b、CD18、CD29、CD49a、CD49b、CD49c、CD49d、CD49e、CD49f、CD51、CD61、CD104。
- 造血系マーカー:CD3、CD9、CD10、CD13、CD14、CD16、CD19、CD28、CD34、CD38、CD45、CD90、CD133、およびグリコホリン。
- 増殖因子受容体:CD105、NGFR。
- 細胞外基質受容体:CD15、CD31、CD44、CD50、CD54、CD62E、CD62L、CD62P、CD102、CD106、CD166。
- その他:CD36、CD55、CD56、CD58、CD59、CD95、HLA-I、HLA-II、β2-ミクログロブリン。
1.1つの試料と他の試料間で、または培養中に経時的に変化するマーカーは除外する。
2.陽性細胞が、ゼロ時間(単離されて間もない細胞)でも陽性であることを検証する。
3.生物学的重要性の関数として選択し、特異的な細胞のタイプに特徴的なマーカーは除外する(例えばCD3はリンパ球に限定的なマーカーである)。
ヒト非骨軟骨性の間葉組織に由来する多能性成体細胞の骨表現型細胞へのインビトロ分化
分化アッセイ法では、特徴が明らかにされた本発明のヒト多能性成体細胞を使用した。細胞は、それぞれ健康なドナーに対応する、解析済みの脂肪吸引物の3つの試料から単離した(実施例1)。多能性成体細胞を、実施例1に記載された手順で単離し、および解析した。ヒト骨髄に由来する間葉幹細胞(MSC)の試料を正の対照として使用した。
- デキサメタゾン 100 M
- アスコルビン酸 50μM
- p-グリセロリン酸 10 mM
ヒト非骨軟骨性の中胚葉性組織に由来する多能性成体細胞の筋肉表現型細胞へのインビトロ分化
分化アッセイ法では、特徴が明らかにされた本発明のヒト多能性成体細胞を使用した。細胞は、それぞれ健康なドナーに対応する、解析済みの脂肪吸引物の3つの試料から単離した(実施例1)。多能性成体細胞を、実施例1に記載された手順で単離し、および解析した。ヒト骨髄に由来するMSCの試料を正の対照として使用した。
- アスコルビン酸-2-リン酸 0.1 mM
- デキサメタゾン 0.01μM
- ITS+1(Sigma-Aldrich)
- 5-アザシチジン 3μM
ヒトの非骨軟骨性の間葉組織に由来する多能性成体細胞のニューロン表現型細胞へのインビトロ分化
分化アッセイ法では、特徴が明らかにされた本発明のヒト多能性成体細胞を使用した。細胞は、それぞれ健康なドナーに対応する、解析済みの脂肪吸引物の3つの試料から単離した(実施例1)。多能性成体細胞を、実施例1に記載された手順で単離し、および解析した。ヒト骨髄に由来するMSCの試料を正の対照として使用した。
- αMEM
- BHA 200μM
- ペニシリン/ストレプトマイシン
- L-グルタミン 2 mM
- フォルスコリン 10μM
- 2% DMSO
- ヒドロコルチゾン 1μM
- インスリン 5μg/ml
- CIK 25 mM
- バルプロ酸 2 mM
Claims (6)
- (a)脂肪組織から単離され、(b)CD9<+>、CD10<+>、CD13<+>、CD29<+>、CD44<+>、CD49A<+>、CD51<+>、CD54<+>、CD55<+>、CD58<+>、CD59<+>、CD90<+>、およびCD105<+>を発現し;ならびに(c)CD11b、CD14、CD15、CD16、CD31、CD34、CD45、CD49f、CD102、CD104、CD106、およびCD133の発現を欠く、
多能性成体細胞を含み、実質的に均質な、連続的に継代された、単離された細胞集団。 - 以下の段階を含む方法で単離される、請求項1記載の細胞集団:
(a)脂肪組織を採取する段階;
(b)酵素による消化で細胞懸濁物を得る段階;
(c)培地中の細胞を沈降させ、再懸濁する段階;
(d)細胞を固体表面上で培養し、固体表面への結合を示さない細胞を除去する段階;ならびに
(e) 細胞を連続的に継代して増殖させる段階。 - 請求項1もしくは2に記載の細胞集団、および薬学的に許容される担体を含む、薬学的組成物。
- 治療で使用するための、請求項1もしくは2に記載の細胞集団。
- 組織の修復および再生に使用するための、請求項1もしくは2に記載の細胞集団。
- 組織の修復および再生のための薬学的組成物の製造を目的とする、請求項1もしくは2に記載の細胞集団の使用。
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CA2583151C (en) | 2015-09-15 |
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SI2292736T1 (sl) | 2015-05-29 |
US20170296585A1 (en) | 2017-10-19 |
EP1812558A1 (en) | 2007-08-01 |
ES2313805B1 (es) | 2009-12-23 |
WO2006037649A1 (en) | 2006-04-13 |
IL182441A0 (en) | 2007-07-24 |
SG192459A1 (en) | 2013-08-30 |
US20070248580A1 (en) | 2007-10-25 |
HUE025155T2 (en) | 2016-03-29 |
KR20070085294A (ko) | 2007-08-27 |
JP2008515413A (ja) | 2008-05-15 |
CN101056974A (zh) | 2007-10-17 |
CN101056974B (zh) | 2015-11-25 |
EP3342857A1 (en) | 2018-07-04 |
PT2292736E (pt) | 2015-04-29 |
US20060073124A1 (en) | 2006-04-06 |
AU2005291353A1 (en) | 2006-04-13 |
EP2292736B1 (en) | 2015-01-21 |
CA2583151A1 (en) | 2006-04-13 |
PL2292736T3 (pl) | 2015-07-31 |
EP3165601A1 (en) | 2017-05-10 |
IL182441A (en) | 2015-08-31 |
DK2292736T3 (en) | 2015-04-20 |
US10729726B2 (en) | 2020-08-04 |
EP2862925A1 (en) | 2015-04-22 |
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