JP2015519907A - 膵内分泌細胞へのヒト胚性幹細胞の分化 - Google Patents
膵内分泌細胞へのヒト胚性幹細胞の分化 Download PDFInfo
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Abstract
Description
本出願は、2012年6月8日に出願された、米国特許仮出願第61/657,160号の利益を主張するものであり、その全体が、あらゆる目的について参照により本明細書に組み込まれる。
本発明は、細胞分化の分野にある。より具体的には、本発明は、内分泌細胞への多能性幹細胞の分化の調節因子として、エフリンリガンド及びスフィンゴシン−1−リン酸塩の使用を開示する。
幹細胞は、単一細胞レベルでの自己再生能及び分化能の両方によって定義される未分化細胞である。幹細胞は、自己再生前駆細胞、非再生性前駆細胞、及び最終分化細胞を含む子孫細胞を生成することができる。幹細胞はまた、複数の胚葉(内胚葉、中胚葉及び外胚葉)から様々な細胞系統の機能性細胞へとインビトロで分化する能力を特徴とする。幹細胞は、移植後に複数の胚葉の組織を生じさせ、胚盤胞に注入後、実質的に(全てではないとしても)ほとんどの組織に寄与する。
多能性幹細胞は、段階特異的胚抗原(SSEA)3及び4、並びにTra−1−60及びTra−1−81と呼ばれる抗体を使用して検出可能なマーカーのうちの1つ以上を発現することができる(Thomsonら、1998、Science 282:1145〜1147)。インビトロでの多能性幹細胞の分化は、SSEA−4、Tra−1−60、及びTra−1−81の発現の消失をもたらす。未分化多能性幹細胞は、一般にアルカリホスファターゼ活性を有し、これは、製造業者(米国カリフォルニア州のVector Laboratories)により説明されているように、細胞を4%パラホルムアルデヒドで固定した後、基質としてVector Redを使用して現像することにより検出することができる。未分化の多能性幹細胞はまた、RT−PCRにより検出されるように、一般にOCT4及びTERTも発現する。
使用が可能な多能性幹細胞の種類としては、妊娠期間中の任意の時期(必ずしもではないが、通常は妊娠約10〜12週よりも前)に採取した前胚性組織(例えば胚盤胞など)、胚性組織、又は胎児組織などの、妊娠後に形成される組織に由来する多能性細胞の樹立株が含まれる。非限定的な例は、ヒト胚性幹細胞(hESCs)又はヒト胚生殖細胞の樹立株であり、例えば、ヒト胚性幹細胞株H1、H7、及びH9(米国ウィスコンシン州MadisonのWiCell Research Institute)などである。フィーダー細胞の不在下で既に培養された多能性幹細胞集団から採取した細胞も好適である。また、OCT4、NANOG、Sox2、KLF4、及びZFP42等の多数の多能性に関係する転写因子の強制発現を用いて、成体体細胞から誘導することができる誘導性多能性細胞(IPS)又は再プログラム化された多能性細胞も好適である(Annu Rev Genomics Hum Genet,2011,12:165〜185)。本発明の方法に使用されるヒト胚性幹細胞は、Thomsonらによって記述されたように調製してもよい(米国特許第5,843,780号;Science,1998,282:1145〜1147;Curr Top Dev Biol 1998,38:133〜165;Proc Natl Acad Sci U.S.A.1995,92:7844〜7848)。
多能性幹細胞の特徴は当業者に周知であり、多能性幹細胞の更なる特徴は、継続して同定されている。多能性幹細胞のマーカーとして、例えば、以下のもの、すなわち、ABCG2、cripto、FOXD3、CONNEXIN43、CONNEXIN45、OCT4、SOX2、NANOG、hTERT、UTF1、ZFP42、SSEA−3、SSEA−4、Tra 1−60、Tra 1−81の1つ以上の発現が挙げられる。
インスリン発現の強力な誘発因子としてのエフリンA4の確認
本実施例は、ヒトES細胞の分化から膵内胚葉/内分泌培養の産出に関する多様なタンパクの役割を理解するために実施された。
a)ステージ1(胚体内胚葉(DE)−3日):細胞は、ステージ1培地(0.1%の無脂肪酸BSA(カタログ番号68700,米国アイオワ州アンケニーのProliant)、0.0012g/mLの重炭酸ナトリウム(カタログ番号S3187、米国ミズーリ州セントルイスのSigmaAldrich)、1X GlutaMax(商標)(Invitrogen、カタログ番号35050−079)、4.5mMのD−グルコース(SigmaAldrich、カタログ番号G8769)、100ng/mLのGDF8(米国ミネソタ州ミネアポリスのR&D Systems)及び1μMのMCX化合物(GSK3B阻害剤、14−Prop−2−エン−1−イル−3,5,7,14,17,23,27−へプタアザテトラシクロ[19.3.1.1〜2,6〜.1〜8,12〜]へプタコサ−1(25),2(27),3,5,8(26),9,11,21,23−ノナエン−16−オン、米国特許出願公開第2010−0015711号;参照によりその全体を本明細書に組み入れる)を補充したMCDB−131培地(カタログ番号10372−019、米国カリフォルニア州カールスバッドのInvitrogen)において1日間培養した。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、100ng/mLのGDF8、及び0.1μMのMCX化合物を補充したMCDB−131倍地でもう1日培養した。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、及び100ng/mLのGDF8を補充したMCDB−131倍地でもう1日培養し、次いで、
b)ステージ2(前駆腸管−2日):細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、0.25mMのアスコルビン酸(米国ミズーリ州セントルイスのSigma)、及び25ng/mLのFGF7(米国ミネソタ州ミネアポリスのR & D Systems)を補充したMCDB−131培地で2日間処理し、次いで、
c)ステージ3(前腸−2日):細胞は、1日目は、ITS−Xの1:200希釈(Invitrogen)、4.5mMのGlucose、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1(米国ミズーリ州セントルイスのSigma)、10ng/mLのアクチビン−A(R & D Systems)、1μMレチノイン酸(RA、Sigma)、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB(PKC賦活体;カタログ番号565740;米国ニュージャージー州ギブスタウンのEMD Chemicals)、10μMのフォルスコリン(FSK、Sigma)、及び100nMのLDN(BMP受容体阻害剤;カタログ番号04−0019;米国カリフォルニア州サンディエゴのStemgent)を補充したMCDB−131培地で処理した。2日目、細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、10ng/mLのアクチビンA、1μMのRA、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB、10μMのフォルスコリン、及び10nMのLDNを補充したMCDB−131倍地で処理し、次いで、
d)ステージ4(膵臓前腸前駆細胞−2日):細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、50μMのLDN−193189、10μMのフォルスコリン、0.25mMのアスコルビン酸、及び100nMのTPBを補充したMCDB−131倍地で2日間処理し、次いで、
e)ステージ5(膵内胚葉/内分泌−3日):ステージ4細胞は、ITS−Xの1:200希釈、20mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、10μMのフォルスコリン、0.25mMのアスコルビン酸を補充し、2〜3日目のみ、100nMのALk5阻害剤SD−208(Molecular Pharmacology 2007,72:152〜161に開示される)を添加したMCDB−131培地で3日間処理した。
S5でのインスリン発現に関するエフリンの影響の検証
この実施例は、実施例1において特定された該当点の検定を説明する。具体的には、プロトコルのS5でのエフリン−A3又はエフリン−A4の添加の影響を以下に列挙する。
a)ステージ1(胚体内胚葉(DE)−3日):細胞は、ステージ1の培地(上記の実施例1を参照)で1日間培養した。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、100ng/mLのGDF8、及び0.1μMのMCX化合物を補充したMCDB−131倍地でもう1日培養した。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、及び100ng/mLのGDF8を補充したMCDB−131倍地でもう1日培養し、次いで、
b)ステージ2(前駆腸管−2日):細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、0.25mMのアスコルビン酸(米国ミズーリ州のSigma)、及び25ng/mLのFGF7(米国ミネソタ州のR & D Systems)を補充したMCDB−131培地で2日間処理し、次いで、
c)ステージ3(前腸−2日):細胞は、1日目、1:200希釈のITS−X(米国カリフォルニア州のInvitrogen)、4.5mMのグルコース、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1(米国ミズーリ州のSigma)、10ng/mLのアクチビン−A(米国ミネソタ州のR & D Systems)、1μMのレチノイン酸(米国ミズーリ州のSigma)、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB(PKC賦活体、カタログ番号565740、米国ニュージャージー州ギブスタウンのEMD Chemicals)、10μMのフォルスコリン、及び100nMのLDN(BMP受容体阻害剤、カタログ番号04−0019、Stemgent)を補充したMCDB−131培地で処理した。2日目、細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、10ng/mLのアクチビン−A、1μMのRA、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB、10μMのフォルスコリン、及び10nMのLDNを補充したMCDB−131倍地で処理し、次いで、
d)ステージ4(膵臓前腸前駆細胞−2日):細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、50μMのLDN−193189、10μMのフォルスコリン、0.25mMのアスコルビン酸、及び100nMのTPBを補充したMCDB−131倍地で2日間処理し、次いで、
e)ステージ5(膵内胚葉/内分泌−3日):ステージ4細胞は、ITS−Xの1:200希釈;4.5mMグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、10μMのフォルスコリン、0.25mMのアスコルビン酸、100nMのALk5阻害剤(2〜3日目のみ)(SD−208、Molecular Pharmacology 2007,72:152〜161に開示)、及び+/−0〜100ng/mLのエフリン−A3又はエフリン−A4(米国ミネソタ州のR & D systems)を補充したMCDB−131培地で3日間処理した。
S6でのスフィンゴシン−1−リン酸塩の添加は、内分泌ホルモンを含む細胞クラスター形成を大幅に加速
この実施例では、ステージ6での内分泌腺クラスター形成の進行、及び内分泌腺リッチクラスターの形成の加速化におけるスフィンゴシン−1−リン酸塩の影響を説明する。
a)ステージ1(胚体内胚葉(DE)−3日):細胞は、ステージ1の培地(上記の実施例1を参照)で1日間培養された。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、100ng/mLのGDF8、及び0.1μMのMCX化合物を補充したMCDB−131倍地でもう1日培養した。次いで、細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、及び100ng/mLのGDF8を補充したMCDB−131倍地でもう1日培養し、次いで、
b)ステージ2(前駆腸管−2日):細胞は、0.1%の無脂肪酸BSA、0.0012g/mLの重炭酸ナトリウム、1X GlutaMax(商標)、4.5mMのD−グルコース、0.25mMのアスコルビン酸(米国ミズーリ州のSigma)及び25ng/mLのFGF7(米国ミネソタ州のR & D Systems)を補充したMCDB−131培地で2日間処理し、次いで、
c)ステージ3(前腸−2日):細胞は、1日目、ITS−Xの1:200希釈(米国カリフォルニア州のInvitrogen)、4.5mMのグルコース、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1(米国ミズーリ州のSigma)、10ng/mLのアクチビン−A(米国ミネソタ州のR & D Systems)、1μMのレチノイン酸(米国ミズーリ州のSigma)、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB(PKC賦活体、カタログ番号565740、米国ニュージャージー州ギブスタウンのEMD Chemicals)、10μMのフォルスコリン(FSK、米国ミズーリ州のSigma)、及び100nMのLDN(BMP受容体阻害剤、カタログ番号04−0019、米国カリフォルニア州のStemgent)を補充したMCDB−131培地で処理した。2日目、細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0017g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、10ng/mLのアクチビン−A、1μMのRA、25ng/mLのFGF7、0.25mMのアスコルビン酸、200nMのTPB、及び10nMのLDNを補充したMCDB−131倍地で処理し、次いで、
d)ステージ4(膵臓前腸前駆細胞−2日):細胞は、ITS−Xの1:200希釈、4.5mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、50μMのLDN−193189、10μMのフォルスコリン、0.25mMのアスコルビン酸、2ng/mLのFGF7、1ng/mLのAA、及び100nMのTPBを補充したMCDB−131倍地で2日間処理し、次いで、
e)ステージ5(膵内胚葉/内分泌−3日):ステージ4細胞は、ITS−Xの1:200希釈、15mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、10μMのフォルスコリン、0.25mMのアスコルビン酸、及び1ng/mLのFGF7、2〜3日目のみ100nMのALK5阻害剤SD208を添加して補充したMCDB−131培地で3日間処理し、次いで、
f)ステージ6(膵内胚葉−3〜10日):ステージ5細胞を、ITS−Xの1:200希釈、15mMのグルコース、1X GlutaMax(商標)、0.0015g/mLの重炭酸ナトリウム、2%の無脂肪酸BSA、0.25μMのSANT−1、50nMのRA、0.25mMのアスコルビン酸を補充したMCDB−131倍地で3〜10日間処理した。一部の培養物は、10μMのスフィンゴシン−1−リン酸塩(米国ミズーリ州のSigma)を3日間添加した。
Claims (27)
- エフリンリガンドを用いて膵内胚葉細胞を培養することを含む、ホルモン発現細胞におけるインスリン発現を誘発する方法。
- 前記エフリンリガンドを用いて前記膵内胚葉細胞を培養することが、NKX6.1の発現も強化する、請求項2に記載の方法。
- エフリンリガンドを用いて前記膵内胚葉細胞を培養することが、非処理の膵臓内胚葉細胞におけるインスリン及びNKX6.1の発現と比較して、前記膵内胚葉細胞におけるインスリン及びNKX6.1の発現を強化する、請求項2に記載の方法。
- 前記膵内胚葉細胞が、CDX2又はSOX2を実質的に発現しない、請求項3に記載の方法。
- 前記膵内胚葉細胞が、ほぼ約10%未満のCDX2又はSOX2を発現する、請求項4に記載の方法。
- 前記エフリンリガンドが、エフリンA3又はエフリンA4である、請求項1〜5のいずれか1項に記載の方法。
- 前記膵内胚葉細胞が、多能性幹細胞の段階的分化によって取得される、請求項6に記載の方法。
- 前記多能性幹細胞が、ヒト胚性多能性幹細胞である、請求項7に記載の方法。
- 請求項1の方法によって調製されたインスリン及びNKX6.1発現細胞。
- エフリンリガンドを用いて膵内胚葉細胞を培養することによって調製された細胞集団であって、前記細胞集団が、エフリンリガンドで処理していない膵内胚葉細胞と比較して、強化されたインスリン及びNKX6.1を発現する、細胞集団。
- 前記エフリンリガンドが、エフリンA3又はエフリンA4である、請求項10に記載の細胞集団。
- アクチビンA又はアクチビンCを含む培地において膵臓内胚葉細胞を培養することを含む、ホルモン発現細胞における成長ホルモン分泌抑制ホルモンの発現を増強する方法。
- インスリン、グルカゴン、及びグレリンの発現が抑制される、請求項12に記載の方法。
- アクチビンA又はアクチビンCで処理した前記膵内胚葉細胞集団が、アクチビンA又はアクチビンCで処理していない膵内胚葉細胞集団より多くの成長ホルモン分泌抑制ホルモンを発現する、請求項12に記載の方法。
- インスリンの前記発現が、アクチビンA又はアクチビンCで処理した前記膵内胚葉細胞集団において、アクチビンA又はアクチビンCで処理していない膵内胚葉細胞集団におけるインスリンの前記発現と比較して抑制される、請求項14に記載の方法。
- グルカゴンの前記発現が、アクチビンA又はアクチビンCで処理した前記膵内胚葉細胞集団において、アクチビンA又はアクチビンCで処理していない膵内胚葉細胞集団におけるグルカゴンの前記発現と比較して抑制される、請求項12に記載の方法。
- グレリンの前記発現が、アクチビンA又はアクチビンCで処理した前記膵内胚葉細胞集団において、アクチビンA又はアクチビンCで処理していない膵内胚葉細胞集団におけるグレリンの前記発現と比較して抑制される、請求項12に記載の方法。
- 前記膵内胚葉細胞が、CDX2又はSOX2を実質的に発現しない、請求項12〜18のいずれか1項に記載の方法。
- アクチビンA又はアクチビンCで処理された前記膵内胚葉細胞が、多能性細胞の段階的分化によって取得される、請求項18に記載の方法。
- 前記膵内胚葉細胞の由来元である前記多能性細胞が、ヒト胚性多能性細胞である、請求項19に記載の方法。
- セマフォリン3a又はエピゲンを含む培地において膵内胚葉細胞を処理することによって、NKX6.1の発現を増強する方法。
- セマフォリン3a又はエピゲンを含む培地で処理した前記膵内胚葉細胞集団が、セマフォリン3a又はエピゲンを含む培地で処理されていない膵内胚葉細胞に比較して強化された量のNKX6.1を発現する、請求項21に記載の方法。
- インスリン、グルカゴン、及びグレリンの発現レベルが、セマフォリン3a又はエピゲンを含む培地で処理した膵内胚葉細胞において、セマフォリン3a又はエピゲンを含む培地で処理していない膵内胚葉細胞に比較して影響を受けない、請求項21に記載の方法。
- スフィンゴシン−1受容体アゴニストを用いて膵内分泌細胞を培養することを含む、内分泌クラスターの形成を誘導するための方法。
- 膵内分泌細胞を処理するために使用された前記スフィンゴシン−1受容体アゴニストが、スフィンゴシン−1−リン酸塩(S1P)である、請求項24に記載の方法。
- 前記膵内分泌細胞が、多能性幹細胞の段階的分化によって取得される、請求項24に記載の方法。
- 前記多能性幹細胞が、ヒト胚性多能性幹細胞である、請求項26に記載の方法。
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