JP5250423B2 - 単離肝幹細胞 - Google Patents
単離肝幹細胞 Download PDFInfo
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- JP5250423B2 JP5250423B2 JP2008546208A JP2008546208A JP5250423B2 JP 5250423 B2 JP5250423 B2 JP 5250423B2 JP 2008546208 A JP2008546208 A JP 2008546208A JP 2008546208 A JP2008546208 A JP 2008546208A JP 5250423 B2 JP5250423 B2 JP 5250423B2
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5067—Liver cells
Description
Najimi and Sokal.2005.Minerva Pediatr 57(5): 243-57 Stromら、1997.Transplant Proc 29(4): 2103-6
一態様では、本発明は、単離した前駆細胞もしくは幹細胞、または前記の前駆細胞もしくは幹細胞を含む細胞集団を入手する方法を提供し、該方法には、以下の工程が含まれる:(a)成人肝またはその一部を分離して、前記成人肝またはその一部から一次細胞集団を形成する工程、(b)細胞を付着させる基質に一次細胞を播種する工程、(c)少なくとも7日間、好ましくは少なくとも10日間、少なくとも13日間、または少なくとも15日間、前記基質に付着した一次細胞集団から細胞を培養する工程。
記載の通り、本発明の方法には、成人肝または成人肝の一部から一次細胞集団を得るため前記成人肝または成人肝の一部を分離する工程が含まれる。
説明の通り、本発明の方法には、肝組織の分離によって得られる一次細胞集団の培養が含まれる。この目的のために、細胞の付着を可能にする基質上に肝細胞の一次集団を播種する。
好ましくは前記環境において、前記基質に付着した一次細胞集団由来の細胞を、続いて、少なくとも7日間、例えば、少なくとも8日間または少なくとも9日間、好ましくは少なくとも10日間、例えば、11日間または少なくとも12日間、少なくとも13日間または少なくとも14日間、より好ましくは少なくとも15日間、例えば、少なくとも16日間または少なくとも17日間、または更に少なくとも18日間、例えば、少なくとも19日間または少なくとも20日間以上にわたり培養する。「培養」は当該技術分野において一般的であり、広義では、細胞および/またはその子孫細胞の維持および/または増殖を指す。
または、血漿や血清は、それらの各凝固点未満(つまり、凍結保存)で保存できる。当該技術分野において公知の通り、血漿または血清の凍結保存に都合の良い温度は約−70℃以下(例、約−75℃以下または80℃以下)でありうる。これらの温度は、保存した血漿または血清の融解を防止して、これらの品質を保つのに都合が良い。血漿または血清の保存期間を問わず、凍結保存を利用できるが、長期保存(例、数日間または1〜2週間以上)が必要な場合に特に適しうる。
前記の一次肝細胞の培養、そして本発明の前駆細胞もしくは幹細胞の出現・増殖後、このようにして得た細胞集団を少なくとも1回継代できる。
本発明の肝臓由来の前駆細胞もしくは幹細胞を含む集団は、本発明の方法によって得られ、恐らくは前記の前駆細胞もしくは幹細胞を更に濃縮させる場合、次に、分化させることなく、前記の前駆細胞もしくは幹細胞を増殖・倍化させることのできる条件において細胞集団を維持および/または増殖させることができる。該条件は、例えば、前駆細胞もしくは幹細胞を得るために利用した条件でよい。細胞分化した有無を評価できる当業者は、他の条件を容易に確立しうる。これによって、他の用途に利用可能な前駆細胞もしくは幹細胞の数を増やすことができれば都合が良い。
前述の一次肝細胞の培養時、また好ましくは継代時に得られた細胞集団が、少なくとも1つの間葉系マーカー、特に1つ以上、例えば2、3、4つの間葉系マーカー、あるいはマーカーCD90、CD73、CD44、ビメンチン、およびα−平滑筋アクチン(ASMA)の全てを、肝細胞マーカー・アルブミン(ALB)で、および恐らくは1つ以上の他の肝臓マーカーまたは肝細胞マーカー、好ましくはCD29、α‐フェトプロテイン(AFP)、α−1アンチトリプシン、および/またはMRP2トランスポーターの好ましくは1つ以上、または全てで、同時発現する(つまり、陽性である)、本発明の肝臓由来前駆細胞もしくは幹細胞を含むことを本発明者らは気づいた。
細胞マーカーの検出に加えて、インビトロおよび/またはインビボでの細胞分化に関する研究は有益になりうる。
前記の成人肝前駆細胞もしくは肝幹細胞を更に改変、例えば、前述の遺伝子組み換えをできる。本発明は、成人肝前駆細胞もしくは肝幹細胞の分化した子孫細胞を含む、その子孫細胞に関する。
単離した肝臓由来の前駆細胞もしくは幹細胞、これらの細胞の細胞株またはこれらの細胞を含む細胞集団は、様々な対象ので利用できる(LMBP 6452CB細胞株の他、先に定義した成人肝前駆細胞もしくは肝幹細胞、特に、先に定義した方法を利用して入手可能、または直接入手した細胞、先に定義した特性を示す細胞、特定の実施態様において、単離した成人由来の肝幹細胞株、好ましくは成人由来のヒト肝幹細胞株(ADHLSC)、これらの子孫細胞、または遺伝子組み換えしたこれらの細胞の誘導体について、以下の用途および応用が広く考察していることを理解する必要がある:限定はされないが、
‐単離した本発明の前駆細胞もしくは幹細胞またはこれらの細胞集団を使用した肝臓代謝欠損、肝臓変性疾患、劇症肝不全を治療するための肝細胞移植、
‐単離した本発明の前駆細胞もしくは幹細胞またはこれらの細胞集団を使用したバイオ人工肝臓デバイスの作製、
‐動物における単離した本発明の前駆細胞もしくは幹細胞またはこれらの細胞集団の移植によるヒト肝臓疾患のモデル動物の作出、
‐単離した本発明の前駆細胞もしくは幹細胞またはこれらの細胞集団を使用した毒物学、薬理学に関するインビトロ・動物モデルの作出、
‐単離した本発明の前駆細胞もしくは幹細胞またはこれらの細胞集団における抗ウイルス剤を含むヒト肝炎ウイルスに対する新規薬剤の試験)。
‐先天性の肝臓代謝欠損症を治療するための肝前駆細胞もしくは肝幹細胞の移植:該疾患の例として、限定はされないが、フェニルケトン尿症および他のアミノ酸血症、血友病および他の凝固因子欠損症、家族性高コレステロール血症および他の脂質代謝異常、尿素回路異常、糖原病、ガラクトーゼ血症、果糖血症、チロシン血症、タンパク質・糖質代謝欠損症、有機酸尿、ミトコンドリア病、ペルオキシソーム・リソソーム異常、タンパク質合成異常、肝細胞トランスポーター欠損、グリコシル化欠損症などが挙げられ、
‐後天性の肝臓変性疾患を治療するための本発明の肝前駆細胞もしくは肝幹細胞の移植、
‐劇症肝不全、急性・慢性肝不全を治療するための本発明の肝前駆細胞もしくは肝幹細胞の使用、
‐バイオ人工肝臓デバイスおよび肝臓補助デバイスにおける本発明の肝前駆細胞もしくは肝幹細胞の使用、
‐小型・大型動物における本発明の肝前駆細胞もしくは肝幹細胞の移植によるヒトの肝疾患の動物モデル、
‐自然経過、伝播、耐性、治療効果を研究するためのヒトの肝親和性ウイルス感染症(HBV、HAV、HCV、HEV、HDV...)の動物モデルの作製、抗ウイルス薬の使用、本発明の肝前駆細胞もしくは肝幹細胞の移植を利用した研究、
‐本発明の肝前駆細胞もしくは肝幹細胞を使用した毒物学、薬理学、薬理遺伝学のインビトロ・動物モデルの作製、‐本発明の肝前駆細胞もしくは肝幹細胞における新薬試験、
‐その後にインビトロで増殖可能な本発明の肝前駆細胞もしくは肝幹細胞におけるウイルス配列の挿入による遺伝子治療、‐ヒトの肝細胞での代謝を研究するための動物モデル、
‐本発明の肝前駆細胞もしくは肝幹細胞の使用による同種異系細胞の寛容、および/または
‐肝臓または肝細胞の同種移植片拒絶を回避、予防、治療するための本発明の肝前駆細胞もしくは肝幹細胞の使用。
本発明の前駆細胞もしくは幹細胞、これらの細胞の細胞株またはこれらの細胞集団(無論、限定はしないが、具体的にはLMBP 6452CB株を指す)、または分化した子孫細胞、特に、任意に遺伝子組み換えした肝細胞もしくは肝細胞様細胞の他の用途について以下で検討している。
肝細胞の単離手順
健常な屍体または心拍の認められるドナーに由来する全肝臓または肝臓部分からヒト肝細胞を得た。総クランプ時間(例、総クランプ時間後6〜12時間)後に細胞を単離して、ウィスコンシン大学において、灌流まで肝臓を氷上の培地中に保存した。古典的な2工程灌流方法を利用して肝細胞を単離した{Seglen、1976}{Stephenne, 2005}。EGTA溶液(Ca2+/Mg2+不含アール平衡塩類溶液、0.5mM EGTA、5mM Hepes、2mg/Lゲンタマイシン、100,000IU/1 ペニシリンG)および消化酵素溶液で37℃、9〜12分間、しっかりと認識できる血管から肝臓を連続灌流させた。消化溶液(Ca2+/Mg2+含有EBSS、5mM Hepes、2mg/Lゲンタマイシン、100,000IU/1 ペニシリンG)には、0.9mg/mLのコラゲナーゼPおよび0.03mg/mLの大豆トリプシン阻害剤が含まれた。肝臓被膜を切開して、穏やかに撹拌させて肝細胞を放出させた。0.03mg/mLの大豆トリプシン阻害剤および100mL/Lのヒト血漿を含む氷冷洗浄培地(培地M199、5mM Hepes、2mg/Lゲンタマイシン、100,000IU/1 ペニシリンG)で消化を停止させた。4個の金属製ふるい(孔径4.5mm、1mm、0.5mm、0.25mm)を通して細胞をろ過、リンスした。1,200rpm、3分間、冷M 199洗浄培地中での遠心分離によって細胞を3回洗った。
他の細胞種が混入する可能性を避けるために、免疫細胞化学を実施して、これらの細胞の表現型を検証した。これらは肝臓に由来するため、パラホルムアルデヒド固定細胞においてアルブミンなどの特異的マーカーの発現を解析した。図2に示す通り、肝細胞でのみ発現するアルブミンをモノクローナル抗体(Sigma clone HAS‐111)またはポリクローナル(Chemicon)抗体を使用して検出した。同時に、間葉細胞マーカーの発現も評価しており、これらの細胞がビメンチンおよびα平滑筋アクチンに免疫陽性であることが示されている(図2)。これまでに、7継代にわたって表現型の特徴を検証しており、高い安定性が認められている。
FCSおよびP/S添加DMEM中においてラットテールコラーゲンI型でコーティングした6枚のウェルプレートに0.5〜1x104/cm2の密度で細胞を播種した。24時間後に培地をIscove改変ダルベッコ培地(IMDM)(Invitrogen)と交換した。誘導では、20ng/mL HGF(Biosource)、10ng/mL bFGF(Peprotech)、0.61g/L ニコチンアミド(Sigma)を添加したIMDMを含む誘導培地とともに細胞を2週間培養させた。その後、20ng/mL オンコスタチンM(Sigma)、1μM デキサメタゾン(Sigma)、50mg/mL ITS (インシュリン、トランスフェリン、セレニウム)(Invitrogen)を添加したIMDMを含む成熟培地とともに細胞を2週間培養させた。誘導・成熟工程では、3日ごとに培地を交換して、解析を行った。これらの混合物への暴露後、細胞の鋭い縁が認められなくなり、徐々に縮小し始め、最初の形態を失って、多角形の形状になった。
1200rpm、5分間の遠心分離後に細胞を回収して、500〜1000/μL PBSの濃度で再懸濁させた。次に、40℃、30分間にわたり細胞を培養させた。モノクローナル抗体の非特異的結合を評価するために、対応する対照アイソタイプを使用した。次に、Beckham Coulter Flow Cytometerでの読み取りのために、細胞を洗って、Isoton(登録商標)(Beckham Coulter)に再懸濁させた。
6枚のウェルプレート内で増殖する細胞からTriPure単離試薬(Roche)を使用して全RNAを抽出して、逆転写キットを使用して、使用説明書に従いcDNAを作製した。最終容量25μL中で、ポリメラーゼ・エロンガーゼおよび適切なプライマーを使用してPCR増幅を実施した。その後、1%アガロースゲルでサンプルを電気泳動させて、エチジウムブロマイド染色によって核酸を可視化させた。
免疫染色では、ラットテールコラーゲンIコーティング済み12mm丸ガラスカバースリップ上で増殖させた細胞を、室温で、15分間、4%パラホルムアルデヒド固定させて、その後、15分間、TBS(Tris−HCl 50mM、NaCl 150mM、pH 7.4)中1% Triton X100(v/v)を浸透させた。3%脱脂粉乳を含むTBS溶液中での37℃、1時間のインキュベーションによって非特異的な免疫染色が起らないようにした。次に、同じ溶液中で、室温で1時間、一次抗体とともに細胞を培養させ、TBSで5回リンスして、引き続き二次抗体(1/500)とともに培養した。核染料DAPI(1/5,000)で30分間に核を染色させた。3回のリンス後、Fluoprep培地(BioMerieux、ベルギーブリュッセル)中に調製物を封入して、CCDカメラ(T.I.L.L. photonics、ドイツマーティンスリート)付きオリンパス1X70倒立顕微鏡を使用して観察した。モノクロメータ(T.I.L.L. photonics、ドイツマーティンスリート)に連結させたキセノンランプから、励起光(Cy−3、FITC、DAPIについて、それぞれ552、488、372nm)を得た。適切なフィルターを使用してデジタルイメージを取得して、TILLvisionソフトウェアを使用して組み合わせた。
前述の方法を利用して、本実施例において樹立した細胞(ADHLSC)に関する実験において以下の多数の細胞マーカーの発現プロファイルを構築した:
限定することを意図せずに、本発明者らは、細胞マーカーに関する自分達の知識に基づいて、前述のデータに関して以下の可能な解釈を提示する:マーカーのこの組み合わせによって、肝臓分化経路に特異的なマーカー(CD29およびアルブミン、alpha−1アンチトリプシン、HNF4、MRP2トランスポーター)の他、間葉系統(CD90、CD73、ビメンチン、CD44)からのマーカーを発現する元の細胞株が定義される。免疫蛍光法およびRT−PCRのいずれでも強く検出されるアルブミンの存在は、星状細胞が混入した可能性に反論している。ADHLSCは、多能性の未分化間葉系幹細胞(CD45陰性、CD34陰性、CD117陰性、Oct‐4陰性)でも、肝臓星状細胞(アルブミン陽性)でもないように思われる。ADHLSC株は、肝臓系統(アルブミンおよびα−1アンチトリプシンを発現するCD29陽性)にコミットメントしていると考えられるが、通常の胆管マーカーを発現していない(CK19、7陰性)。このため、本発明の細胞および細胞株は、限定はされないが、1つとしては、肝細胞前駆体の特徴を有する間葉系幹細胞株と示すことができる。
100万個のADHLSC(生存能力90%以上)を6〜14日齢のuPA+/+−SCIDマウスの脾臓に注入した。移植前、マウスにおいて血清アルブミンは検出されなかった。全体的な組織病理学的評価のためにヘマトキシリン・エオジン(HE)染色した4μm厚の肝臓切片においてマウス肝臓サンプルの免疫組織化学を実施した。免疫染色において、肝臓スライドを室温で一次抗体とオーバーナイトでインキュベートさせた。スライドをペルオキシダーゼ標識ポリマーおよび基質色素原(Envision−DABシステム、Dako、カリフォルニア州カーピンテリア)とインキュベートさせた後、検出した。ヘマトキシリンを使用して対比染色を実施した。
本発明の肝臓由来の前駆細胞もしくは幹細胞、これらの細胞の細胞株、またはこれらの細胞を含む細胞集団(無論、限定はしないが、具体的にはLMBP 6452CB株を指す)、または任意に遺伝子組み換えしたこれらの子孫細胞での例示的な処理は以下でよい。
Claims (35)
- 以下の特徴を持つ成人肝に由来する単離した人前駆細胞もしくは幹細胞;
(a)間葉系マーカーであるビメンチンおよびα−平滑筋アクチン(ASMA)を発現する、
(b)肝細胞マーカーであるアルブミン(ALB)を発現する、及び
(c)サイトケラチン−19(CK−19)陰性である。 - 以下の特徴を持つ請求項1の成人肝に由来する単離した人前駆細胞もしくは幹細胞;
CD90、CD73、CD44から選ばれる少なくとも1つの間葉系マーカーをさらに発現する。 - CD29、α−フェトプロテイン(AFP)、α−1アンチトリプシン、HNF−4、およびMRP2トランスポーターから選択される他の肝マーカーもしくは肝細胞マーカーの1つ以上を更に発現する、請求項1又は2に記載の単離した人前駆細胞または幹細胞。
- CD29、AFP、α−1アンチトリプシン、およびMRP2トランスポーターを発現する、請求項3に記載の単離した人前駆細胞または幹細胞。
- それは、CD90、CD73、及びCD44が陽性であり、
それはアルブミン陽性、ビメンチン陽性、およびα−平滑筋アクチン陽性であり、
及び、それはCD45、CD34、CD117及びCK−19が陽性である
成人肝に由来する単離した人前駆細胞または幹細胞。 - 単層増殖、扁平状、広い細胞質、1または2個の核小体を有する卵円核のいずれか、または全てを含む間葉様形態を有する、請求項1〜5のいずれかに記載の単離した人前駆細胞または幹細胞。
- 前記細胞が肝細胞または肝細胞様細胞に分化可能であり、中胚葉系細胞には分化しない、請求項1〜6のいずれかに記載の単離した人前駆細胞または幹細胞。
- 請求項1〜7のいずれかに記載の単離した人肝前駆細胞または肝幹細胞を含む、細胞株または細胞集団、およびこれらの子孫細胞。
- 2006年2月20日にBudapest Treaty with the Belgian Coordinated Collections of Microorganisms(BCCM)の下で受入番号LMBP6452CBで寄託された、単離したヒト成人肝の前駆細胞または幹細胞、および細胞株、そしてクローン性の亜株を含むその亜株、およびその子孫細胞。
- (i)マーカーCD90、CD73、CD44、ビメンチンおよびα−平滑筋アクチン(ASMA)から選ばれる少なくとも一つの間葉系マーカーを発現し、(ii)肝細胞マーカーであるアルブミン(ALB)を発現し、及び(iii)サイトケラチン−19(CK−19)陰性である、単離した人前駆細胞もしくは幹細胞、または前記の前駆細胞もしくは幹細胞を含む細胞集団の入手方法であって、以下の工程を含む方法:
(a)成人肝またはその一部から一次細胞集団を形成するための前記成人肝またはその一部を分離する工程、
(b)細胞付着を可能にする基質上に該一次細胞を播種する工程と、
(c)少なくとも7日間、又は少なくとも10日間、又は少なくとも13日間、又は少なくとも15日間、前記基質に付着した該一次細胞集団からの細胞を、血清と、EGF、デキサメタゾン、インシュリンから選ばれる少なくとも2つの外因的に添加する成長因子の組合わせを含む培養培地中で培養する工程、及び
(d)該培養培地を高グルコース含有基本培地に変え、さらに該細胞培養し、結果、該前駆細胞若しくは幹細胞が、出現し、増殖する。 - 工程(d)において該細胞を培養することが、少なくとも1回、もしくは少なくとも2回、該細胞を継代させることを含む請求項10の方法。
- 請求項10又は11の方法を用いて入手可能な、または直接入手される、請求項1〜9のいずれか一に記載の単離した成人肝の前駆細胞もしくは幹細胞、これらの細胞の細胞株、および/またはこれらの細胞を含む細胞集団。
- 請求項12に記載の単離した成人肝の前駆細胞もしくは幹細胞、これらの細胞の細胞株、および/またはこれらの細胞を含む細胞集団であって、前記請求項10又は11の方法が以下の工程を含む:
(a)被験体、脊椎動物もしくは哺乳動物、又はヒト被験体から、2段階コラゲナーゼ法により、成人肝またはその一部を分離して、前記の成人肝またはその一部由来の一次細胞集団を形成する工程;
(b)ウシ胎児血清を、10%(v/v)、EGFを、25ng/mL、インシュリンを、10μg/mL、デキサメタゾンを、1μMを含むウィリアムスE培地中のI型コラーゲン被覆基質に該一次細胞集団を播種する工程;
(c)24時間、該一次細胞集団由来の細胞を前記基質に付着させ、その後該培地を(b)と同じ組成物を有する新鮮培地と交換する工程;
(d)2週間、もしくは15日間、の間に、(c)の前記培地中で該細胞を培養する工程;
(e)該培地を、高グルコースおよびFCS含有DMEM、又は高グルコースおよび10%FCS含有DMEMと交換し、該細胞をさらに培養する工程で、それにより該前駆細胞または幹細胞が出現し、増殖し;
(f)任意に、該細胞を(b)と同じ基質へ播種して、(e)と同じ培地中で培養させ、細胞密集度を70%にして、該細胞を少なくとも1回もしくは少なくとも2回継代させる工程。 - 請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団、を含む組成物。
- 治療に使用するための、請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団、または分化子孫細胞、または肝細胞もしくは肝細胞様細胞を含むこれらの子孫細胞。
- 肝疾患治療用の薬剤の製造における、請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団、または分化子孫細胞、または肝細胞もしくは肝細胞様細胞を含むこれらの子孫細胞の使用。
- 請求項16に記載の使用であって、該肝疾患として、以下が挙げられる:フェニルケトン尿症および他のアミノ酸血症、血友病および他の凝固因子欠損症、家族性高コレステロール血症および他の脂質代謝障害、尿素回路障害、糖原病、ガラクトーゼ血症、果糖血症、チロシン血症、タンパク質・糖質代謝欠損症、有機酸尿、ミトコンドリア病、ペルオキシソーム・リソソーム異常、タンパク質合成異常、肝細胞トランスポーター欠損、グリコシル化異常、肝炎、肝硬変、先天性代謝異常、急性肝不全、急性肝感染症、急性化学毒性、慢性肝不全、胆管炎、胆汁性肝硬変症、アラギル症候群、α−1−アンチトリプシン欠損症、自己免疫性肝炎、胆道閉鎖症、肝癌、肝嚢胞性疾患、脂肪肝、ガラクトーゼ血症、胆石、ジルベール症候群、血色素症、A型肝炎、B型肝炎、C型肝炎、および他の肝炎ウイルス感染症、ポルフィリン症、原発性硬化性胆管炎、ライ症侯群、類肉腫症、チロシン血症、1型糖原病、またはウィルソン病。
- 請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団、及びおよび医薬的に許容される担体を含む、医薬組成物。
- 以下の工程を含む、インビトロ毒性試験を行う方法:
請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団を試験薬に触れさせる工程と、もしあるならば、該試験薬が肝細胞集団に及ぼす少なくとも1つの効果を観察する工程。 - 該少なくとも1つの効果に、細胞の生存、細胞の機能、またはこれらの両方に及ぼす効果が含まれる、請求項19に記載の方法。
- 以下の工程を含むインビトロ薬物代謝試験を行う方法:
(i)請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団を試験薬に触れさせる工程と、
(ii)所定の試験期間後に、もしあるならば、該試験薬が関与する少なくとも1つの変化を観察する工程。 - 該少なくとも1つの変化に、該試験薬の構造、濃度、またはこの両方の変化が含まれる、請求項21に記載の方法。
- 請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団を入れるハウジングを含む肝臓補助デバイス。
- 機能的遺伝子コピーを導入された、請求項1〜7、9、12、13のいずれかに記載の該人肝前駆細胞もしくは肝幹細胞または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団の、遺伝子発現異常を治療する医薬の製造のための使用であって、該医薬は該機能的遺伝子コピーを必要とする患者の肝臓に導入されるものである。
- 機能的遺伝子コピーを導入した、請求項1〜7、9、12、13のいずれかに記載の形質転換させた肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の形質転換させた細胞株もしくは細胞集団を含む、遺伝子発現異常を処理するための組成物。
- 機能的遺伝子コピーを導入した、請求項1〜7、9、12、13のいずれかに記載の肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団、及び医薬的に許容可能な担体を含む、遺伝子発現異常を治療するための医薬組成物。
- 請求項1〜7、9、12、13のいずれかに記載の肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団の、損傷もしくは罹患した肝臓の再生を促進する医薬の製造のための使用。
- 以下の工程を含む肝感染症を治療するのに有効な薬剤の試験方法:
(i)請求項1〜7、9、12、13のいずれかに記載の肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団を対象の感染物質に感染させ、感染集団を提供する工程、
(ii)該感染集団を所定量の試験薬に触れさせる工程と、
(iii)もしあるならば、該触れさせたことが該感染集団に及ぼす効果を観察する工程。 - 該感染物質に微生物が含まれる、請求項28に記載の方法。
- 該感染物質に1種以上のウイルス、細菌、菌類、またはこれらの組み合わせが含まれる、請求項28に記載の方法。
- 認められる効果にウイルス感染物質がウイルス複製に及ぼす効果が含まれる、請求項28に記載の方法。
- 該ウイルス感染物質に肝炎ウイルスが含まれる、請求項28に記載の方法。
- 請求項1〜7、9、12、13のいずれかに記載の肝前駆細胞もしくは肝幹細胞、または請求項8、9、12、13のいずれかに記載の細胞株もしくは細胞集団に、対象のタンパク質をコードする機能的遺伝子を導入する工程、転写、翻訳、および任意に翻訳後修飾が起るのに効果的な条件下で肝細胞集団を培養する工程、ならびに対象のタンパク質を回収する工程を含む、対象のタンパク質の生産方法。
- 該肝細胞がヒト肝細胞である、請求項33に記載の方法。
- 該対象のタンパク質がワクチン抗原を含む、請求項34に記載の方法。
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KR20060036933A (ko) * | 2003-10-07 | 2006-05-02 | 바이오마스터 인코포레이티드 | 지방-유래 전구세포의 세포 분화 |
WO2006126219A1 (en) † | 2005-05-26 | 2006-11-30 | Fresenius Medical Care Deutschland G.M.B.H. | Liver progenitor cells |
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US20150306147A1 (en) | 2015-10-29 |
PL2281875T3 (pl) | 2018-08-31 |
US20140127676A1 (en) | 2014-05-08 |
US9775863B2 (en) | 2017-10-03 |
PT2281875T (pt) | 2018-06-11 |
US20170354687A1 (en) | 2017-12-14 |
US8673635B2 (en) | 2014-03-18 |
US8778607B2 (en) | 2014-07-15 |
DE602006020071D1 (de) | 2011-03-24 |
AU2006328988A1 (en) | 2007-06-28 |
US20080311094A1 (en) | 2008-12-18 |
CN103989710A (zh) | 2014-08-20 |
EP2281875A1 (en) | 2011-02-09 |
EP1969118B2 (en) | 2014-09-10 |
EP1969118A1 (en) | 2008-09-17 |
PL1969118T3 (pl) | 2011-07-29 |
DK2281875T3 (en) | 2018-06-06 |
US9107910B2 (en) | 2015-08-18 |
AU2006328988B2 (en) | 2012-08-02 |
ES2672205T3 (es) | 2018-06-13 |
US9931360B2 (en) | 2018-04-03 |
WO2007071339A1 (en) | 2007-06-28 |
PL1969118T5 (pl) | 2015-06-30 |
CN103989710B (zh) | 2019-11-15 |
US20140286917A1 (en) | 2014-09-25 |
ATE498005T1 (de) | 2011-02-15 |
EP1969118B1 (en) | 2011-02-09 |
JP2009520474A (ja) | 2009-05-28 |
CA2634510A1 (en) | 2007-06-28 |
EP2281875B1 (en) | 2018-03-21 |
CA2634510C (en) | 2018-01-09 |
DK1969118T4 (en) | 2014-12-15 |
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