JP2005534302A - 多能性神経幹細胞からの希突起神経膠細胞産生 - Google Patents
多能性神経幹細胞からの希突起神経膠細胞産生 Download PDFInfo
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Abstract
Description
本出願は、米国仮特許出願第60/399,192号の利益を主張し、その全体の開示内容は、本明細書中において参考として援用される。
本発明は、希突起神経膠細胞産生促進因子、特に顆粒球−マクロファージコロニー刺激因子、顆粒球コロニー刺激因子、インターロイキン3、あるいはインターロイキン5を用いて、希突起神経膠細胞を産生する方法に関連する。
多くの脊椎動物ニューロンの軸索はミエリン鞘によって絶縁されており、これは、軸索が活動電位を伝導し得る速度を大きく増加させる。ミエリンは、特殊なグリア細胞、すなわち末梢神経系のシュワン細胞および中枢神経系の希突起神経膠細胞により形成される細胞の鞘である。これらのグリア細胞は軸索の周りに固い螺旋状に、層の上に層を巻きつけており、これによって軸索膜を絶縁している。しかしながら、その鞘は規則正しく間隔を空けたランビエ絞輪において中断され、ここで膜の脱分極が起こり得る。結果として、1つの絞輪における膜の脱分極は、直ちに隣の絞輪に広がる。したがって、能動的興奮は絞輪における軸索の原形質膜の小領域に制限されているため、活動電位は絞輪から絞輪へ跳躍することによりミエリン化された軸索に沿って伝播し、それによって、信号の伝達を加速し、ならびに代謝エネルギーを節約する。
本発明は、希突起神経膠細胞促進因子、特に顆粒球−マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、インターロイキン3(IL−3)、またはインターロイキン5(IL−5)を用いて、多能性神経幹細胞から希突起神経膠細胞を産生する方法に関する。本発明者らは本明細書中において、GM−CSFのようなこれらの因子が、神経幹細胞から産生される希突起神経膠細胞のパーセンテージを有意に増加させたことを示す。GM−CSFが神経幹細胞の増殖培地(proliferation media)に存在した場合、増殖(proliferate)する神経幹細胞は減少し、一方希突起神経膠細胞は増加した。したがって、GM−CSFは神経幹細胞の発生運命決定を、希突起神経膠細胞系統に転向し得る。希突起神経膠細胞産生を最大化するため、まず神経幹細胞の増殖(proliferation)を促進し、続いて増幅(expand)した神経幹細胞を希突起神経膠細胞形成を増加させるための希突起神経膠細胞促進因子に供することが、好ましい。
(a)多能性神経幹細胞を哺乳動物に導入し、そして、神経幹細胞からの希突起神経膠細胞形成をもたらす条件下において、有効量の少なくとも1つの希突起神経膠細胞促進因子を哺乳動物に投与する工程;または
(b)哺乳動物に有効量の上記の薬学的組成物を導入する工程、
を包含する。
本発明は、少なくとも1つの希突起神経膠細胞促進因子、特に顆粒球−マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、インターロイキン3(IL−3)、およびインターロイキン5(IL−5)を用いて、多能性神経幹細胞から希突起神経膠細胞を産生する方法に関する。本発明者らは本明細書中において、GM−CSFが、神経幹細胞から産生される希突起神経膠細胞のパーセンテージを有意に増加させたことを示した。GM−CSFが神経幹細胞の増殖培地(proliferation media)に存在した場合、増殖(proliferate)する神経幹細胞は減少し、一方希突起神経膠細胞は増加した。したがって、GM−CSFは神経幹細胞の発生運命決定を、希突起神経膠細胞系統に転向し得る。希突起神経膠細胞産生を最大化するため、まず神経幹細胞の増殖(proliferate)を促進し、続いて増幅(expand)した神経幹細胞を希突起神経膠細胞形成を増加させるための希突起神経膠細胞促進因子に供することが、好ましい。
「多能性神経幹細胞(multipotent neural stem cell)」もしくは「神経幹細胞」は、神経細胞系統の幹細胞である。幹細胞はそれ自身を再生し得る細胞である。いいかえれば、幹細胞が分裂する場合、生じた娘細胞の少なくともいくつかもまた、やはり幹細胞である。神経幹細胞とそれらの子孫は、神経細胞系統における全てのタイプの細胞(ニューロン、星状細胞、希突起神経膠細胞(星状細胞および希突起神経膠細胞はまとめてグリアもしくはグリア細胞と呼ばれる)が挙げられる)に分化し得る。したがって、神経幹細胞は多能性神経幹細胞である。多能性神経幹細胞は、例えば、米国特許第5,750,376号;同第5,980,885号;および同第5,851,832号に記載されている。
多能性神経幹細胞の単離およびインビトロ培養の方法は、最近開発された(例えば、米国特許第5,750,376号;同第5,980,885号;同第5,851,832号を参照のこと)。インビトロでの多能性神経幹細胞の単離および培養に胎仔の脳が使用され得ることが発見された。さらに、成体脳細胞は脳細胞を複製および再生し得ないと長く信じられていたのとは対照的に、神経幹細胞が成体哺乳動物の脳からも単離され得ることが分かった。これらの幹細胞は、胎生由来および成体由来のいずれも、自己複製し得る。子孫細胞は再び増殖(proliferate)し得るか、もしくは、ニューロン、星状細胞、および希突起神経膠細胞を含む、神経細胞系統のあらゆる細胞に分化し得る。
hr = 時間
min = 分
μM = マイクロモル濃度
mM = ミリモル濃度
M = モル濃度
ml = ミリリットル
μl = マイクロリットル
mg = ミリグラム
μg = マイクログラム
FBS = ウシ胎仔血清
PBS = リン酸緩衝化生理食塩水
DMEM = ダルベッコ改変イーグル培地
α−MEM = α−改変イーグル培地
MHM = 培地ホルモン混合物
GM−CSF = 顆粒球−マクロファージコロニー刺激因子
G−CSF = 顆粒球コロニー刺激因子
IL−3 = インターロイキン3
IL−5 = インターロイキン5
EGF = 上皮増殖因子
PDGF = 血小板由来増殖因子
GalC = ガラクトセレブロシド
MBP = ミエリン塩基性タンパク質
T3 = トリヨードチロニン
CNTF = 毛様体神経栄養因子
DIV = インビトロでの日数(days in vitro)
(実施例1)
(GM−CSFは神経幹細胞からの希突起神経膠細胞産生を促進する)
神経幹細胞分化に対するGM−CSFの効果を決定するため、神経幹細胞の培養物をマウス胎仔から調製し、迅速分化プロトコールに供した。初代ニューロスフェアを生成するため、胎生14日(E14)マウス神経節隆起(ganglionic eminence)を解離し、培地ホルモン混合物(MHM)+20ng/ml上皮増殖因子(EGF)内で、1週間増殖(grow)させた。MHMの組成は以下:
DMEM/F12(1:1)
グルコース(0.6%)
グルタミン(2mM)
炭酸水素ナトリウム(3mM)
HEPES(5mM)
インシュリン(25μg/ml)
トランスフェリン(100μg/ml)
プロゲステロン(20nM)
プロレシン(60μM)
塩化セリン(30nM)
である。
したがって、GM−CSFは、希突起神経膠細胞の発生の全ての段階において、希突起神経膠細胞のパーセンテージを有意に増加させた。このことは、GM−CSFが希突起神経膠細胞をより効率的に産生するのに使用され得ることを示す。T3のような他の希突起神経膠細胞促進因子は、必要に応じてGM−CSFと組み合わせて採用され得る。
(希突起神経膠細胞生存に対するGM−CSFの効果)
希突起神経膠細胞に対するGM−CSFの生存効果を2系統の実験によって調べた。第1の系統の実験では、神経幹細胞を実施例1に記載したように、GM−CSFまたはT3の存在下または非存在下で培養し、分化培地中での培養の1日後、3日後、または5日後に固定した。固定した細胞を、成熟途上希突起神経膠細胞マーカーGalCおよび死に行く細胞のマーカーであるTUNELで免疫染色した。その後、死に行く成熟途上の希突起神経膠細胞(GalC+、TUNEL+細胞)の数を計数した。そして、全GalC+細胞中のパーセンテージを図2に示す。
(幹細胞増殖(proliferation)中のGM−CSFの効果)
神経幹細胞の増殖(proliferation)に対するGM−CSFの効果を評価するため、実施例1にしたがって調製したニューロスフェア培養物中で生成した細胞の数を、種々の培養培地で1週間増殖(grow)させた場合に、計数した。したがって、E14神経節隆起細胞を、40mlの培地中において、200,000細胞/mlの密度で1週間増殖(grow)させた。培地はMHM+EGF、MHM+EGFおよびGM−CSF、またはMHM+EGFおよびT3であった。その後スフェアを集め、解離し、そして細胞を血球計を用いて計数した。細胞数はコントロール(MHM+EGF)のパーセンテージとして計算した。
(神経幹細胞発生運命決定に対するGM−CSFの効果)
初代ニューロスフェア形成中におけるGM−CSFの存在が神経幹細胞の発生運命決定に影響を与えるかどうかを決定するため、初代ニューロスフェアを、EGFのみ、EGF+GM−CSF、またはEGF+T3のいずれかの中で、実施例3での記載にしたがって、生成した。次いで、初代スフェアを解離し、24ウェルプレート内のポリ−L−オルニチンコートしたカバーグラス上で、1ウェルあたり1mlのMHM中で密度200,000細胞/ウェルとして、平板培養し、5日間に渡り分化させた。分化期間の終わりに、細胞は4%パラホルムアルデヒドを用いて固定し、成熟希突起神経膠細胞マーカーMBP、ニューロンマーカーβ−チューブリン、およびヘキストを用いて免疫染色した。ヘキスト染色によって明らかにされた生細胞の全数、および免疫染色された細胞を計数した。結果を図6に示す。
Claims (40)
- 哺乳動物の多能性神経幹細胞から希突起神経膠細胞を産生する方法であって、該方法は、該多能性神経幹細胞から希突起神経膠細胞の産生をもたらす条件下において、多能性神経幹細胞と、有効量の少なくとも1つの希突起神経膠細胞促進因子とを接触させる工程を包含し、ここで該希突起神経膠細胞促進因子は、顆粒球−マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、インターロイキン3(IL−3)、およびインターロイキン5(IL−5)からなる群から選択される、方法。
- 前記希突起神経膠細胞促進因子が、GM−CSFまたはG−CSFである、請求項1に記載の方法。
- 前記希突起神経膠細胞促進因子が、GM−CSFである、請求項1に記載の方法。
- 前記多能性神経幹細胞をトリヨードチロニンに接触させる工程をさらに包含する、請求項1に記載の方法。
- 前記多能性神経幹細胞が、細胞培養物として提供される、請求項1に記載の方法。
- 前記細胞培養物が哺乳動物脳組織を用いて調製される、請求項5に記載の方法。
- 前記哺乳動物脳組織が非胚性哺乳動物から得られる、請求項6に記載の方法。
- 前記哺乳動物脳組織が成体哺乳動物から得られる、請求項6に記載の方法。
- 前記脳組織が脳室下領域から得られる、請求項6に記載の方法。
- 前記多能性神経幹細胞が哺乳動物内にある、請求項1に記載の方法。
- 前記多能性神経幹細胞が哺乳動物の脳室下領域にある、請求項10に記載の方法。
- 前記多能性神経幹細胞がヒト細胞、イヌ細胞、ネコ細胞、げっ歯類細胞、ヒツジ細胞、ヤギ細胞、ウシ細胞、ウマ細胞、ブタ細胞および非ヒト霊長類細胞からなる群から選択される、請求項1に記載の方法。
- 前記多能性神経幹細胞がヒト細胞である、請求項1に記載の方法。
- 前記多能性神経幹細胞を、有効量の少なくとも1つの、多能性神経幹細胞の数を増加し得る生物学的因子に接触させる工程をさらに包含する、請求項1に記載の方法。
- 前記生物学的因子が、上皮増殖因子(EGF)、線維芽細胞増殖因子(FGF)、脳下垂体アデニル酸シクラーゼ活性化ポリペプチド(PACAP)、トランスフォーミング成長因子α(TGFα)、毛様体神経栄養因子(CNTF)、エストロゲン、卵巣ホルモン、プロラクチン、成長ホルモン、およびインシュリン様増殖因子1からなる群から選択される、請求項14に記載の方法。
- 前記生物学的因子がEGF51Nである、請求項14に記載の方法。
- 前記多能性神経幹細胞が前記希突起神経膠細胞促進因子および前記生物学的因子に同時に接触される、請求項14に記載の方法。
- 前記多能性神経幹細胞が、前記希突起神経膠細胞促進因子に先立って前記生物学的因子に接触される、請求項14に記載の方法。
- 請求項4に記載の方法により産生される前記希突起神経膠細胞を含む組成物。
- 薬学的に受容可能な賦形剤および/または薬学的に受容可能なキャリアをさらに含む、請求項19に記載の組成物。
- 哺乳動物に希突起神経膠細胞を提供する方法であって、該方法は、以下:
(a)多能性神経幹細胞を該哺乳動物に導入し、そして、該神経幹細胞からの希突起神経膠細胞形成をもたらす条件下において、有効量の少なくとも1つの希突起神経膠細胞促進因子を該哺乳動物に投与する工程;または
(b)該哺乳動物に有効量の請求項20に記載された組成物を導入する工程、
を包含する、方法。 - 前記(a)が、前記神経幹細胞を、有効量の少なくとも1つの、神経幹細胞の数を増加し得る生物学的因子に接触させる工程をさらに包含する、請求項21に記載の方法。
- 前記神経幹細胞が、前記哺乳動物に導入されることに先立って、前記生物学的因子に接触される、請求項22に記載の方法。
- 前記生物学的因子が、上皮増殖因子(EGF)、脳下垂体アデニル酸シクラーゼ活性化ポリペプチド(PACAP)、線維芽細胞増殖因子(FGF)、トランスフォーミング成長因子α(TGFα)、毛様体神経栄養因子(CNTF)、エストロゲン、プロラクチン、成長ホルモン、およびインシュリン様増殖因子1からなる群から選択される、請求項22に記載の方法。
- 前記生物学的因子がEGF51Nである、請求項22に記載の方法。
- 前記(a)が、前記多能性神経幹細胞をトリヨードチロニンに接触させる工程をさらに包含する、請求項21に記載の方法。
- 前記哺乳動物が、脱髄疾患を被る、請求項21に記載の方法。
- 前記脱髄疾患が、多発性硬化症、急性播種性脳脊髄炎、びまん性脳硬化症、壊死性出血性脳炎、および白質萎縮症からなる群から選択される、請求項27に記載の方法。
- 前記脱髄疾患が多発性硬化症である、請求項27に記載の方法。
- 前記哺乳動物がヒトである、請求項21に記載の方法。
- 哺乳動物における脱髄疾患を処置または回復させる方法であり、該方法は、該哺乳動物に、有効量の少なくとも1つの希突起神経膠細胞促進因子を投与する工程を包含し、ここで該希突起神経膠細胞促進因子は、顆粒球−マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、インターロイキン3(IL−3)、およびインターロイキン5(IL−5)からなる群から選択される、方法。
- 該希突起神経膠細胞促進因子が該哺乳動物の脳室に投与される、請求項31に記載の方法。
- 該希突起神経膠細胞促進因子が該哺乳動物の側脳室に投与される、請求項31に記載の方法。
- 前記哺乳動物に、有効量の少なくとも1つの、神経幹細胞の数を増加し得る生物学的因子を投与する工程をさらに包含する、請求項31に記載の方法。
- 前記生物学的因子が、上皮増殖因子(EGF)、脳下垂体アデニル酸シクラーゼ活性化ポリペプチド(PACAP)、線維芽細胞増殖因子(FGF)、トランスフォーミング成長因子α(TGFα)、毛様体神経栄養因子(CNTF)、エストロゲン、卵巣ホルモン、プロラクチン、成長ホルモン、およびインシュリン様増殖因子1からなる群から選択される、請求項34に記載の方法。
- 前記生物学的因子がEGF51Nである、請求項34に記載の方法。
- トリヨードチロニンを前記哺乳動物に投与する工程をさらに包含する、請求項31に記載の方法。
- 前記脱髄疾患が、多発性硬化症、急性播種性脳脊髄炎、びまん性脳硬化症、壊死性出血性脳炎、および白質萎縮症からなる群から選択される、請求項31に記載の方法。
- 前記脱髄疾患が多発性硬化症である、請求項31に記載の方法。
- 前記哺乳動物がヒトである、請求項31に記載の方法。
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2003
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AU2003250697B2 (en) | 2008-05-01 |
WO2004011632A2 (en) | 2004-02-05 |
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US7704737B2 (en) | 2010-04-27 |
AU2003250697A1 (en) | 2004-02-16 |
US20120189575A1 (en) | 2012-07-26 |
CA2492542A1 (en) | 2004-02-05 |
EP2095823A1 (en) | 2009-09-02 |
US20050244965A1 (en) | 2005-11-03 |
JP4783013B2 (ja) | 2011-09-28 |
WO2004011632A3 (en) | 2004-04-15 |
EP1549740A2 (en) | 2005-07-06 |
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