JP2014097063A - 分化可能細胞の培養に有用な組成物及び方法 - Google Patents
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Abstract
【解決手段】多能性幹細胞と、基礎塩栄養液と、ErbB3リガンドとを含む組成物であって、実質的に無血清であり、多能性幹細胞は3つの胚葉のすべてを生じ得るものであり、ErbB3リガンドはErbB3受容体に結合し、これがErbB2受容体と共に二量体化してErbB2/ErbB3ヘテロ二量体を形成し得るものであり、これにより、ErbB2/ErbB3ヘテロ二量体においてErbB2受容体のチロシンキナーゼ活性が活性化される、組成物。
【選択図】なし
Description
本出願は、2006年2月23日出願の米国仮特許出願第60/776,113号明細書に対する優先権を主張し、これを参照により援用する。
本発明の開発中に実施された作業の一部は、国立衛生研究所(National Institutes of Health)補助金交付番号第5R24RR021313−05号による米国政府資金を利用した。米国政府は本発明に一定の権利を有する。
リアルタイムRT−PCRを使用して、BG01v細胞におけるErbB1〜3、ニューレグリン及びADAM−19の発現を実証した(図1)。100ng/mlのLongR3−IGF1(LR−IGF1)、8ng/mlのFGF2及び1ng/mlのアクチビンAを含有する上記のとおりのDC培地で培養されたBG01v細胞が回収され、RNeasyミニキット(Qiagen)を使用して製造者の指示に従いRNAが調製された。iScriptキット(Biorad)を使用して第1鎖cDNAが調製され、MJ Research Opticonサーマルサイクラーを使用してリアルタイムPCRが実行された。
リガンドのEGFドメインファミリーは、受容体チロシンキナーゼのErbBファミリーと結合する。hESCにおけるErbBチロシンキナーゼの既知の阻害剤の効果を調査するため、BG01v細胞が、6ウェルトレイのなか1:1000で希釈されたMATRIGEL(商標)上、100ng/mlのLongR3−IGF1、8ng/mlのFGF2及び1ng/mlのアクチビンAを含有する限定培養培地(DC)にプレーティングされた。翌日、DMSO(担体対照)、50nM〜20μMのAG1478(ErbB1阻害剤)、又は100nM〜20μMのAG879(ErbB2阻害剤)が新鮮培地と共に添加された。細胞はさらに5日間培養され、培地は毎日交換された。次に培養物は固定され、アルカリホスファターゼ活性について染色された。
ErbB2及びErbB3の発現及びAG879による増殖の阻害から、BG01v細胞が活性な内因性ErbBシグナル伝達を有するとともに、外因性HRG−βにもまた応答し得ることが示唆された。BG01v細胞を、1:1000に希釈されたMATRIGEL(商標)上、10ng/mlのHRG−β、200ng/mlのLongR3−IGF1、8ng/mlのFGF2及び10ng/mlのアクチビンAを含むDC培地で成長させた(図3A及びB)。4代にわたり、すなわち20日超の間成長させたこれらの細胞は、未分化形態を呈し、自発的な分化の上昇は示さなかった。
RT−PCRにより、mESCが、ADAM19、ニューレグリン1(Nrg1)、及びErbB1〜4を発現することが実証された(図4A)。mESCにおいて、ErbB2及び3はErbB1より高いレベルで発現したように見え、ErbB4の検出は低いレベルであった。これらのデータから、内因性HRG−βがmESC自己複製の促進に関与している可能性が示唆される。
マウスES細胞におけるHRG/ErbB2シグナル伝達の役割をさらに調査するため、DC培地中でのR1 ES細胞の増殖が、成長因子の組み合わせを使用して調査された。1×105細胞/ウェルが、0.2%ゼラチンでコーティングされた6ウェルトレイのなか、10ng/mlのHRG−β、100ng/mlのLongR3−IGF1、1ng/mlのアクチビンA、1000U/mlのマウスLIF又は10ng/mlのBMP4(下表1)の組み合わせを含むDCにプレーティングされた。8日間にわたり増殖が観察された。
複数の手法を使用して、DC−HAIFでのhESCの可塑性の維持を確認した。DC−HAIFで6ヶ月間(25代)培養されたBG02細胞は、複合奇形腫(図8A)及び3つの典型的な胚葉をインビトロで(図8B)形成する可能性を維持した。転写解析を使用して、CM及びDC−HAIFで維持されたhESC細胞における全体的な発現を比較した(Liuら、2006年、BMC Dev Biol 6、20頁)。DC−HAIFで10代及び32代にわたり成長させたBG02細胞、及びCMで64代にわたり成長させたBG02細胞においては11,600個より多い転写産物が検出された。全ての集団に共通の転写産物が約10364個あり(図8C)、これにはCD9、DNMT3、NANOG、OCT4、TERT及びUTF1などの既知のhESCマーカーが含まれていた(図示せず)。CM培養物とDC−HAIF培養物との比較(R2選択=0.928)、並びに継代細胞の初期と後期との比較(R2選択=0.959)では、高い相関係数が観測された(図8D)。階層クラスタ分析から、DC−HAIFで維持されたBG02細胞が高度に群化され、CMで維持されたBG02細胞及びBG03細胞との高い類似性を保持したことが明らかとなった(図8E)。これらのデータは、未分化hESCが胚様体又は線維芽細胞と比較して高度にクラスタ化されたことを示した先行分析(Liuら、2006年、BMC Dev Biol 6、20頁)と一致する。このように、本発明の組成物で維持された細胞は、多能性(pluirpotency)の主要なマーカーを維持することが可能である。従って、本発明の組成物は、分化可能細胞の自己複製を支持するための単純培地として使用できる。
ErbB2シグナル伝達の役割を調べてhESC用の限定培地を開発するため、最初に、成長因子低減MATRIGEL(商標)1:30でコーティングした培養皿上でDC−HAIF培養物を増殖させたが、1:200(図9A)、又は1:1000で希釈したこの基質上での長期間の維持にも成功することができた。BG02及びCyT49 hESCはまた、ヒト血清(図9B)、ヒトフィブロネクチン(図9C)、又は専売のヒト化ECMであるVITROGRO(商標)(図9D)でコーティングされた組織培養皿上でも5代より長く維持できた。
複数の研究グループが、特定の三倍性(triplodies)、特にhChr12及び17の三倍性が、特定の準最適培養条件下でhESCに蓄積されることを実証している(Bakerら、2007年 Nat.Biotech.25(2):207−215頁)。三倍性の出現は、継代において培養物が単一細胞に分割されるときの細胞生存率の低さと最も直接的に関係しているものと思われ、これらの異数性を内包する細胞に強い選択的成長の優位性をもたらすことが推定される。逆に、本発明の一実施形態、DC−HAIFで成長するhESCは、単一細胞に分割された後のプレーティングにおいて高い生存率を維持した(図10A〜D)。BG01及びBG02細胞は、ACCUTASE(商標)によりそれぞれ18代及び19代より長く継代された後も正常核型を維持した(図10E)。細胞における正常核型の維持から、hESC培養物の単一細胞への脱凝集は、DC−HAIFで維持されたhESCにおいては本質的にこうしたトリソミーの蓄積につながらないことが実証された。BG01及びBG02培養物はまた、複数の継代作用剤で単一細胞に脱凝集することによっても継代された(図11)。培養物は5代にわたりACCUTASE(商標)、0.25%のトリプシン/EDTA、TrypLE、又はVERSENE(商標)(EDTA)により分割され、核型決定された。データから、本発明の組成物でのhESCの培養及び継代により、様々な細胞解離試薬を使用して、少なくとも2つのヒト胚細胞系において正常核型が維持されたことが実証された。
本質的に、hESCについてこれまで報告されている培養条件の全ては超生理学的なレベルのインスリンを含み、それによりIR及びIGF1Rの双方を刺激できる。IGF1と比較して、インスリン及びインスリン代用物の及ぼす活性を識別するため、hESCが生理学的レベルのこれらの成長因子における限定培地条件下で培養される。インスリン及びIGF1の濃度が約0.2〜約200ng/mlで滴定され、細胞を5日後に計数することにより細胞増殖がモニタされる。増殖に成功した培養物は連続的に5回継代される。生理学的レベルのIGF1がhESC培養物の増殖を支持する一方、生理学的レベルのインスリンは支持せず、これはインスリン又はインスリン代用物の活性がIGF1の代わりにはならないこと、及びIGF1及びインスリン(又はインスリン代用物)がhESCに対する作用に関して別個のクラスの生物活性に相当することを示す。
最初に、中程度の密度で成長するhESCの成長又は分化に対するビタミンB12及びビタミンB6の効果を調査するため、BG02細胞がACCUTASE(商標)を使用して分割され、1×105細胞/ウェルが6ウェルトレイの限定培養(DC)培地にプレーティングされる。DC培地は、10ng/mlのHRG−β、200ng/mlのLongR3−IGF1、及び10ng/mlのFGF10を含む。ビタミンB6(0.5μM)及び/又はビタミンB12(0.5μM)が実験用ウェルに添加される。各条件の細胞数が7日後に計数される。実験用ウェル及び対照ウェルの双方の細胞計数及びコロニー計数から、ビタミンB6及びビタミンB12の細胞成長に対する効果に関する洞察が提供されることとなる。
BG02細胞が20代にわたりDC−HAIで長期間維持され(図13A)、BG01細胞もまたDC−HAIで連続継代され、双方ともFGF2の不在下であった。培養物は劣化したり、又は明白な分化を呈したりはせず、培養期間全体を通じて未分化コロニーの正常な増殖を呈した。BG02培養物における正常な男性核型の維持が、6代後もDC−HAIにおいて実証された(図13B、20/20正常中期伸展)。
Claims (42)
- 基礎塩栄養液及びErbB3リガンドを含む組成物であって、実質的に無血清である、組成物。
- 外因性インスリン及びインスリン代用物を含まない、請求項1に記載の組成物。
- インスリン様成長因子又はその機能断片をさらに含む、請求項2に記載の組成物。
- 前記ErbB3リガンドが、ニューレグリン1、ヘレグリンβ(HRG−β)、ヘレグリンα(HRG−α)、Neu分化因子(NDF)、アセチルコリン受容体誘導活性(ARIA)、グリア成長因子2(GGF2)、運動ニューロン由来因子(SMDF)、ニューレグリン2、ニューレグリン2β(NRG2−β)、エピレギュリン、ビレギュリン及びこれらの機能断片からなる群から選択される、請求項2に記載の組成物。
- 前記ErbB3リガンドがHRG−β又はその機能断片である、請求項4に記載の組成物。
- 形質転換成長因子β(TGF−β)、TGF−βファミリーメンバー又はこれらの機能断片をさらに含む、請求項5に記載の組成物。
- 前記TGF−βファミリーメンバーが、ノーダル、アクチビンA、アクチビンB、骨形態形成タンパク質2(BMP2)、骨形態形成タンパク質4(BMP4)、及びこれらの機能断片からなる群から選択される、請求項6に記載の組成物。
- アクチビンAを含む、請求項7に記載の組成物。
- インスリン様成長因子又はその機能断片をさらに含む、請求項8に記載の組成物。
- 外因性線維芽細胞成長因子を含まない、請求項9に記載の組成物。
- FGF−2、FGF−7、FGF−10、FGF−22及びこれらの機能断片からなる群から選択される少なくとも1つの線維芽細胞成長因子(FGF)をさらに含む、請求項9に記載の組成物。
- 前記少なくとも1つのFGFが、FGF−7、FGF−10及びFGF−22である、請求項11に記載の組成物。
- 血清アルブミン(SA)をさらに含む、請求項12に記載の組成物。
- 前記SAがウシSA(BSA)又はヒトSA(HSA)である、請求項13に記載の組成物。
- 前記SAの濃度が容量対容量(v/v)で約0.2%より高い、請求項14に記載の組成物。
- 前記SAの濃度が約5v/v%未満である、請求項14に記載の組成物。
- 少なくとも1つの不溶性基質をさらに含む、請求項16に記載の組成物。
- 前記少なくとも1つの不溶性基質が、コラーゲン、フィブロネクチン及びこれらの断片からなる群から選択される、請求項17に記載の組成物。
- 基礎塩栄養液と、分化可能細胞におけるErbB2特異的チロシンキナーゼ活性を刺激するための手段とを含む組成物。
- 前記ErbB2特異的チロシンキナーゼ活性を刺激するための手段が、前記分化可能細胞中のErbB3を特異的に結合する少なくとも1つのリガンドを含む、請求項19に記載の組成物。
- 前記分化可能細胞が霊長類胚性幹細胞である、請求項20に記載の組成物。
- 分化可能細胞の培養方法であって、
a)前記分化可能細胞を細胞培養表面にプレーティングする工程と、
b)前記分化可能細胞に基礎塩栄養液を与える工程と、
c)ErbB3と特異的に結合するリガンドを与える工程と、
を含む、方法。 - 前記分化可能細胞が霊長類胚性幹細胞である、請求項22に記載の方法。
- 前記胚性幹細胞にインスリン及びインスリン代用物のどちらも与えない、請求項23に記載の方法。
- インスリン様成長因子又はその機能断片を前記胚性幹細胞に与える工程をさらに含む、請求項23に記載の方法。
- ErbB3を特異的に結合する前記リガンドが、ニューレグリン1、ヘレグリンβ(HRG−β)、ヘレグリンα(HRG−α)、Neu分化因子(NDF)、アセチルコリン受容体誘導活性(ARIA)、グリア成長因子2(GGF2)、運動ニューロン由来因子(SMDF)、ニューレグリン2、ニューレグリン2β(NRG2−β)、エピレギュリン、ビレギュリン及びこれらの機能断片からなる群から選択される、請求項25に記載の方法。
- 前記リガンドがHRG−β又はその機能断片である、請求項26に記載の方法。
- 前記細胞に形質転換成長因子β(TGF−β)、TGF−βファミリーメンバー又はこれらの機能断片を与える工程をさらに含む、請求項27に記載の方法。
- 前記TGF−βファミリーメンバーが、ノーダル、アクチビンA、アクチビンB、骨形態形成タンパク質2(BMP2)、骨形態形成タンパク質4(BMP4)、及びこれらの機能断片からなる群から選択される、請求項28に記載の方法。
- インスリン様成長因子又はその機能断片を前記胚性幹細胞に与える工程をさらに含む、請求項29に記載の方法。
- FGF−2、FGF−7、FGF−10、FGF−22及びこれらの機能断片からなる群から選択される少なくとも1つの線維芽細胞成長因子(FGF)を前記胚性幹細胞に与える工程をさらに含む、請求項30に記載の方法。
- 前記少なくとも1つのFGFが、FGF−7、FGF−10及びFGF−22である、請求項31に記載の方法。
- 血清アルブミン(SA)を前記胚性幹細胞に与える工程をさらに含む、請求項32に記載の方法。
- 前記SAがウシSA(BSA)又はヒトSA(HSA)である、請求項33に記載の方法。
- 前記SAの濃度が容量対容量(v/v)で約0.2%より高い、請求項34に記載の方法。
- 前記SAの濃度が約5v/v%未満である、請求項35に記載の方法。
- 少なくとも1つの不溶性基質を前記胚性幹細胞に与える工程をさらに含む、請求項36に記載の方法。
- 前記少なくとも1つの不溶性基質が、コラーゲン、フィブロネクチン及びこれらの断片からなる群から選択される、請求項37に記載の方法。
- 分化可能細胞の培養方法であって、
a)前記分化可能細胞を細胞培養表面にプレーティングする工程と、
b)基礎塩栄養液を前記分化可能細胞に与える工程と、
c)前記分化可能細胞におけるErbB2特異的チロシンキナーゼ活性を刺激するための手段を提供する工程と、
を含む、方法。 - 前記分化可能細胞が霊長類幹細胞である、請求項39に記載の方法。
- 前記ErbB2特異的チロシンキナーゼ活性を刺激するための手段を提供する工程が、ErbB3を特異的に結合するリガンドを提供する工程を含む、請求項39に記載の方法。
- 分化可能細胞の培養方法であって、
a)細胞溶解試薬を前記分化可能細胞の層に与えて前記細胞を単一細胞に分解する工程であって、前記分化可能細胞の層が消化に先立ち培養チャンバに入れられる工程と、
b)前記単一細胞を組織培養チャンバ内に置く工程と、
c)細胞培養液を与える工程であって、前記幹細胞培養液が基礎塩栄養液及びErbB3リガンドを含む工程と、
d)前記培養された単一細胞を、前記単一細胞の成長及び***が可能な条件下に置く工程と、
を含む、方法。
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