JP7015518B2 - 毛包幹細胞の未分化状態維持剤 - Google Patents
毛包幹細胞の未分化状態維持剤 Download PDFInfo
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Description
(1)デコリンを有効成分として含有することを特徴とする、幹細胞の未分化状態維持剤。
(2)前記幹細胞が、毛包幹細胞である、(1)に記載の幹細胞の未分化状態維持剤。
(3)ラミニンを有効成分としてさらに含有する、(1)又は(2)に記載の幹細胞の未分化状態維持剤。
(4)デコリンを有効成分として含有することを特徴とする、脱毛症の予防及び/又は改善剤。
(5)ラミニンを有効成分としてさらに含有する、(4)に記載の脱毛症の予防及び/又は改善剤。
(6)デコリン遺伝子の発現を促進する物質を有効成分として含有する、脱毛症の予防及び/又は改善剤。
(7)(4)~(6)のいずれかに記載の剤を含む、毛髪用組成物。
(8)デコリンを含有する毛包幹細胞維持用培地。
(9)デコリンでコーティングされたことを特徴とする、毛包幹細胞維持用培養器。
(10)毛包幹細胞を、(8)に記載の培地内で若しくは(9)に記載の培養器内で培養する工程を含む、毛包幹細胞の維持方法。
(11)以下の工程を含む、脱毛症の予防及び/又は改善物質のスクリーニング方法。
(a)被験物質を、デコリン遺伝子を発現する細胞と接触させる工程
(b)(a)の細胞における、デコリン遺伝子の発現量を測定する工程
(c)被験物質を接触させない場合の同細胞におけるデコリン遺伝子の発現量を測定する工程
(d)上記(b)で測定した発現量が、上記(c)で測定した発現量より増加した被験物質を脱毛症の予防及び/又は改善物質として選択する工程
(12)被験対象より採取した毛髪の毛根部におけるデコリン遺伝子の発現量を指標として、毛髪の脱毛化を評価する方法。
(13)被験対象に抗脱毛剤を使用し、使用する前と後の該被験対象より採取した毛髪の毛根部におけるデコリン遺伝子の発現量を指標として、毛髪に対する抗脱毛剤の有効性を評価する方法。
(14)前記デコリン遺伝子の発現量が、デコリンのmRNA又はタンパク質の量を測定することにより行われる、(11)~(13)のいずれかに記載の方法。
本発明の幹細胞の未分化状態維持剤は、デコリンを有効成分として含有する。本発明に係る幹細胞の未分化状態維持剤を、ヒトを含めた哺乳動物の幹細胞に適用することで、幹細胞の未分化状態を維持し、分化を抑制することができる。本発明に係る幹細胞の未分化状態維持剤を適用する幹細胞としては、本発明の目的に沿うものであれば特に限定されず、例えば胚性の幹細胞(ES細胞);骨髄、血液、皮膚(表皮、真皮、皮下組織)、脂肪、毛包、脳、神経、肝臓、膵臓、腎臓、筋肉やその他の組織に存在する体性の幹細胞;遺伝子導入等により人工的に作製された幹細胞(人工多能性幹細胞:iPS細胞)が挙げられるが、毛包の幹細胞に対してより効果を発揮する。本発明に係る幹細胞の未分化状態維持剤は、幹細胞の分化の方向性及び分化の過程等について同等の特性を持っていれば、全ての哺乳動物由来の幹細胞に応用が可能である。例えば、本発明に係る幹細胞の未分化状態維持剤は、ヒト、サル、マウス、ラット、モルモット、ウサギ、ネコ、イヌ、ウマ、ウシ、ヒツジ、ヤギ、ブタ等の哺乳動物の幹細胞に対して効果を発揮することができる。
デコリンはまた、毛包幹細胞の未分化状態を維持させるための培養ツールとして利用できる。すなわち、本発明によれば、デコリンを培地添加剤として添加した毛包幹細胞維持用培地、デコリンをコーティングした毛包幹細胞維持用培養器が提供される。本発明はまた、これらの培養ツールを用いて毛包幹細胞を、その未分化性を保持しつつ培養することを特徴とする、毛包幹細胞の維持方法が提供される。これらの培養ツールや方法は、例えば、毛包幹細胞の維持及び分化のメカニズム、薄毛及び/又は脱毛発生のメカニズム、抗脱毛剤の作用機序の解明に利用できる。
デコリンは、脱毛症の予防及び/又は改善物質のスクリーニング方法にも使用できる。本発明のスクリーニング方法によれば、デコリン遺伝子の発現の亢進を指標として、脱毛症の予防及び/又は改善物質を精度よく、かつ迅速、正確にスクーニングできる。本発明のスクリーニング方法は、具体的には以下の工程を含む。
(a)被験物質を、デコリン遺伝子を発現する細胞と接触させる工程
(b)(a)の細胞における、デコリン遺伝子の発現量を測定する工程
(c)被験物質を接触させない場合の同細胞におけるデコリン遺伝子の発現量を測定する工程
(d)上記(b)で測定した発現量が、上記(c)で測定した発現量より増加した被験物質を脱毛症の予防及び/又は改善物質として選択する工程
本発明の毛髪の脱毛化を評価する方法は、被験対象より採取した毛髪の毛根部におけるデコリン遺伝子の発現量を指標として用いる。具体的には、被験対象の特定部位の毛髪より採取した毛根部を用意し、該毛根部におけるデコリン遺伝子の発現量を測定し、該発現量に基づいて毛髪の脱毛化を評価する。本発明において「脱毛化の評価」とは、脱毛や薄毛の発生の予測、脱毛や薄毛になる素因の有無の判定、脱毛や薄毛の程度(本数や範囲)の判定、脱毛や薄毛の進行度の判定などをいう。
被験対象試料及び対照試料におけるデコリン遺伝子の発現量の測定は、前項の方法と同様に行えばよい。
ヒトの毛髪を毛抜きで採取し、PBS(-)にて2回洗浄した後、毛根部をメスで毛球、バルジ下、バルジ、バルジ上の4区画に分割した。Trizol Reagent(Invitrogen社製)によって各区画の細胞からRNAを抽出した。2-STEPリアルタイムPCRキット(Applied Biosystems社製)を用いて、抽出したRNAをcDNAに逆転写した後、ABI7300(Applied Biosystems社製)により、下記のプライマーセットを用いてリアルタイムPCR(95℃:15秒間、60℃:30秒間、40cycles)を実施し、デコリン遺伝子の発現量を測定した。その他の操作は定められた方法に従って実施した。
5'-TTCTGCCCACCTGGACACA-3' (配列番号3)
5'-GACCGGGTTGCTGAAAAGAC-3' (配列番号4)
18srRNA(内部標準)用プライマーセット:
5'-CCGAGCCGCCTGGATAC-3' (配列番号5)
5'-CAGTTCCGAAAACCAACAAAATAGA-3'(配列番号6)
(1)ヒト毛包幹細胞の培養
ヒトの毛髪を毛抜きで採取し、メス等を用いて毛包組織のバルジ領域を含む組織を回収した。PBS(-)にて洗浄した後、トリプシン(BD Biosciences社製)処理を行った。その後、セルストレイナー(FALCON社製)を用いて、細胞を単離し、回収した。回収した細胞を24ウェルの培養プレートに播種し、KG2培地(KURABO社製)を用いてコンフルエントになるまで維持した。コンフルエントになった細胞を回収し、同培養プレートに再び1×104個ずつ播種し、その後生着し、増殖している細胞を毛包幹細胞として以下の試験に用いた。
デコリンが毛包幹細胞の未分化性にどのように関わっているかを解析するために、毛包幹細胞におけるデコリン遺伝子のノックダウンを行い、その際の細胞の幹細胞性の解析を、未分化マーカーKRT15と分化マーカーIVL(Involucrin)を指標として行った。
上記の培養プレートで増殖した毛包幹細胞1ウェルあたりに、トランスフェクションの最適培地であるOpti-Mem(Invitrogen社製)500μlにデコリン遺伝子に対するsiRNA (siRNA-1(No.1039526), siRNA-2(No.1039527), siRNA-3(No.1039528);Bioneer社製)又はコントロールsiRNA(Bioneer社製)を50nMとなるように添加し、さらにLipofectamine RNAiMAX(Invitrogen社製)1μlを添加し、15分間静置した後、これを用いてsiRNAのトランスフェクションを行った。
5'- GATGCTGCTTGACATAAAGACACG-3' (配列番号7)
5'- ACCTGTCCATCCACTGACTCTTC-3' (配列番号8)
IVL(毛包幹細胞分化マーカー)用プライマーセット:
5'- CCATCAGGAGCAAATGAAACAG-3' (配列番号9)
5'- GCTCGACAGGCACCTTCTG-3' (配列番号10)
(1)ヒト毛包幹細胞の培養
ヒトの毛髪を毛抜きで採取し、メス等を用いて毛包組織のバルジ領域を含む組織を回収した。PBS(-)にて洗浄した後、トリプシン(BD Biosciences社製)処理を行った。その後、セルストレイナー(FALCON社製)を用いて、細胞を単離し、回収した。回収した細胞を培養プレートに播種し、KG2培地(KURABO社製)を用いてコンフルエントになるまで維持した。コンフルエントになった細胞を回収し、同培養プレートに再び播種し、その後生着し、増殖している細胞を毛包幹細胞として以下の試験に用いた。
毛包幹細胞にデコリンを作用させ、デコリンが毛包幹細胞の未分化性にどのように関わっているかを評価した。また、デコリンのラミニンとの併用効果も評価した。未分化性は、KG2培地(KURABO社製)にて培養した毛包幹細胞を24ウェルの培養プレートに1×104個ずつ播種し、デコリン、ラミニン、またはデコリンとラミニン等量混合物の各試験成分をそれぞれ最終濃度が10 ng/mlとなるように添加して培養し、試験成分添加48時間後の毛包幹細胞を回収し、毛包幹細胞の未分化性をKRT15の遺伝子発現量を指標に解析した。なお、デコリンとしてDCN Human Recombinant(PROSPEC社製)、ラミニンとしてiMatrix-511(Nippi社製)を用いた。
Claims (4)
- デコリン及びラミニンを有効成分として含有することを特徴とする、培養レベルでの毛包幹細胞の未分化状態維持剤。
- デコリン及びラミニンを含有する毛包幹細胞維持用培地。
- デコリン及びラミニンでコーティングされたことを特徴とする、毛包幹細胞維持用培養器。
- 毛包幹細胞を、請求項2に記載の培地内で若しくは請求項3に記載の培養器内で培養する工程を含む、毛包幹細胞の維持方法。
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