JP6147191B2 - 細胞不死化のための方法及びベクター - Google Patents
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- 108091005957 yellow fluorescent proteins Proteins 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
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Description
(i)有限寿命の細胞を準備する工程と、
(ii)上記細胞に、以下のカテゴリー:
(a)BMPシグナル伝達の活性化を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
(b)多能性の維持に関与する遺伝子若しくは遺伝子産物、又はその機能的置換体、又は、
(c)細胞周期の進行を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
のうち少なくとも2つのカテゴリーの各々からの少なくとも1つの遺伝子、遺伝子産物又はその機能的置換体、及び任意で形質導入細胞の選択を促進する1つ又は複数の遺伝子又は遺伝子産物を供給する工程と、
を含む、有限寿命の細胞を不死化する方法に関する。
(a)BMPシグナル伝達の活性化を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
(b)多能性の維持に関与する遺伝子又はその機能的置換体、又は、
(c)細胞周期の進行を促進する遺伝子又はその機能的置換体、
のうち1つから選択される少なくとも2つの遺伝子、及び任意で形質導入細胞の選択を促進する1つ又は複数の遺伝子又は遺伝子産物の発現を指向する、ベクター又はベクターセットに関する。
(i)有限寿命の細胞を準備する工程と、
(ii)上記細胞に、以下のカテゴリー:
(a)BMPシグナル伝達の活性化を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
(b)多能性の維持に関与する遺伝子若しくは遺伝子産物、又はその機能的置換体、又は、
(c)細胞周期の進行を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
のうち少なくとも2つのカテゴリーの各々からの少なくとも1つの遺伝子、遺伝子産物又はその機能的置換体、及び任意で形質導入細胞の選択を促進する1つ又は複数の遺伝子又は遺伝子産物を供給する工程と、
を含む、有限寿命の細胞を不死化する方法に関する。
(a)BMPシグナル伝達の活性化を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
(b)多能性の維持に関与する遺伝子若しくは遺伝子産物、又はその機能的置換体、又は、
(c)細胞周期の進行を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
のうち少なくとも2つのカテゴリーの各々からの少なくとも1つの遺伝子、遺伝子産物又はその機能的置換体、及び任意で形質導入細胞の選択を促進する1つ又は複数の遺伝子又は遺伝子産物を含む。
(a)BMPシグナル伝達の活性化を促進する遺伝子若しくは遺伝子産物、又はその機能的置換体、
(b)多能性の維持に関与する遺伝子又はその機能的置換体、又は、
(c)細胞周期の進行を促進する遺伝子又はその機能的置換体、
のうち1つから選択される少なくとも2つの遺伝子、及び任意で形質導入細胞の選択を促進する1つ又は複数の遺伝子又は遺伝子産物の発現を指向する、ベクター又はベクターセットにも関する。
(i)Id2、Fos、TAg、Id3、E7、Bcl2、Core、Id1、Myc、Lmo2、Yap1、Nanog、Sox2、Ezh2、及びRex;
(ii)Id3、E7、Core、Id1、Myc、Lmo2、Yap1、Nanog、Ezh2、及びRex;
(iii)core、Id1、Lmo2、及びNanog;
(iv)RhoA、及びEzh2;
(v)Id2、Fos、Id3、E7、core、Id1、及びMyc;
(vi)E7、及びMyc;
(vii)Myb、E7、HoxA9、Core、及びMyc;
(vii)Id2、Fos、βcat、TAg、Id3、E7、E6、HoxA9、Bmi1、core、Klf4、Id1、Myc、Lmo2、及びNanog
(viii)Sox2、RhoA、Ezh2、及びRex;
(ix)Id2、Fos、Id3、core、Klf4、Id1、Nanog、Ezh2、及びId4;
(x)Id2、Fos、及びId3;
(xi)Klf4、Id1、Lmo2、Yap1、及びNanog;
(xii)Sox2、Ezh2、Rex;
(xiii)Id2、Fos、Myb、Id3、E7、Id1、Myc、Nanog、Ezh2、及びRex;
(xiv)Fos、Id3、Bmi1、Yap1、及びNanog;
(xv)Id2、Fos、及びId3;
(xvi)Suz12、Id4、及びRex;
(xvii)Id2、Fos、βcat、TAg、E7、E6、Id1、及びMyc;
(xviii)Id2、Fos、Id1、及びMyc;
(xix)Id2、Id1、及びMyc;
(xx)Id2、Fos、及びId1;
(xxi)Fos、Id1、及びMyc;
(xxii)Id2、Fos、Myc;
(xxiii)Id2、Fos、Myb、Id3、及びBcl2;
(xxiv)Id2、Fos、Id3、HoxA9、Id1、Nanog、及びEzh2;
(xxv)Id1、Id3、Fos、Ezh2、及びNanog;
(xxvi)E7、HoxA9、Sox2、及びEzh2;
(xxvii)Id1、Id3、Fos、TAg、E7、HoxA9、Nanog、Sox2、及びEzh2;
(xxviii)TAg、Id3、E7、E6、Lmo2、Nanog、Ezh2、及びZFP217;
(xxxix)Id2、TAg、E7、及びMyc;
(xxx)Fos、βcat、TAg、E7、Id1、及びMyc;
(xxxi)Id2、Fos、TAg、E7、及びMyc;
(xxxii)Id2、Fos、Id3、E7、core、Klf4、Id1、Lmo2、Nanog、Sox2、及びEzh2;
(xxxiii)Fos、Nanog、及びEzh2;
(xxxiv)Id2、Fos、TAg、Id3、core、Id1、Lmo2、及びNanog;
(xxxv)Id3、E7、Id1、Lmo2、Yap1、Nanog、及びEzh2;
(xxxvi)Id2、Fos、Id1、及びEzh2;
(xxxvii)Id2、Fos、E7、core、Lmo2、及びNanog;
(xxxviii)Id2、Fos、βcat、Id3、E7、Id1、Lmo2、及びEzh2;
(xxxix)Id2、E7、Nanog、及びEzh2;
(xl)Id2、Myb、Id3、E7、E6、Myc、Yap1、Nanog、及びEzh2;
(xli)Id2、Fos、Id3、E7、E6、core、Id1、Lmo2、Yap1、Nanog、Sox2、及びEzh2;
(xlii)Id2、Fos、E7、Id1、Lmo2、Yap1、Nanog、及びSox2;
(xliii)E7、E6、Bmi1、Id1、Myc、Lmo2、Yap1、Nanog、及びSox2;
(xliv)Id2、E7、Myc、Nanog、Sox2、及びEzh2;
(xlv)Id2、Fos、Id3、E7、E6、Bcl2、HoxA9、Bmi1、Klf4、Id1、Myc、Nanog、Sox2、Ezh2、及びGli1
(xlvi)Fos、Id3、E7、Id1、Nanog、及びSox2
(xlvii)Id2、Fos、Id3、E7、HoxA9、Id1、Myc、Nanog、Sox2、Ezh2、及びGli1
(xlviii)Id3、HoxA9、Myc、及びcore
(xlix)Myb、Id3、core、及びMyc
(l)Id3、Myc、Bcl2、Bmi1、及びHoxA9
(li)PymT、Bcl2、Myc、Id3、及びHoxA9
(lii)PymT、Myc、core、及びβcat
(liii)Id1、及びMyc
(liv)Id2、及びMyc
(lv)Id3、及びMyc
(lvi)Id4、及びMyc
(lvii)βcat、及びMyc
(lviii)βcat、及びPymT、Myc
(lix)βcat、及びMyc、Bmi1
(lx)Myc、BcL2、及びβcat
(lxi)Myc、HoxA9、及びID3
(lxii)βcat、及びMyc
(lxiii)core、Myc、及びID3。
(lxiv)Id3、core、Lmo2、及びEzh2
(lxv)Id3、E7、E6、Yap1、及びNanog
(lxvi)Myc、Klf4
(lxvii)Fos、E7、Klf4、Lmo2
(lxviii)TAg、Klf4
(lxix)TAg、core、Klf4
(lxx)Id3、Klf4、Id4
(lxxi)Fos、E7、Klf4
(lxxii)Fos、E7、Klf4、ID4
(lxxiii)TAg、core
(lxxiv)ID2、ID3、core
(lxxv)Bcl2、core、Myc、Rex
(lxxvi)Id3、Bcl2、core、Myc
(lxxvii)TAg、Myb、ID3、core、Myc
(lxxviii)ID2、Bcl2、core、Myc
(lxxix)TAg、ID3、Bcl2、core、Rex
(lxxx)TAg、E6、Bcl2、core、ID4、Rex
(lxxxi)TAg、ID3、Bcl2、core、Myc、Rex
本発明の技術の目的は、生物学的に関連した哺乳動物細胞を無制限な数で提供することである。現行の細胞株確立プロセスの制限を解決するために、哺乳動物細胞の不死化を誘導することのできる33個の異なる遺伝子を同定した。この遺伝子セットには、ウイルスがん遺伝子、哺乳動物がん遺伝子、腫瘍細胞において過剰発現される遺伝子、及び分化を阻害する遺伝子が含まれる。採用した不死化遺伝子を表1に挙げる。表1には本明細書で使用される略語を示す。加えて、NCBIデータベースから引用した正式な遺伝子名、遺伝子ID及び遺伝子記号、並びに遺伝子が由来する種/生物を記載する。採用した細胞遺伝子はヒト又はマウスのいずれかに由来するものであった。しかしながら、他の種に由来するホモログも本発明に使用することができる。
初代細胞の不死化を達成するためには、初代哺乳動物細胞において不死化遺伝子を組換え発現しなくてはならない。この目的で、不死化遺伝子の組換え発現を可能にする任意の遺伝子又はタンパク質の形質導入法を用いることができる。さらに、不死化遺伝子の発現を誘導することが可能な任意の遺伝子発現カセット(宿主細胞ゲノムに組み込まれるか否かを問わない)を用いることができる。
PymT;HoxA9;Bmi1;Id3;Myb;core;Klf4;Oct3/4;Rex1;Bcl2。
以下の遺伝子を、選択カセットを用いて形質導入した:
Myc;β−cat;Id1;TAg;Fos;E2f1;Jun;Ns1;Sox2;Id2;Lmo2;Nanog;Nfe2l2;Yap1;E7;E6;Gli1;Suz12;Ezh2;Zfp217;RhoA;v−Myc;Id4。
All−全ての不死化遺伝子(表1に挙げられる)を含めた;
MBG−TAg、E6、E7及びMycを除く全ての不死化遺伝子(表1に挙げられる);
1〜10−Id2、Fos、NS1、Jun、E2F1、βCat、Myb、Id3、Bcl2、HoxA9;
11〜20−Bmi1、PymT、Core、Oct3、Klf4、Id1、Lmo2、Nfe2L2、Yap1、Nanog;
21〜29−Sox2、RhoA、Ezh2、Gli1、v−Myc、Suz12、ZFP217、Id4、Rex。
記載の技術はドナーの種、細胞型、遺伝子型、又はドナーの年齢とは独立して新規の哺乳動物細胞株の確立を可能にする。この目的で、対象の初代細胞に33個の不死化遺伝子の全セット、又は好適な不死化遺伝子のより小さなサブセットを形質導入することができる。以下の実施例では、この技術の有用性を種々の種(マウス、ウシ、ヒト)、種々の細胞型(線維芽細胞、骨髄間質細胞、マクロファージ、内皮細胞、骨芽細胞、軟骨細胞、ケラチノサイト、肺上皮細胞、角膜上皮細胞、肝細胞)、種々の遺伝子型(線維芽細胞、骨髄間質細胞)、並びに幼体(ヒト臍帯内皮細胞及びケラチノサイト)及び成体(ヒト成体ケラチノサイト、ヒト成体微小血管内皮細胞)に由来する新規の哺乳動物細胞株の確立によって証明した。しかしながら、本発明の技術は言及した例に限定されず、任意の細胞型及び任意の哺乳動物種の細胞に適用することができる。また、試験したものと同等の機能を有する種々の遺伝子を使用することができる。
次の工程では、初代細胞の不死化に関与する遺伝子を同定した。この目的で、不死化細胞株のゲノム中に存在する遺伝子を検出するPCR戦略を開発した。不死化遺伝子又はより良好には遺伝子の組合せが感染細胞に与えられるという選択的利点のために、ゲノムDNAを単離する前に長い増加期間を選択した(30を超える累積集団倍加数)。これにより、検出される遺伝子が実際に不死化に関与することが確実となるはずである。
1inf.=感染;2det.=検出された;3fre.=頻度
細胞株の最も重要な特性はその生理であり、細胞がin vivoで示すその生理に可能な限り厳密に似るべきである。したがって、確立された細胞株をそれらの生物学的関連性について試験した。不死化が多くの場合、細胞シグナル伝達経路を妨げることが知られている。
Claims (9)
- 有限寿命の哺乳動物細胞がもともと有している分化特異的な生理的特性を本質的に保持したまま有限寿命の哺乳動物細胞を不死化するインビトロ方法であって、
不死化細胞は胚性幹細胞若しくは胚性幹細胞の特徴を持つ細胞ではなく、
(i)単離された有限寿命の哺乳動物細胞を準備する工程と、
(ii)前記有限寿命の細胞に、以下の(1)〜(54)のいずれかを含む遺伝子若しくは遺伝子産物の組合わせ:
(1)Id2、Fos、TAg、Id3、E7、Bcl2、Core、Id1、Myc、Lmo2、Yap1、Nanog、Sox2、Ezh2、及びRex;
(2)Id3、E7、Core、Id1、Myc、Lmo2、Yap1、Nanog、Ezh2、及びRex;
(3)core、Id1、Lmo2、及びNanog;
(4)RhoA、及びEzh2;
(5)Id2、Fos、Id3、E7、core、Id1、及びMyc;
(6)E7、及びMyc;
(7)Myb、E7、HoxA9、Core、及びMyc;
(8)Id2、Fos、βcat、TAg、Id3、E7、E6、HoxA9、Bmi1、core、Klf4、Id1、Myc、Lmo2、Nanog、Sox2、RhoA、Ezh2、及びRex;
(9)Id2、Fos、Id3、core、Klf4、Id1、Nanog、Ezh2、及びId4;
(10)Id2、Fos、及びId3;
(11)Klf4、Id1、Lmo2、Yap1、及びNanog;
(12)Sox2、Ezh2、及びRex;
(13)Id2、Fos、Myb、Id3、E7、Id1、Myc、Nanog、Ezh2、及びRex;
(14)Fos、Id3、Bmi1、Yap1、及びNanog;
(15)Id2、Fos、及びId3;
(16)Suz12、Id4、及びRex;
(17)Id2、Fos、βcat、TAg、E7、E6、Id1、及びMyc;
(18)Id2、Fos、Id1、及びMyc;
(19)Id2、Id1、及びMyc;
(20)Id2、Fos、及びId1;
(21)Fos、Id1、及びMyc;
(22)Id2、Fos、及びMyc;
(23)Id2、Fos、Myb、Id3、及びBcl2;
(24)Id2、Fos、Id3、HoxA9、Id1、Nanog、及びEzh2;
(25)Id1、Id3、Fos、Ezh2、及びNanog;
(26)E7、HoxA9、Sox2、及びEzh2;
(27)Id1、Id3、Fos、TAg、E7、HoxA9、Nanog、Sox2、及びEzh2;
(28)TAg、Id3、E7、E6、Lmo2、Nanog、Ezh2、及びZFP217;
(29)Id2、TAg、E7、及びMyc;
(30)Fos、βcat、TAg、E7、Id1、及びMyc;
(31)Id2、Fos、TAg、E7、及びMyc;
(32)Id2、Fos、Id3、E7、core、Klf4、Id1、Lmo2、Nanog、Sox2、及びEzh2;
(33)Fos、Nanog、及びEzh2;
(34)Id2、Fos、TAg、Id3、core、Id1、Lmo2、及びNanog;
(35)Id3、E7、Id1、Lmo2、Yap1、Nanog、及びEzh2;
(36)Id2、Fos、Id1、及びEzh2;
(37)Id2、Fos、E7、core、Lmo2、及びNanog;
(38)Id2、Fos、βcat、Id3、E7、Id1、Lmo2、及びEzh2;
(39)Id2、E7、Nanog、及びEzh2;
(40)Id2、Myb、Id3、E7、E6、Myc、Yap1、Nanog、及びEzh2;
(41)Id2、Fos、Id3、E7、E6、core、Id1、Lmo2、Yap1、Nanog、Sox2、及びEzh2;
(42)Id2、Fos、E7、Id1、Lmo2、Yap1、Nanog、及びSox2;
(43)E7、E6、Bmi1、Id1、Myc、Lmo2、Yap1、Nanog、及びSox2;
(44)Id2、E7、Myc、Nanog、Sox2、及びEzh2;
(45)Id3、core、Lmo2、及びEzh2;
(46)Id3、E7、E6、Yap1、及びNanog;
(47)c−myc、Klf4;
(48)Fos、E7、Klf4、Lmo2;
(49)TAg、Klf4;
(50)TAg、core、Klf4;
(51)Id3、Klf4、Id4;
(52)Fos、E7、Klf4;
(53)Fos、E7、Klf4、ID4;又は
(54)TAg、core;
を供給する工程、
を含む、方法。 - 有限寿命の哺乳動物細胞が、特定の遺伝的背景を有する個体又は個体群に由来し、該特定の遺伝的背景が少なくとも1つの突然変異、欠失、重複、SNP関連変異及び/又は染色体異常によって野生型と異なる、請求項1に記載の方法。
- 工程(ii)の後に、不死化細胞において増殖を終了若しくは遅延させる、及び/又は分化を誘導する、工程(iii)を更に含む、請求項1又は2に記載の方法。
- 遺伝子の供給が細胞型特異的及び/又は調節性である、請求項1〜3のいずれか一項に記載の方法。
- 遺伝子又は遺伝子産物を、工程(i)の有限寿命の哺乳動物細胞のサブセットのみで供給し、及び/又は該遺伝子を該哺乳動物細胞のサブセットのみで発現させる、請求項1〜4のいずれか一項に記載の方法。
- 請求項1〜5のいずれか一項に記載の方法を用いて産生可能な細胞又は細胞株。
- 少なくとも1つの遺伝子に作動可能に連結した発現制御配列を含む少なくとも1つの発現カセットを含むベクター、又は各々が少なくとも1つの遺伝子に作動可能に連結した発現制御配列を含む少なくとも1つの発現カセットを含むベクターセットの有限寿命の哺乳動物細胞がもともと有している分化特異的な生理的特性を本質的に保持したまま有限寿命の哺乳動物細胞を不死化するための使用であって、
不死化細胞は胚性幹細胞若しくは胚性幹細胞の特徴を持つ細胞ではなく、
ベクター又はベクターセットの各々が、以下の(1)〜(54)のいずれかを含む遺伝子若しくは遺伝子産物の組合わせ:
(1)Id2、Fos、TAg、Id3、E7、Bcl2、Core、Id1、Myc、Lmo2、Yap1、Nanog、Sox2、Ezh2、及びRex;
(2)Id3、E7、Core、Id1、Myc、Lmo2、Yap1、Nanog、Ezh2、及びRex;
(3)core、Id1、Lmo2、及びNanog;
(4)RhoA、及びEzh2;
(5)Id2、Fos、Id3、E7、core、Id1、及びMyc;
(6)E7、及びMyc;
(7)Myb、E7、HoxA9、Core、及びMyc;
(8)Id2、Fos、βcat、TAg、Id3、E7、E6、HoxA9、Bmi1、core、Klf4、Id1、Myc、Lmo2、Nanog、Sox2、RhoA、Ezh2、及びRex;
(9)Id2、Fos、Id3、core、Klf4、Id1、Nanog、Ezh2、及びId4;
(10)Id2、Fos、及びId3;
(11)Klf4、Id1、Lmo2、Yap1、及びNanog;
(12)Sox2、Ezh2、及びRex;
(13)Id2、Fos、Myb、Id3、E7、Id1、Myc、Nanog、Ezh2、及びRex;
(14)Fos、Id3、Bmi1、Yap1、及びNanog;
(15)Id2、Fos、及びId3;
(16)Suz12、Id4、及びRex;
(17)Id2、Fos、βcat、TAg、E7、E6、Id1、及びMyc;
(18)Id2、Fos、Id1、及びMyc;
(19)Id2、Id1、及びMyc;
(20)Id2、Fos、及びId1;
(21)Fos、Id1、及びMyc;
(22)Id2、Fos、及びMyc;
(23)Id2、Fos、Myb、Id3、及びBcl2;
(24)Id2、Fos、Id3、HoxA9、Id1、Nanog、及びEzh2;
(25)Id1、Id3、Fos、Ezh2、及びNanog;
(26)E7、HoxA9、Sox2、及びEzh2;
(27)Id1、Id3、Fos、TAg、E7、HoxA9、Nanog、Sox2、及びEzh2;
(28)TAg、Id3、E7、E6、Lmo2、Nanog、Ezh2、及びZFP217;
(29)Id2、TAg、E7、及びMyc;
(30)Fos、βcat、TAg、E7、Id1、及びMyc;
(31)Id2、Fos、TAg、E7、及びMyc;
(32)Id2、Fos、Id3、E7、core、Klf4、Id1、Lmo2、Nanog、Sox2、及びEzh2;
(33)Fos、Nanog、及びEzh2;
(34)Id2、Fos、TAg、Id3、core、Id1、Lmo2、及びNanog;
(35)Id3、E7、Id1、Lmo2、Yap1、Nanog、及びEzh2;
(36)Id2、Fos、Id1、及びEzh2;
(37)Id2、Fos、E7、core、Lmo2、及びNanog;
(38)Id2、Fos、βcat、Id3、E7、Id1、Lmo2、及びEzh2;
(39)Id2、E7、Nanog、及びEzh2;
(40)Id2、Myb、Id3、E7、E6、Myc、Yap1、Nanog、及びEzh2;
(41)Id2、Fos、Id3、E7、E6、core、Id1、Lmo2、Yap1、Nanog、Sox2、及びEzh2;
(42)Id2、Fos、E7、Id1、Lmo2、Yap1、Nanog、及びSox2;
(43)E7、E6、Bmi1、Id1、Myc、Lmo2、Yap1、Nanog、及びSox2;
(44)Id2、E7、Myc、Nanog、Sox2、及びEzh2;
(45)Id3、core、Lmo2、及びEzh2;
(46)Id3、E7、E6、Yap1、及びNanog;
(47)c−myc、Klf4;
(48)Fos、E7、Klf4、Lmo2;
(49)TAg、Klf4;
(50)TAg、core、Klf4;
(51)Id3、Klf4、Id4;
(52)Fos、E7、Klf4;
(53)Fos、E7、Klf4、ID4;又は
(54)TAg、core;
の発現を指向する、ベクター又はベクターセットの使用。 - 細胞アッセイ、3d細胞培養モデルの確立、組織工学、1つ若しくは複数の異なる細胞株の細胞を用いた共培養、及び/又は細胞カプセル化のための請求項6に記載の細胞若しくは細胞株の使用。
- 請求項6に記載の細胞若しくは細胞株を含む、変性疾患、臓器若しくは細胞の損傷/機能不全、免疫系に関連する病態、がん、心理的病態、又は肥満を含む代謝性疾患の治療又は予防のための薬剤。
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