JPWO2015020113A1 - 膵ホルモン産生細胞の製造法 - Google Patents
膵ホルモン産生細胞の製造法 Download PDFInfo
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Abstract
Description
[1]膵前駆細胞をクロモグリク酸ナトリウムを含む培地で培養する工程を含む、膵ホルモン産生細胞の製造方法。
[2]前記培地が、(a)アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種、(b)ニコチンアミド、(c)ステロイドおよび(d)TGFβ阻害剤から成るからなる群より選択される少なくとも一種の薬剤をさらに含む、[1]に記載の方法。
[3]前記培地が、(a)アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種、(b)ニコチンアミド、(c)ステロイドおよび(d)TGFβ阻害剤をさらに含む、[1]または[2]に記載の方法。
[4]前記アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種が、フォルスコリンである、[2]または[3]に記載の方法。
[5]前記ステロイドがデキサメタゾンである、[2]から[4]いずれか1項に記載の方法。
[6]前記(d)TGFβ阻害剤が、2−(3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル)−1,5−ナフチリジンである、[2]から[4]のいずれか1項に記載の方法。
[7]前記膵前駆細胞が、以下の工程(1)および(2)を特徴とする工程によって、多能性幹細胞から製造された細胞である、[1]から[6]のいずれか1項に記載の方法:
(1)多能性幹細胞を、アクチビン受容体様キナーゼ−4,7の活性化剤、およびGSK3阻害剤を含む培地で培養する工程、および
(2)前記工程(1)で得られた細胞を、(a)レチノイン酸受容体アゴニスト、(b)BMP阻害剤、および(c)TGFβ阻害剤を含む培地で培養する工程。
[8]前記アクチビン受容体様キナーゼ−4,7の活性化剤がアクチビンである、[7]に記載の方法。
[9]前記GSK3阻害剤が、CHIR99021である、[7]または[8]に記載の方法。
[10]前記工程(2)で用いられるTGFβ阻害剤が、SB431542である、[7]から[9]のいずれか1項に記載の方法。
[11]前記BMP阻害剤が、ドーソモルフィン(Dorsomorphin)である、[7]から[10]のいずれか1項に記載の方法。
[12]膵ホルモン産生細胞がインスリン産生細胞、グルカゴン産生細胞、ソマトスタチン産生細胞、および膵ポリペプチド産生細胞からなる群より選択されるいずれかである[1]から[11]のいずれか1項に記載の方法。
[13]膵ホルモン産生細胞がインスリン産生細胞、および/またはグルカゴン産生細胞である、[12]に記載の方法。
[14]前記膵ホルモン産生細胞が、ヒト細胞である、[1]から[13]のいずれか1項に記載の方法。
(1)多能性幹細胞を、アクチビン受容体様キナーゼ−4,7の活性化剤、およびGSK3阻害剤を含む培地で培養する工程、および
(2)前記工程(1)で得られた細胞を、(a)レチノイン酸受容体アゴニスト、(b)BMP阻害剤、および(c)TGFβ阻害剤からなる群より選択される1種を含む培地で培養する工程。
(1)多能性幹細胞を、アクチビン受容体様キナーゼ−4,7の活性化剤、およびGSK3阻害剤を含む培地で培養する工程
(2)前記工程(1)で得られた細胞を、(a)レチノイン酸受容体アゴニスト、(b)BMP阻害剤、および(c)TGFβ阻害剤からなる群より選択される1種を含む培地で培養する工程
(3)前記工程(2)で得られた細胞を、(クロモグリク酸ナトリウムを含む培地で培養する工程。
ES細胞は、ヒトやマウスなどの哺乳動物の初期胚(例えば胚盤胞)の内部細胞塊から樹立された、多能性と自己複製による増殖能を有する幹細胞である。
精子幹細胞は、精巣由来の多能性幹細胞であり、精子形成のための起源となる細胞である。この細胞は、ES細胞と同様に、種々の系列の細胞に分化誘導可能であり、例えばマウス胚盤胞に移植するとキメラマウスを作出できるなどの性質をもつ(M. Kanatsu-Shinohara et al. (2003) Biol. Reprod., 69:612-616; K. Shinohara et al. (2004), Cell, 119:1001-1012)。神経膠細胞系由来神経栄養因子(glial cell line-derived neurotrophic factor (GDNF))を含む培養液で自己複製可能であるし、またES細胞と同様の培養条件下で継代を繰り返すことによって、精子幹細胞を得ることができる(竹林正則ら(2008),実験医学,26巻,5号(増刊),41〜46頁,羊土社(東京、日本))。(本段落に記載の文献は引用により本願の一部を構成する)
胚性生殖細胞は、胎生期の始原生殖細胞から樹立される、ES細胞と同様な多能性をもつ細胞であり、LIF、bFGF、幹細胞因子(stem cell factor)などの物質の存在下で始原生殖細胞を培養することによって樹立しうる(Y. Matsui et al. (1992), Cell, 70:841-847; J.L. Resnick et al. (1992), Nature, 359:550-551)。(本段落に記載の文献は引用により本願の一部を構成する)
人工多能性幹(iPS)細胞は、特定の初期化因子を、体細胞に作用させることによって作製することができる、ES細胞とほぼ同等の特性を有する体細胞由来の人工の幹細胞である(K. Takahashi and S. Yamanaka (2006) Cell, 126:663-676; K. Takahashi et al. (2007), Cell, 131:861-872; J. Yu et al. (2007), Science, 318:1917-1920; Nakagawa, M.ら,Nat. Biotechnol. 26:101-106 (2008);国際公開WO 2007/069666)。初期化因子は、ES細胞に特異的に発現している遺伝子、その遺伝子産物もしくはnon-cording RNAまたはES細胞の未分化維持に重要な役割を果たす遺伝子、その遺伝子産物もしくはnon-coding RNA、あるいは低分子化合物によって構成されてもよい。初期化因子に含まれる遺伝子として、例えば、Oct3/4、Sox2、Sox1、Sox3、Sox15、Sox17、Klf4、Klf2、c-Myc、N-Myc、L-Myc、Nanog、Lin28、Fbx15、ERas、ECAT15-2、Tcl1、beta-catenin、Lin28b、Sall1、Sall4、Esrrb、Nr5a2、Tbx3またはGlis1等が例示され、これらの初期化因子は、単独で用いても良く、組み合わせて用いても良い。初期化因子の組み合わせとしては、WO2007/069666、WO2008/118820、WO2009/007852、WO2009/032194、WO2009/058413、WO2009/057831、WO2009/075119、WO2009/079007、WO2009/091659、WO2009/101084、WO2009/101407、WO2009/102983、WO2009/114949、WO2009/117439、WO2009/126250、WO2009/126251、WO2009/126655、WO2009/157593、WO2010/009015、WO2010/033906、WO2010/033920、WO2010/042800、WO2010/050626、WO 2010/056831、WO2010/068955、WO2010/098419、WO2010/102267、WO 2010/111409、WO 2010/111422、WO2010/115050、WO2010/124290、WO2010/147395、WO2010/147612、Huangfu D, et al. (2008), Nat. Biotechnol., 26: 795-797、Shi Y, et al. (2008), Cell Stem Cell, 2: 525-528、Eminli S, et al. (2008), Stem Cells. 26:2467-2474、Huangfu D, et al. (2008), Nat Biotechnol. 26:1269-1275、Shi Y, et al. (2008), Cell Stem Cell, 3, 568-574、Zhao Y, et al. (2008), Cell Stem Cell, 3:475-479、Marson A, (2008), Cell Stem Cell, 3, 132-135、Feng B, et al. (2009), Nat Cell Biol. 11:197-203、R.L. Judson et al., (2009), Nat. Biotechnol., 27:459-461、Lyssiotis CA, et al. (2009), Proc Natl Acad Sci U S A. 106:8912-8917、Kim JB, et al. (2009), Nature. 461:649-643、Ichida JK, et al. (2009), Cell Stem Cell. 5:491-503、Heng JC, et al. (2010), Cell Stem Cell. 6:167-74、Han J, et al. (2010), Nature. 463:1096-100、Mali P, et al. (2010), Stem Cells. 28:713-720、Maekawa M, et al. (2011), Nature. 474:225-9.に記載の組み合わせが例示される。(本段落に記載の文献は引用により本願の一部を構成する)
nt ES細胞は、核移植技術によって作製されたクローン胚由来のES細胞であり、受精卵由来のES細胞とほぼ同じ特性を有している (T. Wakayama et al. (2001), Science, 292:740-743; S. Wakayama et al. (2005), Biol. Reprod., 72:932-936; J. Byrne et al. (2007), Nature, 450:497-502)。すなわち、未受精卵の核を体細胞の核と置換することによって得られたクローン胚由来の胚盤胞の内部細胞塊から樹立されたES細胞がnt ES(nuclear transfer ES)細胞である。nt ES細胞の作製のためには、核移植技術(J.B. Cibelli et al. (1998), Nature Biotechnol., 16:642-646)とES細胞作製技術(上記)との組み合わせが利用される(若山清香ら(2008),実験医学,26巻,5号(増刊), 47〜52頁)。核移植においては、哺乳動物の除核した未受精卵に、体細胞の核を注入し、数時間培養することで初期化することができる。(本段落に記載の文献は引用により本願の一部を構成する)
Muse細胞は、WO2011/007900に記載された方法にて製造された多能性幹細胞である。詳細には、線維芽細胞または骨髄間質細胞を長時間トリプシン処理、好ましくは8時間または16時間トリプシン処理した後、浮遊培養することで得られる多能性を有した細胞である。Muse細胞はSSEA-3およびCD105が陽性である。
多能性幹細胞は通常接着培養にて培養された形態にて提供される。工程1において、多能性幹細胞を任意の方法で分離して浮遊培養を行っても、あるいはフィーダー細胞上やコーティング処理された培養皿を用いて接着培養を行ってもよい。
工程2は、前記工程1に続いて行われる。工程1にて得られた細胞を別の培養容器に移して培養しても、同じ培養容器にて培地を交換して培養してもよい。工程2においては浮遊培養、接着培養のいずれの培養方法を採用してもよい。工程1にて接着培養を行い、工程2を別の培養容器にて行う場合は、工程1で得られた細胞を任意の方法で分離して移せばよい。工程2の培地は、上述した基礎培地へレチノイン酸受容体アゴニスト、BMP阻害剤、およびTGFβ阻害剤を添加することによって作製される。好ましい基本培地は、B-27サプリメントを含むImproved MEM培地である。
(1)膵前駆細胞を、クロモグリク酸ナトリウムおよび候補薬剤を含む培地で培養する工程、
(2)前記(1)で得られた細胞と、候補薬剤を含まない以外は同じ培地で培養した細胞の膵ホルモン発現量を測定する工程、および
(3)候補薬剤を含まない培地で培養して得た細胞と比べて、候補薬剤を含む培地で培養して得た細胞の膵ホルモン産生細胞数または膵ホルモンの発現量が上昇した場合、当該候補薬剤を膵ホルモン産生細胞の誘導効率を高める薬剤として選択する工程。
(1)本発明の方法で膵ホルモン産生細胞を候補薬剤を含む培地で培養する工程、
(2)前記工程(1)で得られた細胞と、候補薬剤を含まない以外は同じ培地で培養した細胞の膵ホルモン発現量を測定する工程、および
(3)候補薬剤を含まない培地で培養した細胞と比較して、候補薬剤を含む培地で培養して得た細胞の膵ホルモンの発現量が上昇した場合、当該候補薬剤を膵ホルモン分泌促進剤として選択する工程。
ヒトES細胞株KhES3は、京都大学より受領し、従来の方法で培養した(H. Suemori et al. (2006), Biochem. Biophys. Res. Commun., 345:926-932、本文献は引用により本願の一部を構成する)。KhES3を次の工程に従ってインスリン産生細胞へと誘導した。分化誘導にあたり、ヒトES細胞株は、培養皿に対しておおよそ70%コンフルエントに増殖した細胞をCTK溶液(リプロセル)を用いて剥離させ、続いてAccutaseを用いて個々の細胞へと分離し、24well plate (greiner)に2.0×105/wellにて播種して用いた。
ヒトiPS細胞201B7(京都大学iPS細胞研究所より入手可能(Takahashi K et al, Cell. 2007 131:861-72.、本文献は引用により本願の一部を構成する))を用いて、次の工程に従ってインスリン産生細胞へと誘導した。分化誘導にあたり、ヒトiPS細胞株は、培養皿に対しておおよそ70%コンフルエントに増殖した細胞をCTK溶液を用いて剥離させ、続いてAccutaseを用いて個々の細胞へと分離し、24well plateに2.0×105/wellにて播種して用いた。
3種の繊維芽細胞由来のiPS細胞株(418C1および409B2(Okita K, et al, Nat Methods. 2011 8:409-412)および201B7)は、京都大学iPS細胞研究所より入手可能である。京都大学より入手したこれらのiPS細胞株を用いて、上記と同様の工程(ただし、工程3におけるクロモグリク酸ナトリウムの濃度は、10mMとした)により、インスリン陽性細胞へと分化誘導した。
ヒトiPS細胞201B7を用いて、次の工程に従ってインスリン産生細胞へと誘導した。分化誘導にあたり、ヒトiPS細胞株は、培養皿に対しておおよそ80-90%コンフルエントに増殖した細胞をCTK溶液を用いて剥離させ、続いてAccutaseを用いて個々の細胞へと分離し、マトリゲルをコートした24well plateに2.0×105/wellにて播種して用いた。
Insulinのプロモーター下にGFPを発現するマウスの胎児E12.5、E14.5およびE16.5の膵原基を抽出し、それぞれを1%のB−27を含むImproved MEM Zinc Option培地にフォルスコリン(10μM)、ニコチンアミド(10mM)、デキサメタゾン(10μM)、ALK5阻害剤II(5μM)およびクロモグリク酸ナトリウム(10mM)を添加した培地中で、4日間浮遊培養した。その模式図を図7Aに示す。
ヒトiPS細胞201B7を用いて、次の工程に従ってインスリン産生細胞へと誘導した。分化誘導にあたり、ヒトiPS細胞株は、培養皿に対しておおよそ80-90%コンフルエントに増殖した細胞をCTK溶液を用いて剥離させ、続いてAccutaseを用いて個々の細胞へと分離し、マトリゲルをコートした24well plateに2.0×105/wellにて播種して用いた。
Claims (14)
- 膵前駆細胞をクロモグリク酸ナトリウムを含む培地で培養する工程を含む、膵ホルモン産生細胞の製造方法。
- 前記培地が、(a)アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種、(b)ニコチンアミド、(c)ステロイドおよび(d)TGFβ阻害剤から成るからなる群より選択される少なくとも一種の薬剤をさらに含む、請求項1に記載の方法。
- 前記培地が、(a)アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種、(b)ニコチンアミド、(c)ステロイドおよび(d)TGFβ阻害剤をさらに含む、請求項1または2に記載の方法。
- 前記アデニル酸シクラーゼ活性化剤、cAMPホスホジエステラーゼ阻害剤、およびcAMP類縁体からなる群より選択される少なくとも一種が、フォルスコリンである、請求項2または3に記載の方法。
- 前記ステロイドがデキサメタゾンである、請求項2から4いずれか1項に記載の方法。
- 前記(d)TGFβ阻害剤が、2−(3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル)−1,5−ナフチリジンである、請求項2から4のいずれか1項に記載の方法。
- 前記膵前駆細胞が、以下の工程(1)および(2)を特徴とする工程によって、多能性幹細胞から製造された細胞である、請求項1から6のいずれか1項に記載の方法:
(1)多能性幹細胞を、アクチビン受容体様キナーゼ−4,7の活性化剤、およびGSK3阻害剤を含む培地で培養する工程、および
(2)前記工程(1)で得られた細胞を、(a)レチノイン酸受容体アゴニスト、(b)BMP阻害剤、および(c)TGFβ阻害剤を含む培地で培養する工程。 - 前記アクチビン受容体様キナーゼ−4,7の活性化剤がアクチビンである、請求項7に記載の方法。
- 前記GSK3阻害剤が、CHIR99021である、請求項7または8に記載の方法。
- 前記工程(2)で用いられるTGFβ阻害剤が、SB431542である、請求項7から9のいずれか1項に記載の方法。
- 前記BMP阻害剤が、ドーソモルフィン(Dorsomorphin)である、請求項7から10のいずれか1項に記載の方法。
- 膵ホルモン産生細胞がインスリン産生細胞、グルカゴン産生細胞、ソマトスタチン産生細胞、および膵ポリペプチド産生細胞からなる群より選択されるいずれかである請求項1から11のいずれか1項に記載の方法。
- 膵ホルモン産生細胞がインスリン産生細胞、および/またはグルカゴン産生細胞である、請求項12に記載の方法。
- 前記膵ホルモン産生細胞が、ヒト細胞である、請求項1から13のいずれか1項に記載の方法。
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