JP2018075017A - 神経幹細胞および運動ニューロンの生成 - Google Patents
神経幹細胞および運動ニューロンの生成 Download PDFInfo
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Abstract
【解決手段】i)miR−891、miR−378及びmiR−20bからなる群から選択される少なくとも1つの外因性miRをMSC中で発現させること、及び(ii)miR−138ポリヌクレオチド阻害剤をMSC中で発現させ、それにより、MSCを神経幹細胞へ分化させることを含む方法。
【選択図】なし
Description
(a)神経幹細胞の集団を運動ニューロン表現型に向かって分化させること;および
(b)MSCの集団におけるmiRNAの発現における変化を、前記MSCを運動ニューロン表現型に向かって分化させる前および分化させた後において分析すること(ただし、所定のレベルを越えるか、または下回るmiRNAの発現の変化により、前記miRNAが前記運動ニューロン疾患の処置のために調節され得ることが示される)
を含む方法が提供される。
(i)miR−891の発現を、miR−891にハイブリダイゼーションし、かつ、その機能を阻害する少なくとも1つのポリヌクレオチド作用因を使用してダウンレギュレーションすること;
(ii)外因性miR20bのレベルをアップレギュレーションすること;または
(iii)外因性miR378のレベルをアップレギュレーションすること
を含む。
1.間葉系幹細胞を成熟型miRNA(または本明細書中下記で記載されるように改変形態)により一過性にトランスフェクションすること。本発明の教示に従って設計されるmiRNAは、酵素的合成および固相合成の両方を含めて、当技術分野で公知の任意のオリゴヌクレオチド合成法に従って作製することができる。固相合成を実行するための様々な設備および試薬が、例えば、Applied Biosystemsから市販されている。そのような合成のための任意の他の手段もまた用いることができる;オリゴヌクレオチドの実際の合成は十分に当業者の能力の範囲内であり、固相化学(例えば、シアノエチルホスホルアミダイト)、その後、脱保護、脱塩および精製(例えば、自動トリチル・オン法またはHPLCによる精製)を利用して、例えば、下記において詳しく記載されるような確立された方法論により達成することができる:Sambrook,J.およびRussell,D.W.(2001)、“Molecular Cloning:A Laboratory Manual”;Ausubel,R.M.他編(1994、1989)、“Current Protocols in Molecular Biology”、第I巻〜第III巻、John Wiley&Sons、Baltimore、Maryland;Perbal,B.(1988)、“A Practical Guide to Molecular Cloning”、John Wiley&Sons、New York;およびGait,M.J.編(1984)、“Oligonucleotide Synthesis”。
2.間葉系幹細胞を、成熟型miRNAをコードする発現ベクターにより、またはmiRNA模倣体により安定的または一過性にトランスフェクションすること。
3.間葉系幹細胞を、プレ−miRNAをコードする発現ベクターにより安定的または一過性にトランスフェクションすること。プレ−miRNA配列は、45〜90ヌクレオチド、60〜80ヌクレオチド、または60〜70ヌクレオチドを含む場合がある。プレ−miRNAの配列は、本明細書中に示されるようなmiRNAおよびmiRNA*を含む場合がある。プレ−miRNAの配列はまた、プリ−miRNAの5’末端および3’末端から0〜160個のヌクレオチドを除外するプリ−miRNAの配列である場合がある。プレ−miRNAの配列はmiRNAの配列、またはその変化体を含む場合がある。
4.間葉系幹細胞を、プリ−miRNAをコードする発現ベクターにより安定的または一過性にトランスフェクションすること。プリ−miRNA配列は、45〜30000ヌクレオチド、50〜25000ヌクレオチド、100〜20000ヌクレオチド、1000〜1500ヌクレオチド、または80〜100ヌクレオチドを含む場合がある。プリ−miRNAの配列は、本明細書中に示されるようにプレ−miRNA、miRNAおよびmiRNA*、ならびに、それらの変化体を含む場合がある。miRNA模倣体の調製を化学的合成法によって、または、組換え法によって行うことができる。
オリゴ 3’−−A G G T
二重鎖 5’−−A G C T
三重鎖 3’−−T C G A
1)分化MSC(様々な神経細胞または神経始原体細胞に至るもの)が、同種T細胞との一方向混合リンパ球培養において刺激因子として役立つ場合があり、同じドナーから単離される同種リンパ球に対して応答するT細胞との比較での増殖応答が、低応答性を実証するために3H−チミジン取り込みによって評価される場合がある。
2)分化MSCが、T細胞により媒介される増殖応答に対する免疫抑制影響を確認するために、一方向混合リンパ球培養に対して、また、T細胞マイトジェン(フィトヘマグルチニンおよびコンカナバリンA)との細胞培養に対して添加/共培養される場合がある。
3)Brown Norwayラットから培養される臍帯細胞および胎盤細胞(非改変細胞および分化細胞)がMSCについて富化される場合があり、これらの細胞が、誘導された実験的自己免疫性脳脊髄炎(EAE)を有するLewisラットに注入される場合がある。代替では、BALB/cマウスの(BALB/cxC57BL/6)F1から培養される臍帯細胞および胎盤細胞、または、Brown Norwayラットから得られる異種細胞(非改変細胞および分化細胞)がMSCについて富化される場合があり、これらの細胞が、誘導された実験的自己免疫性脳脊髄炎(EAE)を有するC57BL/6またはSJL/jレシピエントに注入される場合がある。麻痺に対する臨床効果が、異種のMHC、完全不一致MSCまたはハプロタイプ一致した不一致MSCの治療効果を評価するために調べられる場合がある。そのような実験は、遺伝的障害または遺伝的傾向のある障害を有する患者を家族の一員のハプロタイプ一致したMSCにより処置するための基礎を提供する場合がある。
4)臍帯および胎盤から培養されるBALB/cのMSCが、GFPまたはRFPにより標識されるプレ−miRとともに輸注される場合がある(この場合、GFPまたはRFPは、本発明者らが、誘導されたEAEを有するC57BL/6レシピエントの脳におけるこれらの細胞の遊走および持続を追跡することを可能にするであろう)。標識されたMHC不一致の分化MSCの臨床効果が、疾患、麻痺および組織病理学の兆候をモニターすることによって評価される場合がある。そのような細胞の遊走および局在化もまた、遺伝的に形質導入されたGFP「緑色」ドナーまたはRed2「赤色」ドナーに由来する蛍光性細胞を使用することによってモニターされる場合がある。
間葉系幹細胞(MSC)の神経幹細胞(NSC)への分化
方法
骨髄、脂肪、胎盤または臍帯のどれからも得られる間葉系幹細胞(MSC)を、細菌用ディッシュにおいて高密度で、10mg/mlのEGFおよびbFGFが補充される血清非含有培地に10日間置床した。細胞は凝集し始め、4〜5日後において、プレートからのそれらの剥離を促進させるために機械的に解離させた。その後、細胞を2週間維持し、その後、細胞をNSCマーカーの発現について、また、低血清(5%)培地においてラミニンに置床したときには、ニューロン、星状膠細胞および乏突起膠細胞を生じさせることができるかについて分析した。
図1A〜図1Bに例示されるように、間葉系幹細胞は神経幹細胞分化の後でニューロンマーカーを発現した。
NSC分化期間中でのmiRNA発現における変化
材料および方法
様々なmiRNAは、様々な神経細胞および神経幹細胞の分化において役割を果たすことが示されている。特異的miRNAの発現および機能をMSC由来のNSCにおいて分析するために、MSCを実施例1に記載されるようにNSCに向かって分化させ、miRNAアレイ分析を対照細胞および分化細胞に対して行った。幹細胞にすべてが関連づけられ、幹細胞とのそれらの公知の関連に基づいてサブグループ(神経関連miRNA、造血miRNAおよび器官関連miRNA)に分けられた96個のmiRNAを含有するqRT−PCRマクロアレイを行った。
図2、図3および図4Aに示されるように、各グループの特異的miRNAの発現における有意な変化が対照MSCと分化MSCとの間に存在した。
MSCのNSCへの分化において役割を果たすmiRNA
本発明者らはさらに、MSCのNSCへの分化のときにmiRマイクロアレイにおいて変化することが見出された特異的miRNAの役割を調べた。これらの実験を、特異的な成熟型miRNA模倣体またはmiRNA阻害剤、あるいは、成熟型miRNA模倣体またはmiRNA阻害剤の組合せのどちらかによりMSCをトランスフェクションすることによって行い、その後、ニューロスフェアを生じさせ、かつ、マーカーのネスチンおよびSox2を発現するそれらの能力を調べた。
miR−124の発現と一緒でのlet−7の阻害がNSC分化を増大させたことが見出された。
MSCのNSCへの分化を促進させるさらなる因子
Related to testis−specific,vespid and pathogenesisタンパク質1(RTVP−1)が、2つのグループによってヒトGBM細胞株からクローン化され、神経膠腫病理発生関連タンパク質、すなわち、GLIPR1またはRTVP−1と名づけられた[3]。RTVP−1は、TPX−1[4]、毒液アレルゲン抗原5[5]、および、植物病理発生関連タンパク質のグループ1(PR−1)を含む他のRTVP−1ホモログにもまた見出される未だに不明の機能とともに、推定されるシグナルペプチド、膜貫通ドメインおよびSCPドメインを含有する。RTVP−1が神経膠腫において腫瘍プロモーターとして作用することが近年には報告されている。したがって、RTVP−1の発現は星状膠細胞腫瘍の悪性度と相関し、また、RTVP−1の過剰発現は、細胞増殖、浸潤、遊走および足場非依存的成長を増大させる。そのうえ、RTVP−1のサイレンシングはアポトーシスを神経膠腫細胞株および原発性神経膠腫培養物において誘導する[6]。興味深いことに、RTVP−1は前立腺ガン細胞において腫瘍抑制因子として作用し、また、RTVP−1のアデノウイルス媒介送達は治療効果をマウス前立腺ガンモデルにおいて有する[7〜9]。
RTVP−1のMSCにおける発現は、ウエスタンブロットによって明らかにされるように非常に大きい(図5A)。そのうえ、RTVP−1のMSCにおけるサイレンシングは、間葉系譜細胞に分化するその能力をなくし、神経幹細胞マーカーおよび神経マーカーの発現を低下させた(図5C〜図5D)。
神経始原体細胞の運動ニューロンへの分化
材料および方法
プレートを20μg/mlのラミニンにより一晩被覆し、その後、PBSにより2回洗浄した。NPCを50%のコンフルエンシーで置床し、24時間後、プライミング培地、すなわち、ヘパリン(10μg/mlを使用する)およびbFGF(100μg/ml)を有するNM培地と5日間インキュベーションした。5日後、培地を、分化培地、すなわち、50mLのF12における1mLのB27(すなわち、2%)、レチノイン酸(RA、1μM)およびSHH(200ng/mL)を有するF12に変更した。RAを1日おきに加えた。5日後、GDNFおよびBDNFを培地に加えた(10ng/mL)。
発達中の脊髄において、運動ニューロン(MN)および乏突起膠細胞(OLP)の逐次生成が認められる。最初にMNを生じさせ、その後、乏突起膠細胞を生じさせるpMNと呼ばれる共通の始原体が存在する。塩基性ヘリックス・ループ・ヘリックス(bHLH)転写因子のOlig2がpMNドメインにおいて発現され、Olig2は、両方の細胞タイプの発達において役割を果たす重要な転写因子の1つである。200ng/mlの組換えSHH、それぞれが20ng/mlのGDNF、BDNF、CNTFおよびNT−3、ならびに、1mMのレチノイン酸が補充されるNM培地で成長させられたMSCにおけるOlig2の過剰発現は、運動ニューロンの2つの特異的マーカー、すなわち、Hb9およびIslet1の発現を誘導した(図6A〜図6D)。
NPCの運動ニューロンへの分化におけるmiRNAの関与
材料および方法
運動ニューロン分化と関係する特異的なmiRNAを特定するために、本発明者らは、実施例5に記載されるプロトコルを使用して、2つのタイプの神経幹細胞/始原体細胞を発達の異なる段階にある運動ニューロンに分化させた。運動ニューロンとしての細胞の特徴づけを、特異的マーカーのislet1、HB9、ならびに、ニューロンマーカーのニューロフィラメントおよびβ3チューブリンの発現によって特徴づけた。
図7A〜図7Bに例示されるように、神経幹細胞が、運動ニューロンに分化するように誘導される場合がある。
配列
Claims (19)
- 間葉系幹細胞(MSC)の神経幹細胞への生体外での分化を促す方法であって、(i)miR−891,miR−378およびmiR−20bからなる群から選択される少なくとも1つの外因性miRを前記MSC中で発現させること、および(ii)miR−138ポリヌクレオチド阻害剤を前記MSC中で発現させ、それにより、前記MSCを前記神経幹細胞へ分化させることを含む方法。
- 前記MSCが、骨髄、脂肪組織、胎盤、臍帯血および臍帯からなる群から選択される組織から単離される、請求項1に記載の方法。
- 前記発現させることが、(i)前記miRを前記MSC中に導入すること、(ii)前記miRのプレ−miRNAをコードするポリヌクレオチド配列を含む発現ベクターにより前記MSCをトランスフェクションすること、または(iii)前記miRをコードするポリヌクレオチド配列を含む発現ベクターにより前記MSCをトランスフェクションすることを含む、請求項1または2に記載の方法。
- ニューロン細胞の増殖および分化を支持する培地中で前記MSCを培養することをさらに含む、請求項1〜3のいずれかに記載の方法。
- ネスチンおよびSox2からなる群から選択される少なくとも1つのマーカーの発現を前記発現させることの後において分析することをさらに含む、請求項1〜4のいずれかに記載の方法。
- 前記分析することが、前記少なくとも1つのマーカーの増大した発現を確認することを含む、請求項5に記載の方法。
- 前記分析することが、MSCのうちの少なくとも50%が前記少なくとも1つのマーカーを発現することを確認することを含む、請求項5に記載の方法。
- 前記ポリヌクレオチド阻害剤が、antagomiRである、請求項1〜7のいずれかに記載の方法。
- miR−891,miR−378およびmiR−20bからなる群から選択される少なくとも1つの外因性miRNAと、miR−138にハイブリダイゼーションし、かつ阻害するポリヌクレオチド作用因とを含む、間葉系幹細胞(MSC)の遺伝子改変され単離された集団であって、前記間葉系幹細胞(MSC)が神経幹細胞の表現型を有する、遺伝子改変され単離された細胞集団。
- 前記MSCが、骨髄、脂肪組織、胎盤、臍帯血および臍帯からなる群から選択される組織から単離される、請求項9に記載の単離された細胞集団。
- 前記ポリヌクレオチド阻害剤が、antagomiRである、請求項9または10に記載の単離された細胞集団。
- 前記細胞集団の少なくとも50%が、ネスチンおよびSox2からなる群から選択される少なくとも1つのマーカーを発現する、請求項9〜11のいずれかに記載の単離された細胞集団。
- 脳疾患または脳障害を処置することにおいて使用するためのものである、請求項9〜12のいずれかに記載の単離された細胞集団。
- 前記脳疾患または脳障害が神経変性障害である、請求項13に記載の単離された細胞集団。
- 前記神経変性障害は、多発性硬化症、パーキンソン病、てんかん、筋萎縮性側索硬化症(ALS)、卒中、レット症候群、自己免疫性脳脊髄炎、脊髄傷害、脳性麻痺、卒中、アルツハイマー病およびハンチントン病からなる群から選択される、請求項14に記載の単離された細胞集団。
- 請求項9〜12のいずれかに記載される単離された細胞集団と、医薬的に許容される担体とを含む医薬組成物。
- 脳疾患または脳障害を処置することにおいて使用するためのものである、請求項16に記載の医薬組成物。
- 前記脳疾患または脳障害が神経変性障害である、請求項17に記載の単医薬組成物。
- 前記神経変性障害は、多発性硬化症、パーキンソン病、てんかん、筋萎縮性側索硬化症(ALS)、卒中、レット症候群、自己免疫性脳脊髄炎、脊髄傷害、脳性麻痺、卒中、アルツハイマー病およびハンチントン病からなる群から選択される、請求項18に記載の医薬組成物。
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