JP2014503176A - 幹細胞培養培地および方法 - Google Patents
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Abstract
Description
本明細書の理解を容易にするため、本発明に関連する幾つかの用語および表現の意味について以下に説明する。さらなる定義は必要に応じ明細書全体を通して記載される。
本発明による培地は、BCMAおよびTACIのリガンドおよび/またはその誘導因子を含む。一つの態様によれば、本発明の培地はBAFFまたはBAFFの代替物を含む。別の態様によれば、本発明の培地はAPRILまたはAPRILの代替物を含む。さらなる態様によれば、本発明の培地はAPRILおよびBAFFの代替物を含む。
本発明の培地は、多能性幹細胞集団を増殖させるために使用できる。従って、本発明は、多能性幹細胞集団を増殖させるための本明細書に開示される任意の培地の使用を提供する。
本発明はまた、本明細書に開示される培地を作製するために用いることのできる培地補助剤も提供する。「培地補助剤」は、それ自体では多能性幹細胞を支持できないが、その他の細胞培養成分と組み合わせた場合に多能性幹細胞培養を可能にするかまたは改善する成分の混合物である。それ故、この補助剤はその他の細胞培養成分と組み合わせて適切な培地製剤を作製することにより、本発明の機能的な細胞培養培地を作製するために用いることができる。培地補助剤の使用は当該技術分野において公知である。本発明は、BCMAおよびTACIのリガンドおよび/またはその誘導因子を含む培地補助剤を提供する。この補助剤は、本明細書に開示される任意のリガンドも含んでよい。補助剤はまた、本明細書に開示される1つ以上のさらなる細胞培養成分、例えばアミノ酸、ビタミン、無機塩、炭素エネルギー源、および緩衝液からなる群より選択される1つ以上の細胞培養成分も含有してよい。
本明細書に開示される細胞培養培地および細胞培養補助剤は、多能性幹細胞集団を増殖させるために使用できる。従って、本発明は、本発明の細胞培養培地および細胞培養補助剤を使用する間に生じる組成物を提供する。例えば本発明は、(a)本発明の培地と、(b)多能性幹細胞とを含む組成物を提供する。
本明細書に開示される培養培地および方法は、多能性幹細胞の多分化能を維持し、かつ該細胞が問題のある分化をしない、多能性幹細胞集団を増殖させるために有用である。
hASCの分離および細胞培養
ヒトASCは、健常成人ドナー由来のヒト脂肪組織の脂肪吸引物から調製した。簡潔に述べると、健常成人男性および女性ドナーから吸引したヒト脂肪組織をリン酸緩衝食塩水(PBS)で2回洗浄し、0.075%コラゲナーゼ(タイプI、Invitrogen、カールズバッド、カリフォルニア州)によって消化した。消化したサンプルを10%ウシ胎仔血清(FBS)で洗浄し、160mMのNH4Clで処理して残りの赤血球を除去し、培地(10%FBSを加えたダルベッコ改変イーグル培地;DMEM)に懸濁した。細胞を組織培養フラスコに播き(2〜3×104細胞/cm2)、培地を3〜4日ごとに交換しながら増殖させた(37℃、5%CO2)。細胞が90%コンフルエンスに達したとき、新しいフラスコに移した(103細胞/cm2)。全ての実験について、健常ドナー(3名の男性および3名の女性、35〜47歳)に由来する、独立して増殖させた培養からプールした細胞を用いた。細胞をプールし、おおよそ同一の集団の倍加(倍加12〜16)にて実験を行った。
APRILおよびBAFFの組換えタンパク質はR&D Systems(ミネアポリス、ミネソタ州)から、CXCL12およびIFN−γはPeprotech(ロンドン、英国)から、LPS(Escherichia coli 055:B5)はSigma Aldrich(セントルイス、ミズーリ州)から、そしてポリI:CはInvivoGen(サンディエゴ、カリフォルニア州)から購入した。フローサイトメトリーについては、BCMA、TACI、HLA−I、HLA−II、CD80、CD86に対する一次モノクローナル抗体およびアイソタイプコントロールをBD Bioscience(サンノゼ、カリフォルニア州)から購入した。ウェスタンブロッティング用の抗体は、抗リン酸化Akt(Ser473)、抗Akt、抗リン酸化ERK1/2(Thr202/Tyr204)、抗ERK1/2、抗JNK(全て、Cell Signaling Technology、ベバリー、マサチューセッツ州から購入)、Invitrogen(カールズバッド、カリフォルニア州)から購入した抗リン酸化JNK(Thr183/Tyr185)であった。二次抗体はホースラディッシュペルオキシダーゼ結合ウシ抗ウサギ、およびヤギ抗マウスIgG(Dako、グロストルップ、デンマーク)であった。
培養したhASCまたは新たに純化したPBMC(陽性コントロール)からTRI試薬(Sigma)を用いて全RNAを分離し、この1〜2μgをHigh Capacity cDNA Reverse Transcription Kit(Applied Biosystems)による逆転写反応に用いた。cDNAの連続希釈(1:0、1:5、1:25)により、5’PRIME マスターミックスキットおよびサーモサイクラー(iCycler;BioRad)を用いて半定量PCRを行った。βアクチンは内部コントロールとした。プライマー配列は以下の通りであった。APRIL 順方向 5’−AAGGGTATCCCTGGCAGAGT−3’(配列番号5)および逆方向 5’−GCAGGACAGAGTGCTGCTT−3’(配列番号6)、BAFF 順方向 5’−ACTGAAAATCTTTGAACCACCAG−3’(配列番号7)および逆方向 5’−TTGCAAGCAGTCTTGAGTGAC−3’(配列番号8)、TACI 順方向 5’−CAACTCGGGAAGGTACCAAGGATT−3’(配列番号9)および逆方向 5’−CGCCACCAGGAAGCAGCAGAGGAC−3’(配列番号10)、BCMA 順方向 5’−TTTTCGTGCTAATGTTTTTGCTAA−3’(配列番号11)および逆方向 5’−TTCATCACCAGTCCTGCTCTTTTC−3’(配列番号12)、BAFF−R 順方向 5’−CTGGTCCTGGTGGGTCTG−3’(配列番号13)および逆方向 5’−ACCTTGTCCAGGGGCTCT−3’(配列番号14)、ベータアクチン 順方向 5’−CCCAGCACAATGAAGATCAA−3’(配列番号15)および逆方向 5’−CGATCCACACGGAGTACTTG−3’(配列番号16)(全てSigmaから購入した)。
hASCを回収し、適切な蛍光色素結合抗体で染色した後、フローサイトメトリー(BD FACS Calibur)によって測定した。データはFlowJoプログラム(TreeStar、アシュランド、オレゴン州)によって解析した。
細胞生存率は、CellTiter AQueous One Solution Cell Proliferation Assay(Promega、マディソン、ウィスコンシン州)を製造者のプロトコルに従って用いることにより評価した。hASC(3.5×103細胞/ウェル)を、96ウェルプレート内で100ng/mlのAPRILまたはBAFFと共に6日間培養した。吸光度(OD 490nm)をELISAプレートリーダーにより測定した(n=少なくとも3回の実験)。測定値を、無刺激で培養した細胞の吸光度(100%)に対して標準化した。加えて、BrdU取り込み比色アッセイにより細胞増殖を測定した。hASCをp60プレート内で100ng/mlのAPRILまたはBAFFと共に培養し、最後の3日間にBrdU(20μM)を添加した。6日目に、抗BrdU抗体を用いたフローサイトメトリーによってBrdUの取り込みを検出した。MTSおよびBrdUアッセイを独立して3回行い、各条件は三重とした。
CFSE標識のため、新たに純化したPBMC(10〜20×106)をよく洗浄してFBSを除去し、200μlの10μM CFSE溶液(Sigma)に再懸濁して、持続的に撹拌しながらインキュベートした(37℃、10分)。細胞を洗浄し、一晩培養して、1アリコートをサイトメーターにおけるCFSEのFL−1電位を設定および制御するために用いた。一晩静置後、CFSE標識PBMCは、Pan T Cell Activation Kit(抗CD3、抗CD2、および抗CD28によりコートされたマイクロビーズ、Miltenyi Biotech)を製造者の指示に従って用いて活性化させるか、または活性化されないままとした。PBMC活性化の2日前に、hASCを24ウェルプレートに播いた(4×104細胞/ウェル)。PBMC(106細胞/ml)を単独で、またはhASCと共に、BAFFまたはAPRIL(100ng/ml)の存在下または非存在下で培養した。5日目にPBMCを回収し、FL−1チャネルのCFSEの減少によって細胞増殖を判定した。ゲーティングされたリンパ球(前方散乱/側方散乱特性に基づいて)について、Cellquest−Proソフトウェアを用いてデータを解析した。増殖しているリンパ球のパーセンテージは、最後の48時間培養(第3世代)に相当するFL−1チャネルの領域(M1)内でのゲーティングによって算出した。サイトメーターのキャリブレーションを行うため、各アッセイの前にCaliBRITEビーズ(BD Bioscience)を用いた。
hASCを100ng/mlのAPRILまたはBAFFで刺激し(10、30、60、120分、37℃)、氷上に静置し、氷冷したPBSで洗浄し、細胞溶解緩衝液(Roche、インディアナポリス、インディアナ州)で溶解した。抽出物を吸光度によって定量し、SDS−PAGEで分離し、免疫ブロットによって分析した。使用した抗体は、抗リン酸化Akt(Ser473)、抗Akt、抗リン酸化ERK1/2(Thr202/Tyr204)、および抗ERK1/2)(BD Bioscience)であり、二次抗体はホースラディッシュペルオキシダーゼ結合ウシ抗ウサギおよびヤギ抗マウスIgGであった。
hASC細胞を100ng/mlのAPRIL、BAFFと共に、または無刺激で培養し、次いで1μg/mlのLPSまたはポリI:Cによって刺激した。Cytometric Bead Array (CBA)免疫アッセイ(BD Bioscience)を製造者のプロトコルに従って用いることにより、培地中の48時間後のIL−6およびIL−8濃度を測定した。データはFACScaliburサイトメーターを用いて取得し、FCAPアレイソフトウェア(BD Bioscience)を用いて分析した。あるいは、hASC細胞を、培地、または10、30、もしくは100ng/mlのIFNγ、または10、30、もしくは100nMのCXCL12と共に培養し、5日後に上清を回収した。培地(BAFFに対してはR&D Systems、APRILに対してはBender MedSystem)中のAPRILおよびBAFF濃度をELISAによって測定した。
播いたhASC(1.5×104細胞/cm2)をAPRILまたはBAFF(100ng/ml)で刺激し、プロテアーゼおよびホスファターゼ阻害剤を加えた溶解緩衝液(Roche)によって溶解した。抽出物中のタンパク質を、BCAプロテインアッセイキット(Pierce)を用いて吸光度により定量し、同量のタンパク質ホモジネートをSDS−PAGEで分離した後、PVDF膜(Millipore)へ転写した。5%BSAを含むTBS−T中でブロットを遮断し、抗リン酸化Akt(Ser473)、抗Akt、抗リン酸化ERK1/2(Thr202/Tyr204)、および抗ERK1/2抗体(全てCell Signaling Technologyから購入した)によって探索した。TBS−T中で膜を洗浄し、HRP結合二次抗体(Dako)と共にインキュベートして、反応性をECL(GE Healthcare)により検出した。
統計解析(スチューデントt検定)は、GraphPad Prism 4.0(GraphPadソフトウェア)を用いて行った。結果を平均±SDで表す。P値(両側)***p<0.0001、**p<0.001、および*p<0.001を統計学的に有意であるとみなした。
hASCにおけるAPRIL、BAFF、およびそれらの受容体の発現
APRIL/BAFF系の発現特性をRT−PCRによって調べるため、培養したhASC由来のmRNAサンプルを調製し、上記のヒトプライマーを用いて分析した。両リガンドに対する、APRILおよびBAFFにより共有される受容体であるBCMAおよびTACIに対する、およびBAFF単独に結合するBAFF−Rに対するmRNA転写産物が検出された(図1A)。バッフィーコートから精製したPBMCは全てのファミリーメンバーを発現することから、陽性コントロールとして用いた。APRILおよびBAFFは単球によって産生され、TACI、BCMA、およびBAFF−RはB細胞および形質細胞によって産生される。hASCの上清の分析により、APRILタンパク質の濃度は3.97±0.72ng/ml(n=6、6日目)であったが、BAFFは検出されなかったことが示された(図1B)。
ヒトASCをAPRILまたはBAFFで刺激し、MAPキナーゼ(p38、ERK1/2、JNK)、Akt、およびIκBαのリン酸化動態をウェスタンブロットによって分析した。APRILおよびBAFFの両方によって、AktおよびERK1/2の急速なリン酸化が誘導され、Aktの活性化はERK1/2の活性化よりも強力であった(図2、JNK、IκBα、またはp38については明らかな効果がみられなかった)。おそらくはBAFF特異的受容体であるBAFF−RとTACIおよび/またはBCMAのシグナル伝達との相乗作用のため、BAFFはAPRILよりもさらに強い持続性の応答を促進することがウェスタンブロットのバンドによって示唆された。これらのデータにより、APRILおよびBAFFリガンドは、hASCにおけるそれらの受容体を介し、キナーゼタンパク質であるAktおよびERK1/2を活性化することによってシグナル伝達を可能にすることが示される。
MTSアッセイにおいて、両サイトカインは共にhASCの基礎増殖を培養の6日後に増大させたが、BAFFの刺激はAPRILよりも強力であった(基礎増殖を100%と考えると、それぞれ140%および114%増大した。図3A)。APRILと比較したBAFFのより大きな効果は、そのBAFF−Rへの結合による可能性がある。APRILまたはBAFFによって刺激したhASCにおけるBrdU取り込みによって細胞増殖を測定すると、BrdU陽性細胞のパーセンテージによって同様の増大が観察されたが、これは13%(コントロール)から29.4%(BAFF)および27.5%(APRIL)であった(図3B)。APRIL/BAFFによって増大したhASCの増殖の基礎をなす機序にAktまたはERKが関わっているか否かについて、これらの経路を遮断するPI3K(LY294002)およびERK(U0126)の活性化に対する阻害剤を用いて試験した。PI3Kの阻害剤を培地に添加したときに、hASCの基礎増殖は100%(コントロール)から60.3%に低下したが、ERK阻害剤では低下しなかったことがMTSアッセイにより示されたことから(図3C)、hASCの基礎増殖にはPI3Kの伝達経路が関与していることが示される。ERKを阻害したときにAPRILおよびBAFFは細胞増殖を促進しなかったが、PI3Kを阻害した際には促進したことから、両TNFリガンドはERKのシグナル伝達を介してこの効果を誘導していることが示唆される(図3C)。
APRILおよびBAFFは、RAまたはSLEのような慢性炎症性疾患の患者の血清および組織病変部に過剰発現している。それ故、BAFFおよびAPRILがhASCの免疫学的特性を調節し得るか否かを理解することは、臨床上および治療上の観点から価値がある。APRIL/BAFFはTLR(Toll様受容体)リガンドの共刺激分子として説明され、さらにこれらの分泌がTLRの活性化によって誘導されることから、このことがhASCでも当てはまるかどうかについて調べた。細胞を単独またはAPRILもしくはBAFFと共に培養した後、LPSまたはポリI:Cで活性化した。いずれのリガンドもAPRILまたはBAFFの分泌を誘導せず、APRILもBAFFも、LPSまたはポリI:Cにより誘導されるIL−6またはIL−8の産生に影響を与えなかった(図4A)。hASCの免疫調節能は、それらの治療への使用の可能性において鍵となる因子である。活性化されたCFSE標識PBMCの増殖を単独で、あるいは培地のみかまたはBAFFもしくはAPRILを補って培養した同種のhASCの存在下で分析することにより、hASCの免疫応答抑制能におけるBAFF/APRILの効果を試験した(図4B)。予想したように、hASCはPBMCの増殖を効果的に抑制した。APRILまたはBAFFの培地への添加によって、hASCがPBMCの増殖を抑制する能力は変化しなかった。BAFF/APRILの活性化により、リンパ球増殖の抑制に関わる、トリプトファン代謝酵素であるインドールアミン−2,3−ジオキシゲナーゼ(IDO)は誘導されなかった。APRILまたはBAFFの活性化がhASCの免疫原性特性を変化させるか否かについて試験するため、HLA−I、HLA−II、CD80、およびCD86の発現をフローサイトメトリーによって分析すると、BAFFおよびAPRILは、hASCにおけるこれらの活性化分子の発現に影響しないことが見出された。これらの結果により、APRILまたはBAFFの刺激によって、hASCの免疫原性および免疫調節性の性質が顕著には損なわれないことが示される。
hASCを介した免疫抑制および細胞の遊走にそれぞれ関係する2つのサイトカイン、IFN−γおよびCXCL12に焦点を合わせ、hASCにおけるAPRILまたはBAFFの分泌を促進し得る分子について調べた。図4Cに、IFN−γ(10、30、100ng/ml)またはCXCL12(10、30、100nM)による刺激後のAPRILおよびBAFF濃度を測定した用量反応曲線を示す。これらの結果によって、CXCL12はAPRILを選択的に増加させるが、IFN−γはBAFFの分泌を促進することが実証されたことから、それぞれのTNFサイトカインは異なった刺激に応答してhASCから分泌されることが示された。
Claims (12)
- BCMAおよびTACIのリガンドおよび/またはその誘導因子を含んでなる、幹細胞集団を増殖させるための培地。
- 約10pMないし約100mMの、BCMAおよびTACIのリガンドおよび/またはその誘導因子を含んでなる、請求項1に記載の培地。
- BCMAおよびTACIのリガンドおよび/またはその誘導因子を含んでなる、培地補助剤。
- (a)固体表面と、(b)BCMAおよびTACIのリガンドおよび/またはその誘導因子を含む培地とを含んでなる、細胞培養用容器。
- (a)請求項1〜3のいずれか一項に記載の培地と、(b)幹細胞とを含んでなる、組成物。
- 幹細胞集団を増殖させる方法であって、(a)幹細胞集団を用意する工程と、(b)請求項1〜3のいずれか一項に記載の培地を用意する工程と、(c)前記幹細胞を前記培地に接触させる工程と、(d)前記幹細胞を適切な条件下で培養する工程とを含んでなる、方法。
- 細胞治療薬の製造における、BCMAおよびTACIのリガンドおよび/またはその誘導因子の使用。
- 幹細胞集団を増殖させるための、(a)固体表面と、(b)BCMAおよびTACIのリガンドおよび/またはその誘導因子との使用。
- 幹細胞集団を増殖させるための、請求項1〜3のいずれか一項に記載の培地、容器、または補助剤の使用。
- 前記リガンドがBAFFおよび/またはAPRILを含んでなる、先行する請求項のいずれか一項に記載の培地、組成物、方法、容器、または使用。
- BAFFまたはBAFF代替物を含んでなる、先行する請求項のいずれか一項に記載の培地、組成物、方法、容器、または使用。
- APRILまたはAPRIL代替物を含んでなる、先行する請求項のいずれか一項に記載の培地、組成物、方法、容器、または使用。
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