JP2018524023A - Nt細胞の保管方法、及びそのバンキングシステム - Google Patents
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Abstract
Description
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、
d)複数個の幹細胞を冷凍保存する段階と、を含む免疫適合型NT細胞由来幹細胞の保管方法を提供する。
また、本発明は、a)複数の寄贈者組織から同型接合いかんをスクリーニングする段階と、
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、を含む免疫適合型NT細胞由来幹細胞の製造方法を提供する。
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、
d)前記製造された幹細胞から、細胞移植のための分化された細胞に製造する段階と、を含む免疫適合型NT細胞由来幹細胞から分化された細胞の製造方法を提供する。
また、本発明は、a)複数の寄贈者組織を収集する手段、b)収集された組織をスクリーニングする手段、c)組織から幹細胞を製造する手段、及びd)幹細胞を冷凍保存する手段を含む免疫適合型NT由来幹細胞のバンキングシステムを提供する。
本発明で使用された「成熟」は、最終的に分化された細胞種類に向けて導く調和した生花学的段階で構成された過程を意味する。
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、を含む免疫適合型NT細胞由来幹細胞の製造方法を提供する。
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、
d)前記製造された幹細胞から細胞移植のための分化された細胞に製造する段階と、を含む免疫適合型NT細胞由来幹細胞から分化された細胞の製造方法を提供する。
前記収集された組織から免疫適合型いかんをスクリーニングする手段、
免疫適合型組織から幹細胞を製造する手段、及び
幹細胞を冷凍保存する手段を含む免疫適合型NT細胞由来幹細胞バンキングシステムを提供する。
寄贈者細胞から同型接合細胞のスクリーニング及び供与細胞の選別
Cha病院寄贈臍帯血銀行において、7億個未満の廃棄用臍帯血に対して同型接合細胞をスクリーニングした。HLA−A,B,DRB1 genotypingのために、Gentra PuregeneTM Blood Kits(QIAGEN,Hilden、ドイツ)を使用してgenomic DNAを抽出した後、SeCore A, B and DRB1 Locus Sequencing Kit(Invitrogen,Brown Deer,WI、米国)を使用して、sequence-based typingを実施した。特に、HLA−AとBとの場合、exon 2−4を、HLA−DRB1の場合、exon 2を、キット(kit)に含まれているlocus specific primerを使用して増幅させ、ABI3130XL Genetic Analyzer(Applied Biosystems,Foster City,CA、米国)を利用して形成されたPCR productに係わるシーケシング(sequencing)を行い、HLA SBT u−type software v3.0(Invitrogen)及びSequencher(Gene Codes Corp.,Ann Arbor,MI、米国)を使用してデータ分析を実施した。結局、かような方法を介して、寄贈臍帯血から、韓国人に最も頻度数が高いHLA同型接合供与細胞(A*33:03−B*44:03−DRB1*13:02)(haplotype frequency:4.6%)を見い出し、もしそこからNT細胞を製作する場合、全体人口の約9%を包括することができる。
2.1 卵母細胞の回収及び製造
CHARMI(CHA Regenerative Medicine Institute)のSCRO(Stem cell Research Oversight)委員会及びEIRB(Essex Institutional Review Board)の承認下で進められた。
卵母細胞の脱核は、以前に公知された方法によって遂行され(Tachibana et al., 2013)、卵母細胞の脱核、及び体細胞の核置換は、ステージウォーマ(stage warmer)、ナリシゲマイクロマニピュレータ(Narishige micromanipulator)、OosightTMイメージングシステム(poloscopic microscopy)、及びレーザを備えた倒立顕微鏡(inverted microscope)を使用して行った。レーザを備えた倒立顕微鏡の代わりに、ピエゾを備えた倒立顕微鏡が選択的に使用される。
NT細胞からのstem cell line製造及びその特性分析
前記実施例2で培養された胚盤胞を、酸性Tyrode溶液(pH2.0)で数秒間処理し、透明帯(ZP)を除去した。ZP除去後、胚芽をHepes−HTF培地で強力に(vigorously)洗浄し、微量のTyrode溶液までも除去した。レーザ補助胚盤胞切除システム(Hamilton-Thorne In.。)を利用して、内細胞塊(ICM)を分離し、胚盤胞の残余部分(栄養膜)を廃棄し、胚盤胞がそれ以上正常状態ではないということを確認した。プレーティング1日前に準備されたMEF上に、ICMをプレーティングし、しかし複製された胚盤胞を区別することができないICMを有する場合、全体胚芽をプレーティングした。hPSC誘導培地は、血清代替物(serum replacement)(5% SR、Invitrogen)、FBS(10%、Hyclone)、plasmamate(5%)、bFGF(32ng/ml)及びヒトLIF(2,000units/mI,Sigma-Aldrich)が補充されたノックアウトDMEMを含んでいる。同一培地において、3日間変化なしにICMを培養した後、4日目、培地の約1/3を交換した。6日目から一日おきに培地の1/2を交換した。プレーティング後7日以内に、最初成長(outgrowth)が確認された。
NT細胞凍結保存及びバンキング
実施例3で製造された細胞に対して、同型接合性細胞によって、分類されて保管され、文書またはプログラムに記録されるようにする。特に、細胞供与体の情報が共に保存されるようにする。おって、同種(autologous)または異種(allogenic)の授与者(患者)に、直接に利用されるか、あるいは分化された細胞に利用されるように保存される。
NT由来幹細胞から機能性網膜色素上皮細胞(RPE)への分化
RPEへの分化を誘導するために、未分化状態のNT由来幹細胞を、解剖顕微鏡下で、滅菌されたチップを使用して、機械的にさまざまな断片(clump-form of NT−ES cells;1断片は、約300〜600個の未分化状態の胚芽幹細胞株である)に切る。clump状のNT由来幹細胞は、low attachment 6−well plates(Corning,CA、米国)に入れ、胚芽体培養液(EBDM;knockoutTM DMEM(Thermo Scientific,CA、米国)supplemented with 15%(v/v)knockoutTM serum replacement(Thermo)、1%(v/v)glutamax(Thermo)、1%(v/v)NEAA(Thermo)、1%(v/v)penicillin-streptomycin(Thermo)and 0.1mM β−mercaptoethanol(Thermo))で浮遊状態で4日間培養する。培養された胚芽体は、培養皿に移され、付着した状態でRPE分化を誘導する。
胚芽体は、0.1%ゼラチンコーティングされた6−well培養皿に移し、付着するように、3日間培養器内に静置させた後、2〜3日間隔でEBDM培養液を交替しつつ、胚芽体から伸びて育つ細胞のうち、網膜色素上皮細胞が現れるまで、約50〜55日間培養した。色素沈着で色が区分されるRPE cellを分離するために、該細胞は、生理食塩水(DPBS containing Ca2+Mg2+(Thermo))で2回洗浄した後、コラゲナーゼタイプ4が含まれた生理食塩水(type IV collagenase(Thermo)in DPBS with Ca2+Mg2+(Thermo))で交替し、2時間37℃、5% CO2が維持される培養基で培養した。酵素を除去するために、培養皿から離れ出てくる細胞塊(detached cell clusters)を50mlチューブに集め、遠心分離機(1,500rpm、5分)を利用して、DMEM−FBS培養液で2回洗浄した。細胞塊は、60mmペトリ皿に移した後、解剖顕微鏡下で、細型のガラスピペットを利用して、網膜色素上皮細胞塊(pigmented cell clusters)を、色素が沈着していない他の細胞塊と区分して収集した。
網膜色素上皮細胞塊(pigmented cell clusters)は、単一細胞に分離させて培養するために、カルシウムとマグネシウムとが除去された生理食塩水(DPBS without Ca2+Mg2+(Thermo))で2回洗浄した後、分離酵素液(1:1 mixture of 0.25% trypsin−EDTA(Thermo)and Cell Dissociation Buffer(Thermo))を処理して分離した。単一細胞に分離された網膜色素上皮細胞は、遠心分離機(1,500rpm、5分)を利用して、DMEM−FBS培養液で洗浄した後、EGM2培養液(Lonza,PA、米国)で細胞を砕き、200,000細胞/4 well培養皿1個wellの濃度で、0.1%ゼラチンコーティングされた4 well培養皿に入れ、詰まるまでEGM−2培養液で培養した。約3〜4日後、培養皿に細胞が詰まれば、網膜色素上皮細胞の形態及び特性(cobble stone morphology and pigmentation)を示すように、RPE分化培養液(RGMM;1:1 mixture of EBDM and DMEM−FBS media)で培養液を交替して日間培養した。
Claims (22)
- a)複数の寄贈者組織から同型接合いかんをスクリーニングする段階と、
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、
d)複数個の幹細胞を冷凍保存する段階とを含む免疫適合型NT細胞由来幹細胞の保管方法。 - a)段階において、スクリーニングは、HLA−A、HLA−B及びHLA−DRの遺伝子が同型接合であることを特徴とする請求項1に記載の方法。
- b)段階において、NT製造は、卵母細胞を脱核する段階と、脱核された卵母細胞に体細胞の核を融合させる段階と、融合された卵母細胞をポスト活性化培地で培養する段階と、からなることを特徴とする請求項1に記載の方法。
- 前記卵母細胞の脱核は、タンパク質リン酸加水分解酵素阻害剤を含む培地でなされることを特徴とする請求項3に記載の方法。
- 前記体細胞の核を融合させる段階は、センダイウイルスまたはセンダイウイルス抽出物を含む培地でなされることを特徴とする請求項3に記載の方法。
- 前記ポスト活性化培地は、ヒストンデアセチラーゼ阻害剤を含むことを特徴とする請求項3に記載の方法。
- 前記ポスト活性化培地は、後成学的調節因子を含んだことを特徴とする請求項3に記載の方法。
- 前記後成学的調節因子は、ヒストンアセチル基伝達酵素(HAT)タンパク質、ヒストン脱アセチル酵素(HDAC)タンパク質、リジンデメチラーゼ(KDM)ドメインタンパク質及びタンパク質メチル伝達酵素(PMT)ドメインタンパク質を含む群のうちから選択されるいずれか1以上に関与することを特徴とする請求項7に記載の方法。
- 前記c)段階において、幹細胞の製造は、NT細胞を活性化させた後、胚盤胞を生成する段階と、生成された胚盤胞から内細胞集団(ICM)細胞を単離する段階と、分離された内細胞集団細胞を幹細胞に追加して培養する段階と、からなることを特徴とする請求項1に記載の方法。
- a)複数の寄贈者組織から同型接合いかんをスクリーニングする段階と、
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、を含む免疫適合型NT細胞由来幹細胞の製造方法。 - a)段階において、スクリーニングは、HLA−A、HLA−B及びHLA−DRの遺伝子が同型接合であることを特徴とする請求項10に記載の方法。
- b)段階において、NT製造は、卵母細胞を脱核する段階と、脱核された卵母細胞に体細胞の核を融合させる段階と、融合された卵母細胞をポスト活性化培地で培養する段階と、からなることを特徴とする請求項10に記載の方法。
- 前記卵母細胞の脱核は、タンパク質リン酸加水分解酵素阻害剤を含む培地でなされることを特徴とする請求項12に記載の方法。
- 前記体細胞の核の融合は、センダイウイルスまたはセンダイウイルス抽出物を含む培地でなされることを特徴とする請求項12に記載の方法。
- 前記ポスト活性化培地は、TSAを含むことを特徴とする請求項12に記載の方法。
- 前記ポスト活性化培地は、後成学的調節因子を含んだことを特徴とする請求項12に記載の方法。
- 前記後成学的調節因子は、ヒストンアセチル基伝達酵素(HAT)タンパク質、ヒストン脱アセチル酵素(HDAC)タンパク質、リジンデメチラーゼ(KDM)ドメインタンパク質、及びタンパク質メチル伝達酵素(PMT)ドメインタンパク質を含む群のうちから選択されるいずれか1以上に関与することを特徴とする請求項13に記載の方法。
- a)複数の寄贈者組織から同型接合いかんをスクリーニングする段階と、
b)同型接合細胞から核を分離してNT細胞に製造する段階と、
c)製造されたNT細胞から幹細胞を生成する段階と、
d)前記製造された幹細胞から細胞移植のための分化された細胞に製造する段階と、を含む免疫適合型NT細胞由来幹細胞から分化された細胞の製造方法。 - 前記c)段階後、幹細胞は、凍結保存される段階、及び凍結保存された細胞を解凍する段階が追加されることを特徴とする請求項18に記載の製造方法。
- d)段階の分化された細胞は、造血母細胞、筋肉細胞、心筋細胞、肝細胞、軟骨細胞、上皮細胞、泌尿器官細胞、脂肪細胞、腎臓細胞、血管細胞、網膜細胞、間葉系幹細胞(MSC)及びニューロン細胞からなる群から選択されたいずれか1以上であることを特徴とする請求項18に記載の 製造方法。
- 請求項1に記載の方法によって製造された免疫適合型幹細胞を含む細胞集団。
- 複数の寄贈者組織を収集する手段と、
前記収集された組織から免疫適合型いかんをスクリーニングする手段と、
免疫適合型組織から幹細胞を製造する手段と、
幹細胞を冷凍保存する手段と、を含む免疫適合型NT細胞由来幹細胞バンキングシステム。
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