JP2018064550A - 幹細胞からエクソソームを生成する方法およびその使用 - Google Patents
幹細胞からエクソソームを生成する方法およびその使用 Download PDFInfo
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Abstract
Description
本出願は、2016年7月11日に出願された台湾出願第105121824号の優先権を主張し、その全体が参照により本明細書に組み込まれる。
また、特許文献1について、神経幹細胞株からのエクソソームが、生体内での神経の修復を高める、または、脳の記憶力および認識力を促進しつつ、PC−12細胞の非幹細胞状態または非幹細胞の変調に何らかの効果をもたらすことを示すデータはない。
さらに、非特許文献3について、造血系外の組織ではPGE2によるシグナル伝達が幹細胞/がん幹細胞機能に貢献していることを示す証拠は見つけられなかった。
方法は、人工エクソソームを含む組成物と非幹細胞集団を接触させることにより人工幹細胞を生成するステップを含むいくつかの実施形態では、組成物は無細胞である。
実施形態の他の特徴、目的、および、長所も明細書、図面、および、特許請求の範囲から明らかになるだろう。
EP4アンタゴニストにより幹細胞からエクソソームを生成し、放出した。
EPアンタゴニストに誘導されたエクソソームの性質および含量を分析した。
本実施例では、EP4アンタゴニストGWに誘導されたエクソソーム、および、EP4アゴニストPGE2に誘導されたエクソソームの含量をさらに分析し、幹細胞の状態を転換するそれらの異なる能力の原因となる相違点を見出した。図4に示すように、GWで処理したNAMECから放出されたエクソソームのタンパク質の総量は、溶媒(Crl)またはPGE2で処理したNAMECからのエクソソームの総量よりはるかに多かった。また、GWに誘導されたエクソソーム、および、PGE2に誘導されたエクソソームにおけるさまざまなタンパク質の相対含量も異なっていた。
GWで処理したNSCの培養中、エクソソームマーカーCD81およびGAPDHの含量が増加した(図10C)。EP4が媒介するシグナル伝達をEP4アンタゴニストによって遮断することにより、神経幹細胞から放出されるEV/エクソソームが増加し、NSCの幹細胞ホメオスタシスを維持するために必要なEV/エクソソームのタンパク質含有量が増加することをデータは示唆している(図10C)。さらに、NSCマーカーであるSOX2の発現レベルは、GWで処理しなかったNSCに比べ、GWで処理したNSCがかなり低いことがわかった。これは、GWで処理したNSCがそれらの幹細胞の性質を失ったことを示唆している(図10C)。
EP4アンタゴニストの誘導によって放出されたエクソソームは、再計画により非幹組織細胞を幹細胞に転換させることができる。
EP4アンタゴニストに誘導された乳房上皮基底幹細胞(NAMEC)からのエクソソームは、乳房上皮(HMLE)非幹細胞の移動性および腫瘍様塊形成能力を向上させた。
図17に示す結果は、GWに誘導されたMSCからのEV/エクソソームによって前処理された神経外胚葉細胞は、より多くのより長い神経突起を有する神経細胞へと分化され得ることを示している。データは、EP4アンタゴニストに誘導されたMSCからのEV/エクソソームを神経外胚葉細胞に取り込むことにより、神経細胞へと分化する細胞の能力を高めることを示している。
EP4アンタゴニストに誘導される間葉系幹細胞(MSC)からのEV/エクソソームは、海馬の退化による認知、学習、記憶能力の障害を回復させた。
本例では、モリス水迷路を用いて、海馬障害を有するマウスの学習および記憶力を評価した。マウスは、処理あり(図18のI−PBSおよびI−EXO;図22(C)のinduce、NCexoおよびGWExo)と、処理なし(図18のNI−PBSおよびNI−EXO;図22(C)のNC)とを比較した。学習および記憶力は、訓練の後に目標を達成するためにかかる時間によって評価された。図18および22(C)に示すように、海馬を損傷したマウスの学習および記憶能力は、GWに誘導されたMSCからのエクソソーム(図18のI−EXOおよび図22(C)のGWExo)で処理したものが、PBSを注射したもの(図18のI−PBSおよび図22(C)のinduce)、および、MSCからのエクソソーム(図22(C)のNCExo)で処理しないものよりも著しく優れていた。さらなる認知力テスト(新しい位置再認識テスト、および、新しい物体認識テスト)によって認知の回復がさらに検証された(図22(A)および(B)参照)。また、MAP2神経細胞マーカー(図23(A))、および、β3−チューブリン神経細胞マーカー(データなし)を用いて、脳組織における神経細胞、核周部、および、神経細胞樹状突起を視覚化することにより、GWに誘導された間葉系幹細胞(MSC)からのエクソソームは、海馬を損傷したマウスの脳における神経細胞の再生を誘導し得ることを示した。さらに、ミクログリアマーカーIba1を用いて、中枢神経系のミクログリアおよびマクロファージの減少を視覚化することにより、GWに誘導されたMSCからのエクソソームは、海馬を損傷したマウスの脳内炎症を抑えることが可能であることを示した(図23(B))。損傷した脳内の炎症を抑制することにより、脳の神経細胞の再生を促す。これらのデータを総合し、例えば、アルツハイマー病およびパーキンソン病など、海馬の退化によって引き起こされる神経変性病へのEP4アンタゴニストに誘導されたEV/エクソソームの治療効果を実証した。
Claims (20)
- 人工エクソソームを生成する方法であって、
幹細胞から人工エクソソームが放出されるよう誘導する有効量のプロスタグランジンEレセプター4(EP4)アンタゴニストに単離された幹細胞を接触させるステップと、
前記人工エクソソームを単離するステップと、
を含む方法。 - 前記接触させるステップは、前記EP4アンタゴニストを含む培地で前記幹細胞を前記人工エクソソームが放出される期間培養することによって実行される、請求項1に記載の方法。
- 前記幹細胞は、4〜8日間培養される、請求項2に記載の方法。
- 前記EP4アンタゴニストは、抗PGE2抗体、EP4に対抗するsiRNA、EP4に対抗するshRNA、COX−2アンタゴニスト、mPGES−1アンタゴニスト、GW627368x、AH23848、L−161,982、CJ−023、423、ONO AE3 208、BGC20−1531塩酸塩、MF498、および、CJ−42794からなるグループから選ばれる、請求項1に記載の方法。
- 前記EP4アンタゴニストは、GW627368X、または、AH23848である、請求項4に記載の方法。
- 前記EP4アンタゴニストの有効量は、1.0〜40μg/mlである、請求項4に記載の方法。
- 前記幹細胞は、胚幹細胞、人工多能性幹細胞、がん幹細胞、間葉系幹細胞、造血幹細胞、乳房幹細胞、神経幹細胞、小腸幹細胞、皮膚幹細胞、臍帯血幹細胞、角膜輪部幹細胞、毛包幹細胞、脂肪組織由来幹細胞、骨髄幹細胞、角膜幹細胞、および、卵巣幹細胞から選択される、請求項1に記載の方法。
- 前記幹細胞は、間葉系幹細胞、乳房上皮幹細胞、がん幹細胞、または、神経幹細胞である、請求項7に記載の方法。
- 前記単離するステップは、前記幹細胞を含む前記培地を遠心分離することにより、前記人工エクソソームを含むペレットを得ることを含む、請求項3に記載の方法。
- 請求項1に記載された方法により生成された人工エクソソームを含む組成物。
- 前記人工エクソソームは、
(1)50nm〜150nmの直径を有し、
(2)CD44、CD90、インテグリンβ1、インテグリンα6、CD81、GAPDH、N−カドヘリン、フィブロネクチン、CD146、CD91、コフィリン、フィラミンA、CD91、CNP、タリン、トロポミオシン、ガレクチン3、Rap1、CD146、β−カテニン、TGFβ1、TGFβ2、LRP6、Ago1、Ago2、FZD5、EGFR、HER2、Met、EP2、PI3K、PDK1、Akt、p−Akt、c−Src、p−Src、SAPK/JNK、PSA、VCAM1、VEGFR2、VEGFR3、PDGFβ、NGFR、IL−2Rβ、IL−18Rβ、BMP−7、MIP−3α、RANTES、DR6、LIF、BDNF、TIMP1、VEGFa、および、IL−10のうちの1つ以上をコントロールの幹細胞から放出されたエクソソームより高い濃度で含み、
(3)前記コントロールの幹細胞から放出されるエクソソームよりもE−カドヘリンの濃度が低く、
(4)前記コントロールの幹細胞から放出されるエクソソームよりもsmallRNA含量が高く、
(5)mir−17−92、mir−106a−363、mir−106b−25クラスター、mir−24、mir−130、mir−17、mir−18a、mir−20a、mir−20b、mir−24、mir−25、mir−29a、mir−106b、mir−130a、および、mir−130bのうちの1つ以上を前記コントロールの幹細胞から放出されるエクソソームよりも高い濃度で含み、
(6)前記コントロールの幹細胞から放出されるエクソソームよりも脂質ラフト会合型タンパク質を高い濃度で含み、
(7)前記コントロールの幹細胞から放出されるエクソソームよりもサイトカイン含量が多い、
という特徴のうちの1つ以上を有し、
前記コントロールの幹細胞は、EP4アンタゴニストによって処理されていない幹細胞である、
請求項10に記載の組成物。 - 前記組成物は無細胞である、請求項10に記載の組成物。
- 前記人工エクソソームは、間葉系幹細胞、乳房上皮幹細胞、がん幹細胞、または、神経幹細胞から放出される、請求項10に記載の組成物。
- 生理学的に許容可能な賦形剤をさらに含む、請求項13に記載の組成物。
- 人工幹細胞を生成する方法であって、非幹細胞集団を請求項9に記載の組成物と接触させることにより人工幹細胞を生成するステップを含む方法。
- 前記接触させるステップは、前記組成物を必要としている被検体に前記組成物を投与することによって実行される、請求項15に記載の方法。
- 前記組成物は、前記組成物を必要としている前記被検体の全身にまたは前記被検体の部位に局所的に投与される、請求項16に記載の方法。
- 前記被検体は、変性疾患、組織もしくは臓器障害、または、細胞欠損を有する、請求項17に記載の方法。
- 前記組成物は、前記被検体または他の被検体から得られた幹細胞から放出されたエクソソームを含む、請求項16に記載の方法。
- 前記組成物は、無細胞である、請求項15に記載の方法。
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JP2022530086A (ja) * | 2019-04-29 | 2022-06-27 | サムスン ライフ パブリック ウェルフェア ファウンデーション | プロテアーゼ活性化受容体媒介シグナル伝達経路の活性を用いた細胞外小胞の高効率生成能を有する幹細胞の選別方法 |
JP7345953B2 (ja) | 2019-04-29 | 2023-09-19 | サムスン ライフ パブリック ウェルフェア ファウンデーション | プロテアーゼ活性化受容体媒介シグナル伝達経路の活性を用いた細胞外小胞の高効率生成能を有する幹細胞の選別方法 |
WO2021029408A1 (ja) | 2019-08-09 | 2021-02-18 | 宇部興産株式会社 | エクソソームの産生方法 |
KR102316777B1 (ko) * | 2020-06-26 | 2021-10-25 | 주식회사 씨케이엑소젠 | 엑소좀 생산 조절 세포, 이를 포함하는 조성물, 이로부터 얻은 엑소좀 및 엑소좀 생산 방법 |
KR102427786B1 (ko) * | 2020-06-26 | 2022-08-02 | 주식회사 씨케이엑소젠 | 엑소좀 생산 조절 세포, 이를 포함하는 조성물, 이로부터 얻은 엑소좀 및 엑소좀 생산 방법 |
WO2022080461A1 (ja) * | 2020-10-16 | 2022-04-21 | 富士フイルム和光純薬株式会社 | 細胞外小胞の産生用培地、培地キット、添加剤及び細胞外小胞の産生方法 |
JP2023018676A (ja) * | 2021-07-27 | 2023-02-08 | ナショナル ヤン ミン チアオ トゥン ユニバーシティー | 限外濾過によるエクソソームの濃縮 |
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US20180010133A1 (en) | 2018-01-11 |
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US11149277B2 (en) | 2021-10-19 |
GB2557696B (en) | 2022-08-10 |
TW201802112A (zh) | 2018-01-16 |
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