JP6050033B2 - 幹細胞から外胚葉系細胞への分化誘導剤 - Google Patents
幹細胞から外胚葉系細胞への分化誘導剤 Download PDFInfo
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Landscapes
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Description
(1)フコイダンを有効成分として含有することを特徴とする、幹細胞から外胚葉系細胞への分化誘導剤。
(2)外胚葉系細胞が感覚器系細胞又は神経系細胞である、(1)に記載の分化誘導剤。
(3)感覚器系細胞が眼の構成細胞である、(2)に記載の分化誘導剤。
(4)眼の構成細胞が、網膜、水晶体、角膜上皮又は虹彩の細胞である、(3)に記載の分化誘導剤。
(5)(1)〜(4)のいずれかに記載の分化誘導剤を含有することを特徴とする、医薬品又は飲食品。
(6)眼疾患又は神経疾患の治療用又は予防用の、(5)に記載の医薬品又は飲食品。
(7)フコイダンの存在下で幹細胞を培養して外胚葉系細胞へ分化誘導することを特徴とする、幹細胞から外胚葉系細胞への分化誘導方法。
(8)フコイダンの存在下で幹細胞を培養して外胚葉系細胞へ分化誘導する工程を含む、外胚葉系細胞の製造方法。
(9)(8)に記載の方法により製造された外胚葉系細胞。
本願発明の幹細胞から外胚葉系細胞への分化を誘導する分化誘導剤(以下、「外胚葉系細胞分化誘導剤」と称する場合がある)は、フコイダンを有効成分とする。
0.001重量%未満では効果が得にくく、30重量%を超えても効果に大きな増強はみられにくい。又、製剤化における有効成分の添加法については、予め加えておいても、製造途中で添加してもよく、作業性を考えて適宜選択すればよい。
(1)ES細胞の調製
ゼラチンコート処理した35mmシャーレにMMC(mitomycin C)処理済みのMEF細胞(Mouse embryonic fibroblast)をコンフルエントの状態で培養し、その上にマウスES細胞を10〜20×104個播種し、37℃、5%CO2インキュベーターで前培養した。培地はDMEMにchemicon社製のES細胞用添加因子(L−グルタミン液、2−メルカプトエタノール液、ヌクレオシド液、非必須アミノ酸液、ESGRO)を推奨濃度で添加した後、LIF(leukemia inhibitory factor)を1000units/mL、FBS(Fetal Bovine Serum)を15%添加したES細胞未分化維持用培地(以下、「ES細胞用培地」という)を用いた。
MEFから分離したES細胞を、24wellプレートで培養したMMC処理済のMEF細胞上に再び播種し(5×104 cells/well)、ES細胞用培地からLIFを除いた培地を用いて培養した。その際、市販のフコイダン(焼津水産化学工業株式会社製、フコイダンYSK(NB))を25、50、100μg/mLの濃度で添加した。
ATGCCTGCAGTTTTTCATCC(配列番号1)
GAGGCAGGTCTTCAGAGGAA(配列番号2)
Otx2(外胚葉、神経細胞マーカー)用プライマーセット:
GAAAATCAACTTGCCAGAATCCA(配列番号3)
GCGGCACTTAGCTCTTCGAT(配列番号4)
Sox1(神経細胞マーカー)用プライマーセット:
GCCGAGTGGAAGGTCATGT(配列番号5)
TGTAATCCGGGTGTTCCTTCAT(配列番号6)
Six3(前脳領域)用プライマーセット:
CCCTAGATCTCTATTCCTCCCACTTC(配列番号7)
GAAGTAGGGAGCAGTGGTGAGAA(配列番号8)
GAPDH(内部標準)用プライマーセット:
CCGTGTTCCTACCCCCAAT(配列番号9)
TGCCTGCTTCACCACCTTCT(配列番号10)
MEFから分離した未分化のES細胞をゼラチンコート処理した24wellプレートに直接(MEF細胞なしの状態で)播種し(5×104 cells/well)、上記方法と同様にES細胞用培地からLIFを除いた培地を用いて培養し、各濃度のフコイダンを添加した。培養4日後にRNAを回収し、Nanog(未分化マーカー)、Otx2(外胚葉・神経細胞マーカー)、Sox1(神経細胞マーカー)、Six3(前脳領域マーカー)の各マーカー遺伝子の発現を確認した。各マーカー遺伝子の発現をリアルタイムPCRにより解析した。その結果を表2に示す。
MEFから分離した未分化のマウスES細胞を、LIFを除いたES細胞用培地に懸濁し、2000cells/20μLの細胞濃度でhanging dropを形成し、EB(embryoid body)を作製した。その際、各濃度のフコイダンを添加し、培養4日後にRNAを回収し、Nanog(未分化マーカー)、Otx2(外胚葉・神経細胞マーカー)、Sox1(神経細胞マーカー)、Six3(前脳領域マーカー)の各マーカー遺伝子の発現をリアルタイムPCRにより解析した。その結果を表3に示す。
無血清培養下、ES細胞を各種のストローマ細胞と共培養することにより、成熟した神経系細胞を分化誘導する技術が確立されている(特許4294482号; Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S, Nishikawa SI, Sasai Y., Neuron 2000 Oct;28(1):31−40. Induction of midbrain dopaminergic neurons from ES cells by stromal cell−derived inducing activity)。本神経分化誘導系にフコイダンを添加したところ、成熟した神経細胞への誘導が促進された。
GCACCAAAGGGTCATCGC(配列番号11)
TGGGGGGTGGATGGAAG(配列番号12)
Tuj−1(神経細胞マーカー)用プライマーセット:
CTCAAAATGTCATCCACCTT(配列番号13)
GTGAACTCCATCTCATCCAT(配列番号14)
Map2(成熟神経細胞マーカー)用プライマーセット:
ACTCAGCAACGTCTCATCTT(配列番号15)
GTATTCACAAGCCCTGCTTA(配列番号16)
ES細胞をストローマ細胞であるST2細胞と共培養することにより、メラノサイトを分化誘導する系が確立されている(Yamane T, Hayashi S, Mizoguchi M, Yamazaki H, Kunisada T., Dev Dyn. 1999 Dec;216 (4−5):450−8. Derivation of melanocytes from embryonic stem cells in culture.)。本分化誘導系では、メラノサイト以外にも、心筋細胞、血球系細胞等様々な細胞が分化してくることが知られている。このような様々な細胞が分化してくる系に、フコイダンを添加して、以下の分化誘導試験を行った。
GAAAATCAACTTGCCAGAATCCA(配列番号3)
GCGGCACTTAGCTCTTCGAT(配列番号4)
Six3(前脳領域、眼の分化マーカー)用プライマーセット:
CCCTAGATCTCTATTCCTCCCACTTC(配列番号7)
GAAGTAGGGAGCAGTGGTGAGAA(配列番号8)
Pax6 (眼の分化マーカー)用プライマーセット:
GCACCAAAGGGTCATCGC(配列番号11)
TGGGGGGTGGATGGAAG(配列番号12)
Crystalin(水晶体マーカー)用プライマーセット:
TGGCTGCTGGATGCTCTATG(配列番号17)
CCGCGACGCAGGAAGTA(配列番号18)
(1)ヒトiPS細胞の調製
ゼラチンコート処理した60mmシャーレにMMC(mitomycin C)処理済みのMEF細胞をコンフルエントの状態で培養し、その上に解凍したヒトiPS細胞の細胞塊を播種し、37℃、5%CO2インキュベーターで前培養した。培地はカルディオ社製のiPSellonに5ng/mLの濃度でbFGFを添加したiPS細胞未分化維持用培地(以下、「iPS細胞用培地」という)を用いた。
CCTTCCTCCATGGATCTGCTT(配列番号19)
AAGTGGGTTGTTTGCCTTTGG(配列番号20)
Otx2(外胚葉、神経細胞マーカー)用プライマーセット:
TTCACTCGGGCGCAGCTAG(配列番号21)
CCATACCTGCACCCTCGACTC(配列番号22)
Sox1(神経細胞マーカー)用プライマーセット:
GGTCAAACGGCCCATGAAC(配列番号23)
TGATCTCCGAGTTGTGCATCTT(配列番号24)
Six3(前脳領域)用プライマーセット:
GTATTCCGCTCCCCCCTAGA(配列番号25)
TGGTGAGAATCGGCGAAGTT(配列番号26)
GAPDH(内部標準)用プライマーセット:
TGCACCACCAACTGCTTAGC(配列番号27)
TCTTCTGGGTGGCAGTGATG(配列番号28)
ヒトやマウスの体性幹細胞から神経細胞を分化誘導する系が確立されている(Stem Cells Dev. 2008 Oct;17(5):909−16.Neuronal differentiation potential of human adipose−derived mesenchymal stem cells. Anghileri E, Marconi S, Pignatelli A, Cifelli P, Galie M, Sbarbati A, Krampera M, Belluzzi O, Bonetti B.SourceDepartment of Neurological Sciences and Vision, University of Verona, Verona, Italy.)。これらの分化誘導系にフコイダンを添加したところ、神経細胞への分化が有意に促進され、フコイダンはES細胞やiPS細胞を用いた場合と同様に、体性幹細胞に対しても外胚葉への分化を顕著に促進した。
Claims (7)
- フコイダンを有効成分として含有することを特徴とする、多能性幹細胞から外胚葉系細胞への分化誘導剤。
- 外胚葉系細胞が感覚器系細胞又は神経系細胞である、請求項1記載の分化誘導剤。
- 感覚器系細胞が眼の構成細胞である、請求項2記載の分化誘導剤。
- 眼の構成細胞が、網膜、水晶体、角膜上皮又は虹彩の細胞である、請求項3記載の分化誘導剤。
- 請求項1〜4のいずれか一項に記載の分化誘導剤を含有することを特徴とする、眼疾患の治療用又は予防用の医薬品。
- フコイダンの存在下で多能性幹細胞を培養して外胚葉系細胞へ分化誘導することを特徴とする、幹細胞から外胚葉系細胞への分化誘導方法。
- フコイダンの存在下で多能性幹細胞を培養して外胚葉系細胞へ分化誘導する工程を含む、外胚葉系細胞の製造方法。
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