JPWO2017170925A1 - Egfr及びmic−abからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞及びその調製方法、並びに上記間葉系幹細胞を含む医薬組成物及びその調製方法 - Google Patents
Egfr及びmic−abからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞及びその調製方法、並びに上記間葉系幹細胞を含む医薬組成物及びその調製方法 Download PDFInfo
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Abstract
本発明は、EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞である。上記特定マーカーを高発現する間葉系幹細胞は、CD29、CD73、CD90、CD105及びCD166陽性であり、未分化性を維持している。
Description
(2)CD29、CD73、CD90、CD105及びCD166陽性である、(1)記載の間葉系幹細胞。
(3)臍帯又は脂肪由来である、(1)又は(2)記載の間葉系幹細胞。
(4)(1)から(3)のいずれか記載の間葉系幹細胞を含む、医薬組成物。
(5)EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞の比率が、医薬組成物の含む間葉系幹細胞全体の70%以上である、(4)記載の医薬組成物。
(6)EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞の比率が、医薬組成物の含む間葉系幹細胞全体の90%以上である、(4)又は(5)記載の医薬組成物。
(7)癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される疾患の予防又は治療のために用いられる、(4)から(6)のいずれか記載の医薬組成物。
(8)上皮若しくは内皮のバリア機能の低下に起因する疾患、又はIL−1が関与する疾患の予防又は治療のために用いられる、(4)から(7)のいずれか記載の医薬組成物。
(9)バリア機能の低下が、上皮又は内皮細胞層におけるタイトジャンクション機能の低下に起因する、(8)記載の医薬組成物。
(10)EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を誘導、濃縮又は分離選別する工程を含む、特定マーカーを高発現する間葉系幹細胞の調製方法。
(11)EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を誘導、濃縮又は分離選別する工程を含む、疾患の予防又は治療のために用いられる医薬組成物の調製方法。
(12)疾患が、癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される、(11)記載の医薬組成物の調製方法。
(13)EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を用いる、癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される疾患の予防又は治療方法。
(14)
EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を用いる、上皮若しくは内皮のバリア機能の低下に起因する疾患、又はIL−1が関与する疾患の予防又は治療方法。
本発明において間葉系幹細胞とは、骨細胞、心筋細胞、軟骨細胞、腱細胞、脂肪細胞等の間葉系に属する細胞への分化能を有し、この分化能を維持したまま増殖できる細胞を意味する。例えば骨髄、脂肪、血液、骨膜、真皮、臍帯、胎盤、羊膜、絨毛膜、脱落膜、筋肉、子宮内膜、真皮、歯小嚢、歯根膜、歯髄、歯胚等由来の間葉系幹細胞が挙げられ、好ましくは臍帯由来、脂肪由来、骨髄由来の間葉系幹細胞であり、より好ましくは臍帯由来の間葉系幹細胞である。ここで、「由来」とは、上記細胞が供給源である組織から獲得され、成長、或いはin vitroで操作された細胞であることを示す。なお、本発明の特定マーカーを高発現する間葉系幹細胞は、上記間葉系幹細胞の集合体であり、互いに異なる特性を有する複数種の間葉系幹細胞が含まれていてもよいし、実質的に均一な間葉系幹細胞の集合体であってもよい。
特定マーカーを高発現する本発明の間葉系幹細胞は、未分化性の指標となるCD29、CD73、CD90、CD105及びCD166を発現している。
本発明における特定マーカーを高発現する間葉系幹細胞は、特定マーカー遺伝子に加えて、他の遺伝子発現の有無によって特徴付けられてもよい。本発明の特定マーカーを高発現する間葉系幹細胞が発現している遺伝子としては、例えば、MT1X、NID2、CPA4、DKK1、ANKRD1、TIMP3、MMP1、オステオプロテゲリン(Osteoprotegerin;TNFRSF11B)、IGFBP5、SLC14A1等が挙げられる。特定マーカーを高発現する本発明の間葉系幹細胞は、MT1X、NID2、CPA4、DKK1、ANKRD1、TIMP3、MMP1、オステオプロテゲリン(Osteoprotegerin;TNFRSF11B)、IGFBP5及びSLC14A1からなる群より選択される少なくとも1種の遺伝子を発現していることが好ましい。より好ましくは2種以上、3種以上、4種以上、5種以上、さらに好ましくは6種以上、7種以上、8種以上、9種以上の、特に好ましくは、上記の全ての遺伝子を発現している。
特定マーカーを高発現する本発明の間葉系幹細胞は、miRNAの発現の有無によってさらに特徴付けられてもよい。本発明の間葉系幹細胞が発現しているmiRNAとしては、例えば、hsa−miR−145−5p、hsa−miR−181a−5p、hsa−miR−29b−3p、hsa−miR−34a−5p、hsa−miR−199b−5p、hsa−miR−503−5p、hsa−let−7e−5p、hsa−miR−132−3p、hsa−miR−196a−5p、hsa−miR−324−3p、hsa−miR−328−3p、hsa−miR−382−5p、hsa−let−7d−5p等が挙げられる。本発明の間葉系幹細胞は、hsa−miR−145−5p、hsa−miR−181a−5p、hsa−miR−29b−3p、hsa−miR−34a−5p、hsa−miR−199b−5p、hsa−miR−503−5p、hsa−let−7e−5p、hsa−miR−132−3p、hsa−miR−196a−5p、hsa−miR−324−3p、hsa−miR−328−3p、hsa−miR−382−5p、及びhsa−let−7d−5pからなる群より選択される少なくとも1種のマイクロRNAを発現していることが好ましい。より好ましくは2種以上、3種以上、4種以上、5種以上、6種以上の、さらに好ましくは7種以上、8種以上、9種以上、10種以上、11種以上、12種以上の、特に好ましくは、上記の全てのマイクロRNAを発現している。
特定マーカーを高発現する本発明の間葉系幹細胞は、サイトカイン分泌の有無によってさらに特徴付けられてもよい。本発明の間葉系幹細胞が分泌しているサイトカインとしては、例えば、デコリン、オステオプロテゲリン、MMP1等が挙げられる。本発明の間葉系幹細胞は、デコリン、オステオプロテゲリン及びMMP1からなる群より選択される少なくとも1種のサイトカインを分泌していることが好ましく、少なくとも2種のサイトカインを分泌していることがより好ましく、3種全てのサイトカインを分泌していることがさらに好ましい。
特定マーカーを高発現する本発明の間葉系幹細胞は、骨、脂肪、軟骨への分化能を有する。それぞれの分化能については、当業者に公知の分化誘導条件により上記間葉系幹細胞集団を培養して、判断することができる。
本発明の特定マーカーを高発現する間葉系幹細胞は、特定マーカー陰性の間葉系幹細胞と比較して、ロテノン等による酸化ストレスによるダメージを受けにくい。即ち、特定マーカー陽性である間葉系幹細胞と、特定マーカー陰性の間葉系幹細胞に対して、同じ濃度のロテノンで処理し、細胞のViability(%)を比較すると、特定マーカー陰性の間葉系幹細胞は、ロテノンの濃度依存的にViabilityが顕著に低下するのに対して、本発明の間葉系幹細胞は、Viabilityの低下が抑えられ、細胞によっては、ほぼ100%のViabilityとなる場合もある。
特定マーカーを高発現する間葉系幹細胞の調製方法は特に限定されないが、例えば以下のようにして調製することができる。すなわち、臍帯、脂肪組織、骨髄等の組織から、当業者に公知の方法に従って、間葉系幹細胞を分離、培養し、特定マーカーに特異的に結合する抗体(抗EGFR抗体、抗MIC−AB抗体)を用いて、特定マーカー陽性細胞をセルソーター、磁気ビーズ等で分離することにより取得することができる。また、後述する処方培地を用いる培養により、間葉系幹細胞における特定マーカー発現を誘導、増強することで、特定マーカーを高発現する間葉系幹細胞を効率的に取得することもできる。この誘導によって得られる細胞集団において、細胞集団の70%以上が特定マーカー陽性であることが好ましく、80%以上が特定マーカー陽性であることがより好ましく、90%以上が特定マーカー陽性であることがさらに好ましく、実質的に特定マーカー陽性の均一な細胞集団であることが特に好ましい。以下に、特定マーカーを高発現する間葉系幹細胞の調製方法を具体的に説明する。
基礎培地に加える上記血清代替物としては、例えば、アルブミン、トランスフェリン、脂肪酸、インスリン、亜セレン酸ナトリウム、コラーゲン前駆体、微量元素、2−メルカプトエタノール、3’−チオールグリセロール等が挙げられる。
特定マーカーを高発現する間葉系幹細胞を効率的に取得するために用いる培地としては、PTEN阻害剤、p53阻害剤、p38阻害剤、Wntシグナル活性化剤及びROCK阻害剤からなる群より選択される少なくとも2種の成分と、動物細胞培養用基礎培地とを含有する培地(処方培地)が挙げられる。処方培地は、これらの成分を含有することで、間葉系幹細胞において特定マーカーの発現を誘導又は促進すると共に、間葉系幹細胞の未分化性を長期に渡って維持しながら培養することができる。また、処方培地は、間葉系幹細胞を長期に渡って良好な細胞状態を維持しながら、効率的に増殖させることができる。さらに、処方培地は、増殖因子及びステロイド性化合物からなる群より選択される少なくとも1種の成分をさらに含有することが好ましい。以下に、処方培地が含む成分について詳細に説明する。
本発明においてPTEN阻害剤とは、PTEN(Phosphatase and Tensin Homolog Deleted from Chromosome 10)遺伝子、又はPTENタンパク質の作用を阻害する機能を有するすべての物質をいう。PTEN遺伝子は、染色体上の10q23.3に位置し、腫瘍抑制因子として同定されている。PTENタンパク質は広く全身の細胞に発現しており、イノシトールリン脂質であるフォスファチジルイノシトール 3,4,5−トリフォスフェイト(phosphatidylinositol 3,4,5−trisphosphate;PIP3)の脱リン酸化反応を触媒する酵素として知られている。PIP3は、PI3キナーゼ(PI3K)により細胞内で合成され、プロテインキナーゼB(PKB)/ AKTの活性化を引き起こす。PTENは、このPIP3の脱リン酸化反応を担い、フォスファチジルイノシトール 4,5−ビスフォスフェイト(phosphatidylinositol 4,5−bisphosphate;PIP2)に変換する作用があるとされている。従って、PTENは、PI3K/AKT情報伝達系を負に制御する。PTENの活性が阻害されると、細胞内にPIP3が蓄積し、PI3K/AKT情報伝達系が活性化する。
本発明においてp53阻害剤とは、p53遺伝子又はp53タンパク質の作用を阻害する機能を有するすべての物質をいう。p53遺伝子は、染色体上の17p13.1に位置し、腫瘍抑制遺伝子としても知られている。p53タンパク質は、転写因子として作用し、多様な生理活性を有する。
本発明においてp38阻害剤とは、p38遺伝子又はp38タンパク質の作用を阻害する機能を有するすべての物質をいう。p38は、セリン/スレオニンキナーゼであるMAPキナーゼ (Mitogen−Activated Protein Kinase)の1つである。MAPキナーゼは、外界刺激を伝達するシグナル分子、細胞増殖、分化、遺伝子発現、アポトーシス等への関与が明らかにされている。
本発明においてWntシグナル活性化剤とは、Wntシグナルを活性化させるすべての物質をいう。Wntは、分泌性の細胞間シグナル伝達タンパク質で、細胞内シグナル伝達に関与している。このシグナル伝達経路は細胞の増殖や分化、運動、初期胚発生時の体軸形成や器官形成等の機能を制御している。Wntシグナル経路では、Wntが細胞に作用することにより、いくつかの別々の活性化される細胞内シグナル伝達機構が含まれる。Wntシグナル経路にはβ−カテニンを介して遺伝子発現を制御するβ−カテニン経路、細胞の平面内極性を制御するPCP(planar cell polarity, 平面内細胞極性)経路、Ca2+の細胞内動員を促進するCa2+経路等が知られている。本明細書において、Wntシグナル活性化剤とは、そのいずれの経路を活性化するものであってもよい。
本発明においてROCK阻害剤とは、Rhoキナーゼ(ROCK)の作用を阻害するすべての物質をいう。Rhoキナーゼ(ROCK)は、低分子量GTP結合タンパク質であるRhoの標的タンパク質として同定されたセリン・スレオニンタンパク質リン酸化酵素である。Rhoキナーゼは、筋肉等の収縮、細胞増殖、細胞遊走及び他の遺伝子発現誘導等の生理機能に関与している。
処方培地における増殖因子としては、当業者に公知のいずれの増殖因子でも用いることができる。代表的には、トランスフォーミング成長因子(TGF)、上皮成長因子(EGF)等が挙げられるがこれに限定されず、インスリン様成長因子(IGF)、神経成長因子(NGF)、脳由来神経栄養因子(BDNF)、血管内皮細胞増殖因子(VEGF)、顆粒球コロニー刺激因子(G−CSF)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、血小板由来成長因子(PDGF)、エリスロポエチン(EPO)、トロンボポエチン(TPO)、塩基性線維芽細胞増殖因子(bFGF又はFGF2)、肝細胞増殖因子(HGF)等が挙げられる。さらにアルブミン、トランスフェリン、ラクトフェリン、フェツイン等も例示される。これらは単独で用いてもよいし、2種以上を組み合わせて用いることもできる。
処方培地におけるステロイド性化合物としては、当業者に公知のいずれのステロイド性化合物でも用いることができる。代表的には、エストラジオール、プロゲステロン、テストステロン、コルチゾン、コルチゾール、ハイドロコルチゾン等のステロイドホルモンを使用することができるが、これらに限定されない。これらは単独で用いてもよいし、2種以上を組み合わせて用いることもできる。
本発明における動物細胞培養用基礎培地とは、動物細胞の培養に必須の炭素源、窒素源及び無機塩等を含有させた培地をいう。ここで、動物細胞とは、哺乳類細胞、特にはヒト細胞を指す。本発明における動物細胞培養用基礎培地は、培養して得られる細胞やその培養上清を動物(ヒトを含む)の疾患の治療のために用いる可能性を考慮すると、できるだけ生物由来原料を含まない培地(例えば、無血清培地)であることが好ましい。動物細胞培養用基礎培地には、必要に応じて、微量栄養促進物質、前駆物質等の微量有効物質を配合してもよい。このような動物細胞培養用基礎培地としては、当業者に公知の動物細胞培養用培地を使用することができる。具体的には、イーグル培地のような最小必須培地(MEM)、ダルベッコ改変イーグル培地(DMEM)、最小必須培地α(MEM−α)、間葉系細胞基礎培地(MSCBM)、Ham’s F−12及びF−10培地、DMEM/F12培地、Williams培地E、RPMI−1640培地、MCDB培地、199培地、Fisher培地、Iscove改変ダルベッコ培地(IMDM)、McCoy改変培地等、これらの混合培地等が挙げられる。動物細胞培養培地として用いる場合には、特にはDMEM/F12培地が好ましく用いられるがこれに限定されない。
本発明の医薬組成物は、特定マーカーを高発現する間葉系幹細胞を含むことを特徴とする。特定マーカーを高発現する間葉系幹細胞は、IL−6等の炎症性サイトカインの産生抑制作用やバリア機能亢進作用に優れると共に、酸化ストレスに対する耐性もあり、ダメージを受け難い細胞である、といった特性を有する。また、未分化性を維持していると同時に、分化条件下では目的の機能を有する細胞に効率よく分化することができる。このような特定マーカーを高発現する間葉系幹細胞を含む本発明の医薬組成物は、種々の疾患に対する優れた治療効果を奏する。本発明の医薬組成物は、本発明の効果を損なわない範囲で、特定マーカーを高発現する間葉系幹細胞に加えて、その他の成分を含んでいてもよい。
本発明は、特定マーカーを高発現する間葉系幹細胞を誘導、濃縮又は分離選別する工程を含む、疾患の予防又は治療のために用いられる医薬組成物の調製方法も含む。上記疾患としては、癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される疾患が挙げられる。
(培養上清のバリア機能亢進作用)
特定マーカーを高発現する本発明の間葉系幹細胞の培養上清は、従来の間葉系幹細胞の培養上清と比較して、より優れた細胞のバリア機能亢進効果を示す。即ち、本発明における特定マーカーを高発現する間葉系幹細胞の培養上清は、炎症によって障害を受けた細胞のバリア機能を回復させる顕著な効果を有するため、本発明の特定マーカーを高発現する間葉系幹細胞及びそれを含む医薬組成物は、炎症に関連する疾患の治療に好適に用いることができる。また、特定マーカーを高発現する間葉系幹細胞又はその培養上清は、化粧品用組成物、食品用組成物等としても用いることもできる。
特定マーカーを高発現する本発明の間葉系幹細胞は、炎症状態において、マクロファージからの炎症性サイトカインの産生を抑制する効果を有する。この効果は、特定マーカー陰性の従来の間葉系幹細胞と比較して、有意に高いものである。そのため、本発明の特定マーカーを高発現する間葉系幹細胞及びそれを含む医薬組成物は、炎症に関連する疾患の治療に好適に用いることができる。また、特定マーカーを高発現する間葉系幹細胞又はその培養上清は、化粧品用組成物、食品用組成物等としても用いることもできる。
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地(以下、単に「推奨培地」ともいう)にて馴化した後、推奨培地又は下記組成の処方培地*に交換し、2〜3日おきに継代しながら培養を続けた。
(FACS解析)
処方培地中、推奨培地中で培養して得られたそれぞれの間葉系幹細胞(LifeLine社)について、FACSにてEGFR、MIC−ABの発現を解析した。結果を図1に示す。また、細胞の未分化性を確認する目的で、FACSにて細胞表面マーカー(CD29、CD73、CD90、105及びCD166)の発現を解析した。結果を図2に示す。さらに、処方培地で培養して得られた間葉系幹細胞は、上記特定マーカー以外に、CD49f、β2ミクログロブリン、HLA−ABCを発現していることを、FACS解析により確認した(データは示していない)。
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地にて馴化後、処方培地に培地交換した。2〜3日おきに継代を行い、培地交換から8日目の細胞を回収した。回収した細胞から上記試験と同様の方法によりmRNAを調製し、miRNAアレイ(miScript miRNA PCR array;MIHS−105Z及びMIHS−117Z(inflammatory response & autoimmunity及びFibrosis、QIAGEN社製)により、細胞中のmiRNA発現を解析した。対照としては、推奨培地で継続して培養して得られた細胞を用いた。結果の解析は、処方培地で培養して得られた特定マーカー発現間葉系幹細胞における各種miRNA発現量を推奨培地で培養して得られた対照細胞におけるそれぞれのmiRNA発現量で除した値(Fold change値)により行った。同様の実験を2回行った。
(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地にて馴化後、処方培地に交換した。培地交換から8日間培養後に播種し直し、翌日0.2%FBS含有DMAM/F12に交換し、2日後(48時間後)、培養上清を回収した。回収した培養上清中のDecorin、Osteoprotegerin、MMP1量をELISAにて測定した。対照としては、推奨培地で継続して培養して得られた細胞の培養上清を用いた。結果を図3示す。
(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社;UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells ScienCell社;及びUmbilical Cord derived Mesenchymal Stem Cells ATCC社)を、37℃、5%CO2の条件下、各社推奨培地にて馴化後、各社推奨培地又は処方培地に培地交換した(0.3〜1X105cells/well;6well plate)。2〜3日おきに継代を行った細胞に対してRotenoneを各濃度で処理した(0nM、100nM、200nM、500nM、1μM)。48時間後にHoechest33358で染色し、ImageXpressで核数を計測した。結果を図4に示す。
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地にて馴化後、LifeLine社推奨培地又は処方培地に交換した(1X105cells/well;6well plate)。それぞれの培地に変えてから8日間培養後に、培地を10%FCS含有DMEM/F−12培地、2ml/wellに交換した。1日後に培養上清(Sup−1)を回収し、新しい培地を2ml/well注ぎ、培養を継続した。さらに24時間後に再び培養上清(Sup−2)を回収した。
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地にて馴化後、LifeLine社推奨培地又は処方培地に交換した(1X105cells/well;6well plate)。それぞれの培地に変えてから8日間培養後の細胞を以下の試験に用いた。
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、LifeLine社推奨培地にて馴化後、LifeLine社推奨培地又は処方培地に交換した(1X105cells/well;6well plate)。2〜3日おきに継代を行い、継代数8の細胞を準備した。継代数8の両MSCを各2枚のCell BIND T−75 flaskに7000 cells/cm2で播種し、両MSC1枚は翌日に処方培地へ交換し、残り1枚は推奨培地のまま90−100%コンフルエントに達するまで培養を継続した。継代数9にて再度継代し、T−75 flask4枚ずつとなるようにまき直し、群分け後8日(継代数10)の細胞を下記の分化試験に供した。
群分け後8日目に、各群ごとに細胞を回収し、クラボウ分化プロトコール推奨細胞密度にて、骨細胞分化用培地(ヒト間葉系幹細胞用 骨細胞分化用培地:OsteoLife Complete Osteogenesis Medium (Lifeline, LM−0023))を用いて、24well plate (cellbind, 3337, Corning)に播種した。骨分化のための培養では、分化培養用播種から48時間後に培地交換を行い、以後、28日まで3−4日ごとに培地交換を行った。染色方法としては、播種後21日目以降に、染色するwellをPBSで1回洗浄した後、無水エタノールを添加し30分間室温で置くことで細胞の固定を行った。無水エタノールを吸引し、クリーンベンチ内で約30分間静置、乾燥させた。2%アリザリンレッド溶液を添加し、15分間室温で静置した後、DW(蒸留水)で2回洗浄し、乾燥させた。染色写真は顕微鏡(Olympus IX70)を用いて撮影した。 アリザリンレッド染色の結果を図7に示す。
分化実験に供する間葉系幹細胞の調製は骨分化実験の際と同様の方法により行った。
群分け後8日目に、各群ごとに細胞を回収し、クラボウ分化プロトコール推奨細胞密度にて、分化培地{ヒト間葉系幹細胞用 脂肪細胞分化用培地:AdipoLife DfKt−1 (Lifeline, LL−0050) or AdipoLife DfKt−2 (Lifeline , LL−0059)を用いて、24well plate (cellbind, 3337, Corning)、に播種した。脂肪分化のための培養では、分化培養用播種から48時間後に培地交換を行い、以後、28日まで3−4日ごとに培地交換を行った。染色方法としては、播種後21日目以降に、染色するwellをPBSで1回洗浄した後、4% (v/v) パラホルムアルデヒド・リン酸緩衝液で培地を少し残すようにしながら2回洗浄した。4% (v/v) パラホルムアルデヒド・リン酸緩衝液を再度添加し、20分間室温で静置した。その後、培地を少し残すようにしながら、DW(蒸留水)で2回洗浄し、100%イソプロパノールで1回洗浄した。DW(蒸留水)で60%に希釈したオイルレッドO染色原液を添加し、30分間37℃で静置後、完全に吸引した。その後60%イソプロパノールを添加し、10秒ほど待ち、DW(蒸留水)を加えた。DW(蒸留水)で2回洗浄後、顕微鏡(Olympus IX70)で写真撮影した。なお、AdipoLife DfKt−1のAdipoLife BM (100ml)を15mlと85mlに分け、15mlにはDifFactor 1 (1ml)を加えてAD−MSC用の分化開始培地とし、85mlにはDifFactor 2 (5ml)を加えてAD−MSC用の分化維持培地とした。また、AdipoLife DfKt−2のAdipoLife BM (100ml) にDifFactor 3 (10ml)を加えてUC−MSC用の分化培地とした。 オイルレッドO染色の結果を図8に示す。
分化実験に供する間葉系幹細胞の調製は骨分化実験の際と同様の方法により行った。
群分け後8日目に、各群ごとに細胞を回収し、クラボウ分化プロトコール推奨細胞密度にて、分化培地(ヒト間葉系幹細胞用 軟骨細胞分化用培地:ChondroLife Complete Chondrogenesis Medium (Lifeline, LM−0023))を用いて、24well plate (3527, Corning)に播種した。軟骨分化のための培養では、マイクロマス法で播種を行った。具体的には、回収した細胞を各維持培地で1.6 x 107 cells/mlに濃縮し、24well plate (3526, Corning)に5ulずつ4drops/wellで滴下し、2時間37℃, 5%CO2で静置した後、500ul/wellで軟骨分化培地を添加した。その後、21日まで3日ごとに培地交換を行った。染色方法としては、播種後21日目以降に、染色するwellをPBSで1回洗浄した後、10%中性緩衝ホルマリン液を添加し、30分間室温で置くことで細胞の固定を行った。その後、DW(蒸留水)で1回洗浄し、3%酢酸を添加し、1分間静置した。アルシアンブルー染色液を添加後20分間室温で静置した後、染色液を吸引し、3%酢酸を添加して3分間待った。最後にDW(蒸留水)で2回洗浄し、デジタルカメラで撮影した。
Claims (14)
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞。
- CD29、CD73、CD90、CD105及びCD166陽性である、請求項1記載の間葉系幹細胞。
- 臍帯又は脂肪由来である、請求項1又は2記載の間葉系幹細胞。
- 請求項1から3のいずれか1項記載の間葉系幹細胞を含む、医薬組成物。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞の比率が、医薬組成物の含む間葉系幹細胞全体の70%以上である、請求項4記載の医薬組成物。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞の比率が、医薬組成物の含む間葉系幹細胞全体の90%以上である、請求項4又は5記載の医薬組成物。
- 癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される疾患の予防又は治療のために用いられる、請求項4から6のいずれか1項記載の医薬組成物。
- 上皮若しくは内皮のバリア機能の低下に起因する疾患、又はIL−1が関与する疾患の予防又は治療のために用いられる、請求項4から7のいずれか1項記載の医薬組成物。
- バリア機能の低下が、上皮又は内皮細胞層におけるタイトジャンクション機能の低下に起因する、請求項8記載の医薬組成物。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を誘導、濃縮又は分離選別する工程を含む、EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを発現する間葉系幹細胞の調製方法。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を誘導、濃縮又は分離選別する工程を含む、疾患の予防又は治療のために用いられる医薬組成物の調製方法。
- 上記疾患が、癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される、請求項11記載の調製方法。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を用いる、癌、前癌性症状、炎症性疾患、免疫疾患、神経変性疾患、代謝疾患、心血管疾患、骨疾患、胃腸疾患、肺疾患、肝疾患及び腎疾患からなる群より選択される疾患の予防又は治療方法。
- EGFR及びMIC−ABからなる群より選択される少なくとも1種の細胞表面マーカーを高発現する間葉系幹細胞を用いる、上皮若しくは内皮のバリア機能の低下に起因する疾患、又はIL−1が関与する疾患の予防又は治療方法。
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US20200294785A1 (en) | 2020-09-17 |
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