JP2015006137A - 肝前駆細胞増殖用培地 - Google Patents
肝前駆細胞増殖用培地 Download PDFInfo
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- JP2015006137A JP2015006137A JP2013132152A JP2013132152A JP2015006137A JP 2015006137 A JP2015006137 A JP 2015006137A JP 2013132152 A JP2013132152 A JP 2013132152A JP 2013132152 A JP2013132152 A JP 2013132152A JP 2015006137 A JP2015006137 A JP 2015006137A
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Landscapes
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
1)HEX遺伝子、HNF4α遺伝子、HNF6遺伝子及びSOX17遺伝子から選択されるいずれか1又は複数の遺伝子をアデノウイルスベクターに組み込むことにより、ヒト胚性幹細胞やヒト人工多能性肝細胞に導入することを特徴とする、幹細胞から肝細胞への分化誘導方法(国際公開WO2011/052504号パンフレット参照):
2)FOXA2遺伝子をアデノウイルスベクターを用いてヒト胚性幹細胞やヒト人工多能性肝細胞に導入し、次いで、FOXA2遺伝子を組み込んだアデノウイルスベクターとHNF1α遺伝子を組み込んだアデノウイルスベクターとを、ヒト胚性幹細胞やヒト人工多能性肝細胞に導入することにより、ヒトiPS細胞由来肝前駆細胞を調製する方法:
なお、上記RPMI1640/B27(インスリン−)培地は、RPMI(Roswell Park Memorial Institute medium)1640培地に、2%のインスリン不含B−27サプリメントを添加した培地を例示することができる。RPMI1640/B27(インスリン+)培地は、上記RPMI1640/B27(インスリン−)培地において、インスリン不含B−27サプリメントの代わりに、2%のB−27サプリメント(50X)を添加した培地を例示することができる。
(a)肝前駆細胞を、市販の肝細胞専用培地に、肝細胞培養用添加因子セットからhEGF(組換えヒト上皮細胞成長因子)を除いたものを添加し、20ng/mLオンコスタチンMを添加した培地に、解凍した肝前駆細胞を播種し、2〜8日間、好ましくは4〜7日間培養することにより、ヒトES細胞由来肝前駆細胞やヒトiPS細胞由来肝前駆細胞を、肝細胞へ分化する方法(NIHセンター肝細胞分化方法):
(b)肝前駆細胞を、8.3%のウシ胎児血清(FBS)を添加したL15培地に、10ng/mLのHGF、及び20ng/mLのオンコスタチンMを添加した培地を用い、解凍した肝前駆細胞を播種し、3〜10日間、好ましくは5〜9日間培養することにより、ヒトES細胞由来肝前駆細胞やヒトiPS細胞由来肝前駆細胞を、肝細胞へ分化する方法(WeiCui肝細胞分化方法):
(c)肝前駆細胞を、ポリビニルアルコール(PVA)を添加したCDM培地に、30ng/mLのFGF4、50ng/mLのHGF、50ng/mLのEGFを添加した培地を用い、解凍した肝前駆細胞を播種し、5〜15日間、好ましくは8〜12日間培養することにより、ヒトES細胞由来肝前駆細胞やヒトiPS細胞由来肝前駆細胞を、肝細胞へ分化する方法(Vallier肝細胞分化方法):
[ヒトiPS細胞由来ヘパトブラスト様細胞(1)の作製]
アデノウイルス(Ad)ベクターを用いてヒトiPS細胞に遺伝子導入を行い、ヒトiPS細胞からヒトiPS細胞由来ヘパトブラスト様細胞を作製した。
ヒトiPS細胞として、DotcomクローンJCRB1327株(JCRB細胞バンクより入手)を使用した。中内胚葉(mesoendoderm)分化を促進するために、上記ヒトiPS細胞を、細胞分離試薬アキュターゼ(ミリポア社製)を用いて単細胞に分離し、かかる分離単細胞は、BDマドリゲル(登録商標)上にて、ヒトES細胞分化誘導用基礎培地hESF−DIF(細胞科学研究所製)に、10μg/mLのヒトリコンビナントインスリン(シグマ社製)、5μg/mLのヒトアポトランスフェリン(シグマ社製)、10μMの2−メルカプトエタノール(シグマ社製)、10μMのエタノールアミン(シグマ社製)、10μMのセレン酸ナトリウム(シグマ社製)、0.5mg/mLのウシ血清アルブミン(シグマ社製)(PBS(phosphate-buffered saline)にて調整)、及び100ng/mLのアクチビンA(R&Dシステムズ社製)をサプリメントとして添加した培地に播種した。この日を分化0日目とする。2日間培養し、ヒトiPS細胞由来中内胚葉様細胞(mesoendoderm cells)を得た。
[ヒトiPS細胞由来ヘパトブラスト様細胞(1)の維持培養]
以下の表3に記載されている基礎培地を構成する成分(群)と、表4に記載されているサプリメントを構成する成分(群)からなるHepSC−F培地を調製した。タイプIブタコラーゲン(新田ゼラチン社製)でコートしたHepSC−F培地で、上記ヒトiPS細胞由来ヘパトブラスト様細胞を培養し、培地交換は2日毎に行った。培養された上記ヒトiPS細胞由来ヘパトブラスト様細胞は0.01%トリプシンと0.01%EDTA4Na(Ethylenediaminetetraacetic acid‐4Na)とをPBSに溶解した剥離溶液を用いて剥離することにより、7日毎に4〜6倍に希釈して継代された。トリプシンはその後、0.1%ダイズトリプシンインヒビター(シグマ社製)により失活処理された。かかる剥離溶液による処理は、これ以降の本実施例・参考例を通して必要に応じて用いられた。
図1から明らかなとおり、AFP、EpCAM、N−カドヘリン、CK19、E−カドヘリンにおいて強い陽性を示した。
i)肝前駆細胞マーカーとして知られ、肝幹細胞や肝実質細胞では発現しないと報告されているAFPの陽性率は、約69.9%であった。
ii)肝幹細胞のマーカーとして知られ、肝前駆細胞や肝実質細胞では発現しないとされているNCAMの陽性率は、約9.1%であった。
iii)肝幹細胞で発現することが報告されているN−カドヘリンの陽性率は、約56.1%であった。
iv)肝前駆細胞と肝実質細胞において発現するとの報告があるICAMの陽性率は、約30.4%であった。
v)肝前駆細胞において発現するとの報告があるEpCAMの陽性率は、約76.9%であった。
vi)肝前駆細胞において発現するとの報告があるCK19の陽性率は、約48.6%であり、比較的高い陽性率であった。
vii)肝前駆細胞においても発現することがある旨報告されているが、肝実質細胞の強力なマーカーとして知られるALBの陽性率は、約0.5%であった。
viii)肝幹細胞と肝前駆細胞のマーカーとして知られているE−カドヘリンの陽性率は、約35.67%であった。
ix)肝幹細胞と肝前駆細胞の比較的弱いマーカーとして知られているCD13の陽性率は、約10.2%であった。
[ヒトiPS細胞由来ヘパトブラスト様細胞(2)の作製]
Touboul, T. et. al., Hepatology. 2010 May;51(5):1754-65記載の方法を改良した方法に依拠してヒトiPS細胞由来ヘパトブラスト様細胞を作製した。ヒトiPS細胞として、DotcomクローンH9−201B7株を使用した。分化0日目に、10ng/mLのリコンビナントヒトアクチビンA、及び12ng/mLのFGF2を添加したCDM培地に播種し、2日目まで培養した。本実施例において、CDM培地としては、IMDM培地(シグマ社製)とF12NUT−MIX培地(Gibco BRL社製)とを、50:50の割合で混合した培地を使用した。
[ヒトiPS細胞由来ヘパトブラスト様細胞(2)の増幅能の検討]
上記ヒトiPS細胞由来ヘパトブラスト様細胞(2)を分化17日目に細胞を回収し、単細胞分離処理をせず塊のまま、第一継代細胞(P=1)として、HepSC−F培地に播種した。培地は2日毎に交換した。第一継代細胞の培養7日目に継代し、第二継代細胞(P=2)とした。第二継代細胞の培養9日目に継代し、第三継代細胞(P=3)とした。第三継代細胞の培養11日目に継代し、第四継代細胞(P=4)とした。P=1、P=3、P=4の各継代細胞について、生細胞タイムラプスイメージング装置(BioStation IM-Q、ニコン社製)を用いて、細胞の位相差像を取得し、細胞の占める面積を測定した。結果を図2(a)〜(c)に示す。
図2より明らかなとおり、P=1において、約125時間で130万ピクセルから250万ピクセルへと約2倍弱細胞面積が増加し(図2(a)参照)、P=3において、約200時間で290万ピクセルから、760万ピクセルへ約2.5倍強細胞面積が増加し(図2(b)参照)、P=4において、約150時間で600万ピクセルから1200万ピクセルへと約2倍細胞面積が増加した(図2(c)参照)ことが確認された。したがって、HepSC−F培地で培養した場合、継代数にかかわらず、上記ヒトiPS細胞由来ヘパトブラスト様細胞は、順調に増幅をおこなうことができることが確認された。
上記ヒトiPS細胞由来ヘパトブラスト様細胞(2)をP=1について、各マーカーに対する抗体を用いて免疫抗体染色を行った。用いたマーカーは、EpCAM、ALB、AFP、ICAM、CK19、HNF−4α、N−CAMである。各々のマーカーの陽性率を表したグラフを図3に示す。
図3より以下の事項が確認された。
i)肝前駆細胞マーカーとして知られ、肝幹細胞や肝実質細胞では発現しないと報告されているAFPの陽性率は、約49%であった。
ii)肝前駆細胞において発現するとの報告があるCK19の陽性率は、約38%であった。
iii)肝前駆細胞と肝実質細胞において発現するとの報告があるICAMの陽性率は、約14%であった。
iv)肝実質細胞においては発現しないとの報告があるEpCAMマーカーの陽性率は約12%であった。
v)肝実質細胞の強力なマーカーであるALBマーカーの陽性率は、約5%であった。
vi)肝細胞核因子マーカーであるHNF4αの陽性率は、約15%であった。
vii)肝幹細胞のマーカーとして知られ、肝前駆細胞や肝実質細胞では発現しないとされているNCAMの陽性率は、約4%であった。
なお、縦軸は陽性率を表す。以上の結果より、HepSC−F培地で培養・継代されたiPS細胞由来ヘパトブラスト様細胞は、肝前駆細胞としての性格を維持しながら増殖していることが確認された。
[ヒトiPS細胞由来ヘパトブラスト様細胞から肝実質細胞様細胞への分化能の検討]
参考例1により調製した上記ヒトiPS細胞由来ヘパトブラスト様細胞について、培地を、50ng/mLのFGF10を添加したBSA−FAF含有CDM培地に変更し、3日間培養した。培地を、PVAを添加したCDM培地に50ng/mLのFGF10と、1×10−7Mのレチノイン酸と、1×10−6MのSB431542を添加した培地に変更してさらに2日間培養後、さらに、PVAを添加したCDM培地に30ng/mLのFGF、50ng/mLのHGF、50ng/mLのEGFを添加した培地に変更し、毎日培地交換を行い分化させた。分化0日目(D0)から分化42日目(D42)までの細胞について、培地の培養上清を回収し、ELISA法を用いて培養上清中のアルブミン量を測定した。
図4より明らかなとおり、参考例1において作製されたヘパトブラスト様細胞について、肝実質細胞様細胞への分化誘導を進めたところ、培養開始後15日目(D15)ごろから細胞上清中のアルブミン量が徐々に増加し。D42には、40〜50マイクログラム/mLに達したことが確認された。このことより、上記iPS細胞由来ヘパトブラスト様細胞は、アルブミンが強く発現する肝実質細胞様細胞に分化することができる分化能を有していることが確認された。
Claims (6)
- 0.03mM〜1mMのカルシウムイオンと、500mg/L〜4500mg/Lのグルコースと、0.1mM〜2.0mMのピルビン酸イオンとを含む基礎培地に、インスリン、トランスフェリン、2−メルカプトエタノール、2−エタノールアミン、セレン酸、脂肪酸不含アルブミン、ヘパリン、FGF−2、FGF−4、及びHGFからなるサプリメントを添加することにより作製されることを特徴とするヒト肝前駆細胞を増殖するための培地。
- ヒト肝前駆細胞の増殖が、分化能を保持した状態での増殖であることを特徴とする請求項1記載の培地。
- ヒト肝前駆細胞の増殖が、ヒト肝前駆細胞の増殖、凍結保存、解凍、増殖の各工程を有することを特徴とする請求項1又は2記載の培地。
- ヒト肝前駆細胞が、ヒトiPS細胞又はヒトES細胞をウイルスベクターを用いてヒトヘパトブラスト様細胞に分化させた細胞であることを特徴とする請求項1〜3いずれか記載の培地。
- 請求項1〜4いずれか記載の培地を用いることを特徴とするヒト肝前駆細胞の培養方法。
- 水に添加して調製した場合に、0.03mM〜1mMのカルシウムイオンと、500mg/L〜4500mg/Lのグルコースと、0.1mM〜2.0mMのピルビン酸イオンとを含む基礎培地を構成する成分群と、インスリン、トランスフェリン、2−メルカプトエタノール、2−エタノールアミン、セレン酸、脂肪酸不含アルブミン、ヘパリン、FGF−2、FGF−4、及びHGFからなるサプリメントを含む、ヒト肝前駆細胞を増殖用培地を作製するためのキット。
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