JP7161775B2 - 中間中胚葉細胞から腎前駆細胞への分化誘導方法、および多能性幹細胞から腎前駆細胞への分化誘導方法 - Google Patents
中間中胚葉細胞から腎前駆細胞への分化誘導方法、および多能性幹細胞から腎前駆細胞への分化誘導方法 Download PDFInfo
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Description
また、本発明者らのグループは、中間中胚葉細胞を、TGFβシグナル刺激剤およびBMP阻害剤を含む培地で培養する工程を含む、中間中胚葉細胞から腎前駆細胞の製造方法について開示しているが(特許文献1)、より効率よく腎前駆細胞を分化誘導できる方法が求められていた。
[1]中間中胚葉細胞をGSK(グリコーゲン合成酵素キナーゼ)-3β阻害剤およびFGF(線維芽細胞増殖因子)9を含む培地で接着培養し、中間中胚葉細胞から腎前駆細胞を誘導する工程を含む、腎前駆細胞の製造方法。
[2]前記腎前駆細胞がSIX2陽性細胞である、[1]に記載の方法。
[3]前記中間中胚葉細胞がOSR1陽性細胞である、[1]または[2]に記載の方法。
[4]GSK-3β阻害剤がCHIR99021である、[1]~[3]のいずれかに記載の方法。
[5]前記培地はさらにROCK阻害剤を含む、[1]~[4]のいずれかに記載の方法。
[6]前記接着培養は細胞外基質でコートされた培養容器を用いて行われる、[1]~[5]のいずれかに記載の方法。
[7]前記細胞外基質はラミニン511のE8フラグメントである、[6]に記載の方法。
[8]前記中間中胚葉細胞が、多能性幹細胞から誘導された中間中胚葉細胞である、[1]~[7]のいずれかに記載の方法。
[9]前記中間中胚葉細胞が、以下の工程(i)~(v)を含む方法で製造された中間中胚葉細胞である、[8]に記載の方法。
(i)多能性幹細胞を、FGF2、BMP(骨形成タンパク質)4、GSK-3β阻害剤およびレチノイン酸またはその誘導体を含む培地で培養する工程;
(ii)工程(i)で得られた細胞を、FGF2、GSK-3β阻害剤およびBMP7を含む培地で培養する工程;
(iii)工程(ii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7およびTGFβ阻害剤を含む培地で培養する工程;
(iv)工程(iii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7、アクチビンおよびROCK阻害剤を含む培地で培養する工程;および
(v)工程(iv)で得られた細胞を、レチノイン酸またはその誘導体およびFGF9を含む培地で培養する工程。
[10]工程(v)の培地はさらにBMP阻害剤を含む、[9]に記載の方法。
[11]前記多能性幹細胞が人工多能性幹(iPS)細胞である、[8]または[10]のいずれかに記載の方法。
[12]前記iPS細胞がヒトiPS細胞である、[11]に記載の方法。
[13]多能性幹細胞から腎前駆細胞を製造する方法であって、以下の工程(i)~(vi)を含む、方法。
(i)多能性幹細胞を、FGF2、BMP4、GSK-3β阻害剤およびレチノイン酸またはその誘導体を含む培地で培養する工程;
(ii)工程(i)で得られた細胞を、FGF2、GSK-3β阻害剤およびBMP7を含む培地で培養する工程;
(iii)工程(ii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7およびTGFβ阻害剤を含む培地で培養する工程;
(iv)工程(iii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7、アクチビンおよびROCK(Rho-kinase)阻害剤を含む培地で培養する工程;
(v)工程(iv)で得られた細胞を、レチノイン酸またはその誘導体およびFGF9を含む培地で培養する工程;および
(vi)工程(v)で得られた細胞を、GSK-3β阻害剤およびFGF9を含む培地で培養し、中間中胚葉細胞から腎前駆細胞を誘導する工程。
[14]工程(v)の培地はさらにBMP阻害剤を含む、[13]に記載の方法。
[15]前記腎前駆細胞がSIX2陽性細胞である、[13]または[14]に記載の方法。
[16]前記工程(v)で得られた細胞がOSR1陽性細胞である、[13]~[15]のいずれかに記載の方法。
[17]前記GSK-3β阻害剤がCHIR99021である、[13]~[16]のいずれかに記載の方法。
[18]前記工程(vi)の培地はさらにROCK阻害剤を含む、[13]~[17]のいずれかに記載の方法。
[19]前記培養は細胞外基質でコートされた培養容器を用いて行われる、[13]~[18]のいずれかに記載の方法。
[20]前記細胞外基質はラミニン511のE8フラグメントである、[19]に記載の方法。
[21]前記多能性幹細胞が人工多能性幹(iPS)細胞である、[13]~[20]のいずれかに記載の方法。
[22]前記iPS細胞がヒトiPS細胞である、[21]に記載の方法。
[23][1]~[22]のいずれかに記載の方法で製造された、腎前駆細胞。
[24][1]~[22]のいずれかに記載の方法で製造された腎前駆細胞を用いて得られる、腎臓オルガノイド。
[25][1]~[22]のいずれかに記載の方法で製造された腎前駆細胞またはそれを用いて得られる腎臓オルガノイドを含む、医薬組成物。
[26][1]~[22]のいずれかに記載の方法で製造された腎前駆細胞またはそれを用いて得られる腎臓オルガノイドを含む、腎疾患治療剤。
後腎は成体腎を形成する胎児腎組織の一つであり、腎臓再生において必須のコンポーネントである。また、後腎ネフロン前駆細胞やそこから派生する糸球体、尿細管に発生する腎疾患は多いため、腎疾患モデル作製においても本発明の方法は有用である。従って、本発明の方法は、腎疾患に対する治療方法や治療薬探索の観点においても有用である。
本発明は、中間中胚葉細胞をGSK-3β阻害剤およびFGF9を含む培地で培養する工程(腎前駆細胞分化誘導工程ともいう)を含む、腎前駆細胞を製造する方法を提供する。
本発明において、多能性幹細胞から中間中胚葉細胞への分化誘導に際して、以下の工程を含む方法を用いることができる。
(i)多能性幹細胞を、FGF2、BMP(骨形成タンパク質)4、GSK-3β阻害剤およびレチノイン酸またはその誘導体を含む培地で培養する工程;
(ii)工程(i)で得られた細胞を、FGF2、GSK-3β阻害剤およびBMP7を含む培地で培養する工程;
(iii)工程(ii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7およびTGFβ阻害剤を含む培地で培養する工程;
(iv)工程(iii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7、アクチビンおよびROCK阻害剤を含む培地で培養する工程;および
(v)工程(iv)で得られた細胞を、レチノイン酸またはその誘導体およびFGF9を含む培地で培養する工程。
この工程では、多能性幹細胞から後期後方エピブラストが誘導される。後期後方エピブラストは、CDX1、OCT4、NANOG、E-CDH(CDH1)の少なくとも1つ以上のマーカーが陽性である細胞として特徴づけられ、好ましくはこれらすべてのマーカーが陽性である細胞として特徴づけられる。後期後方エピブラストはさらに、EOMESおよびBRACHYURYが陰性であることが好ましい。
多能性幹細胞の分離の方法としては、例えば、力学的分離や、プロテアーゼ活性とコラゲナーゼ活性を有する分離溶液(例えば、Accutase(TM)およびAccumax(TM)(Innovative Cell Technologies,Inc)が挙げられる)またはコラゲナーゼ活性のみを有する分離溶液を用いた分離が挙げられる。好ましくは、プロテアーゼ活性とコラゲナーゼ活性を有する分離溶液を用いて解離し、力学的に細かく単一細胞へ分散する方法である。工程(i)で用いるヒト多能性幹細胞としては、使用したディッシュに対して70%~80%コンフルエントになるまで培養されたコロニーを用いることが好ましい。
工程(i)で用いるレチノイン酸またはその誘導体の濃度は、例えば、1nMから100nM、好ましくは、5nMから50nM、より好ましくは、5nMから25nMである。
この工程では、後期後方エピブラストから中胚葉系譜原始線条が誘導される。中胚葉系譜原始線条は、CDX1およびBRACHYURYが陽性である細胞として特徴づけられる。中胚葉系譜原始線条はさらに、OCT4、NANOGおよびE-CDHが陰性であることが好ましい。
この工程では、中胚葉系譜原始線条から中胚葉系譜後期原始線条が誘導される。中胚葉系譜後期原始線条は、CDX2およびBRACHYURYが陽性である細胞として特徴づけられる。
培養液中におけるTGFβ阻害剤の濃度は、ALKを阻害する濃度であれば特に限定されないが、0.5μMから100μM、好ましくは、1μMから50μM、さらに好ましくは、5μMから25μMである。
この工程では、中胚葉系譜後期原始線条から後腎系譜後期原始線条が誘導される。後腎系譜後期原始線条は、HOX11およびBRACHYURYが陽性である細胞として特徴づけられる。
この工程では、後腎系譜後期原始線条から後期後方中間中胚葉が誘導される。中間中胚葉は、OSR1、HOX11およびWT1が陽性である細胞として特徴づけられる。
BMP阻害剤としては、Chordin、Noggin、Follistatin、などのタンパク質性阻害剤、Dorsomorphin (すなわち、6-[4-(2-piperidin-1-yl-ethoxy)phenyl]-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine)、その誘導体 (P. B. Yu et al. (2007), Circulation, 116:II_60; P.B. Yu et al. (2008), Nat. Chem. Biol., 4:33-41; J. Hao et al. (2008), PLoS ONE, 3(8):e2904)およびLDN193189(すなわち、4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline)が例示される。
BMP阻害剤としてより好ましくはNOGGINであり、その濃度は、例えば、1~100ng/mlとすることができる。
本発明において、腎疾患治療剤に含まれる腎前駆細胞の細胞数は、移植片が投与後に生着できれば特に限定されなく、患部の大きさや体躯の大きさに合わせて適宜増減して調製されてもよい。
以下のプロトコールにてiPS細胞から腎前駆細胞を分化誘導した。なお、iPS細胞は201B7由来のOSR1-GFP/SIX2-tdTomatoレポーターヒトiPS細胞を使用した。
2.24時間後(day1)にvitamin A free B27 supplement(Thermo Fisher Scientific Inc.)を添加したDMEM/F12 Glutamax(Thermo Fisher Scientific Inc.)を基礎培地とし、1μM CHIR99021, 10 nM Retinoic acid, 1 ng/ml BMP4, 100 ng/ml FGF2を添加した培地で培地交換。(後期後方エピブラストの作製・・・1)
3.Day2に同基礎培地に 3μMCHIR99021, 1 ng/ml BMP7, 100 ng/ml FGF2 を添加した培地に培地交換 (中胚葉系譜原始線条の作製・・・2)
4.Day3, Day4に同基礎培地に 3μMCHIR99021, 1 ng/ml BMP7, 100 ng/ml FGF2, 10μM A83-01 を添加した培地に培地交換(中胚葉系譜後期原始線条の作製・・・3)
5.Day5, Day6, Day7に同基礎培地に 3μMCHIR99021, 1 ng/ml BMP7, 100 ng/ml FGF2, 10 ng/ml ACTIVIN, 30μM Y27632を添加した培地に培地交換(後腎系譜後期原始線条の作製・・・4)
6.Day8, Day9に同基礎培地に100 ng/ml FGF9, 100 nM Retinoic acidを添加した培地に培地交換(後期後方中間中胚葉の作製・・・5)
7.Day10, Day11, Day12に同基礎培地に10 ng/ml FGF9, 1 μM CHIR99021を添加した培地に培地交換(腎前駆細胞の作製・・・6)
陰性マーカーは発現していないことを確認した。図1に、各段階の細胞のマーカー染色結果を示す。後期後方中間中胚葉および腎前駆細胞については、80%以上のマーカー陽性細胞を得ることができた。なお、上記5の工程における培地を、200 ng/ml FGF9, 100 nM Retinoic acid, 25 ng/ml NOGGINとした時も同様の結果が得られた。
<1>で得られた腎前駆細胞を1.0×105の大きさの細胞塊とし、1 μM CHIR99021および10 ng/ml FGF9を添加した基礎培地で1日間培養した。そこに、E11.5のマウス胎仔脊髄と半気相培養で共培養した。その結果、図2に示すように、糸球体や尿細管が確認でき、腎臓オルガノイドの作製に成功した。
<1>で得られた腎前駆細胞を1.0×105の大きさの細胞塊とし、1 μM CHIR99021および200 ng/ml FGF9を添加した基礎培地で1~2日間培養した。その細胞塊を5 μM CHIR99021および200 ng/ml FGF2を添加した基礎培地で2日間半気相培養し、さらに、基礎培地のみで8日間半気相培養を行った。その結果、図3に示すように、糸球体や尿細管が確認でき、腎臓オルガノイドの作製に成功した。また、BRN1(+)CDH1(+)DBA(-)ヘンレのループを観察できた。
Claims (10)
- 多能性幹細胞から腎前駆細胞を製造する方法であって、以下の工程(i)~(vi)を含む、方法。
(i)多能性幹細胞を、FGF2、BMP4、GSK-3β阻害剤ならびにレチノイン酸または3-デヒドロレチノイン酸、4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbonyl]amino]-Benzoic acid(AM580)、4-[(1E)-2
-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]-Benzoic
acid(TTNPB)、パルミチン酸レチノール、レチノール、レチナール、3-デヒドロレチノールおよび3-デヒドロレチナールから選択されるレチノイン酸誘導体を含む培地で培養して後期後方エピブラストを誘導する工程;
(ii)工程(i)で得られた細胞を、FGF2、GSK-3β阻害剤およびBMP7を含む培地で培養して中胚葉系譜原始線条を誘導する工程;
(iii)工程(ii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7およびTGFβ阻害剤を含む培地で培養して中胚葉系譜後期原始線条を誘導する工程;
(iv)工程(iii)で得られた細胞を、FGF2、GSK-3β阻害剤、BMP7、アクチビンおよびROCK(Rho-kinase)阻害剤を含む培地で培養して後腎系譜後期原始線条を誘導する工程;
(v)工程(iv)で得られた細胞を、レチノイン酸または3-デヒドロレチノイン酸、4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbonyl]amino]-Benzoic acid(AM580)、4-[(1E)-2-(5,6,7,8-tetrah
ydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]-Benzoic acid(TTNPB)、パルミチ
ン酸レチノール、レチノール、レチナール、3-デヒドロレチノールおよび3-デヒドロレチナールから選択されるレチノイン酸誘導体ならびにFGF9を含む培地で培養して後期後方中間中胚葉を誘導する工程;および
(vi)工程(v)で得られた細胞を、GSK-3β阻害剤およびFGF9を含む培地で
培養し、後期後方中間中胚葉細胞から腎前駆細胞を誘導する工程。 - 工程(v)の培地はさらにBMP阻害剤を含む、請求項1に記載の方法。
- 前記腎前駆細胞がSIX2陽性細胞である、請求項1または2に記載の方法。
- 前記工程(v)で得られた細胞がOSR1陽性細胞である、請求項1~3のいずれか一項に記載の方法。
- 前記GSK-3β阻害剤がCHIR99021である、請求項1~4のいずれかに一項記載の方法。
- 前記工程(vi)の培地はさらにROCK阻害剤を含む、請求項1~5のいずれか一項に記載の方法。
- 前記培養は細胞外基質でコートされた培養容器を用いて行われる、請求項1~6のいずれか一項に記載の方法。
- 前記細胞外基質はラミニン511のE8フラグメントである、請求項7に記載の方法。
- 前記多能性幹細胞が人工多能性幹(iPS)細胞である、請求項1~8のいずれか一項に記載の方法。
- 前記iPS細胞がヒトiPS細胞である、請求項9に記載の方法。
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EP3633026A1 (en) | 2020-04-08 |
KR20200010279A (ko) | 2020-01-30 |
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KR102594102B1 (ko) | 2023-10-25 |
EP3633026A4 (en) | 2021-03-10 |
US20200248148A1 (en) | 2020-08-06 |
JPWO2018216743A1 (ja) | 2020-03-26 |
KR20230150412A (ko) | 2023-10-30 |
WO2018216743A1 (ja) | 2018-11-29 |
US11821007B2 (en) | 2023-11-21 |
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CN117802033A (zh) | 2024-04-02 |
JP7458012B2 (ja) | 2024-03-29 |
US20240043811A1 (en) | 2024-02-08 |
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