JP5480504B2 - ヒト胚性幹細胞を作製するためのヒト卵母細胞の単為生殖的活性化 - Google Patents
ヒト胚性幹細胞を作製するためのヒト卵母細胞の単為生殖的活性化 Download PDFInfo
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Description
本発明は、概して胚性幹細胞、より具体的には単為生殖的活性化卵母細胞を用いてヒト胚性幹細胞を得る過程に関する。
ヒト胚性幹細胞(ES)細胞は、多様な細胞型に分化し得る多能性細胞である。胚性幹細胞は、免疫不全マウスに注射した場合に分化型腫瘍(奇形腫)を形成する。しかし、胚様体(EB)を形成するようにインビトロで誘導される胚性幹細胞は、特定の増殖条件下でいくつかの組織に特有である複数の細胞型に分化する可能性がある胚性幹細胞株の供給源を提供する。例えば、ES細胞は、神経成長因子およびレチノイン酸の存在下でニューロンに分化する。
本発明は、特定の条件がヒト卵母細胞を単為生殖的に活性化するのに最適であるという将来性のある発見に基づく。
本組成物、方法、および培養法について記載する前に、本発明が記載の特定の組成物、方法、および実験条件に限定されず、したがって組成物、方法、および条件が変更可能であることが理解されるべきである。本発明の範囲は添付の特許請求の範囲によってのみ限定されるため、本明細書で使用する専門用語は特定の態様を説明する目的のためのみのものであって、限定を意図するものではないこともまた理解されるべきである。
ヒト単為生殖胚形成幹細胞の作製
材料および方法
ドナーは、金銭的報酬を受けずに卵母細胞、卵丘細胞、および血液(DNA解析用)を自発的に提供した。ドナーは包括的なインフォームドコンセント書類に署名し、提供された材料はすべて研究のために使用し、生殖目的で使用しないことが通知された。卵母細胞ドナーは卵巣刺激の前に、ヒトの細胞、組織、ならびに細胞および組織に基づく製品のドナーに関するFDA適格性判定指針(食品医薬品局。2004年5月付の(法案)Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue Based Products (HCT/Ps))およびロシア保険省の規則N 67(02.26.03)に従って、適合性に関する健康診断を受けた。これには、X線、血液および尿検査、ならびに肝機能試験が含まれた。ドナーはまた、梅毒、HIV、HBV、およびHCV検査を受けた。
最初のドナーから卵母細胞4個を活性化し、活性化卵母細胞を5% O2、5% CO2、および90% N2を含む気体環境においてIVF培地中で培養し、5日間にわたり追跡した。表2は、活性化卵母細胞の成熟の過程を示す。卵母細胞はそれぞれ4ウェルプレートで分離した。
*細胞は、1日目はM1(商標)培地(MediCult)中で、2〜5日目はM2(商標)培地(MediCult)中で培養した。培地は毎日交換した。M1(商標)およびM2(商標)は、ヒト血清アルブミン、グルコースおよび派生代謝産物、生理的塩類、必須アミノ酸、非必須アミノ酸、ビタミン類、ヌクレオチド、炭酸水素ナトリウム、ストレプトマイシン(40 mg/l)、ペニシリン(40,000 IU/l)、ならびにフェノールレッドを含んでいた。
ドナー5名による卵母細胞から、MediCult培地の使用およびその後の低減酸素下での培養により、培養の5および6日目に胚盤胞23個が生成された。この胚盤胞のうち11個は、目に見えるICMを有していた(表3)。
1-卵母細胞2個は活性化されなかった;2-卵母細胞1個は活性化後に変性した;3-卵母細胞1個は活性化されなかった;4-卵母細胞2個は中期Iにあったため廃棄した。
免疫染色のため、フィーダー層上のhES細胞コロニーおよびphESC細胞をマイクロカバーガラス上に播種し、PBSで2回洗浄し、100%メタノールで-20℃にて5分間固定した。細胞をPBS+0.05% Tween-20で2回洗浄し、PBS+0.1% Triton X-100で室温にて10分間透過処理した。細胞を洗浄した後、ブロッキング溶液(PBS+0.05% Tween-20+4パーセントヤギ血清+3パーセントヒト臍帯血血清)を用いて室温(RT)で30分間インキュベートすることにより、非特異的結合をブロッキングした。モノクローナル抗体をブロッキング溶液で希釈し、RTで1時間使用した:ChemiconによるSSEA-1(MAB4301)(1:30)、SSEA-3(MAB4303)(1:10)、SSEA-4(MAB4304)(1:50)、OCT-4(MAB4305)(1:30)、TRA-1-60(MAB4360)(1:50)、およびTRA-1-81(MAB4381)(1:50)。細胞を洗浄した後、二次抗体Alexa Fluor 546(オレンジ色蛍光)および488(緑色蛍光)(Molecular Probes、Invitrogen)をPBS+0.05% Tween-20で1:1000希釈し、RTで1時間適用した。細胞を洗浄し、核をPBS+0.05% Tween-20中のDAPI(Sigma) 0.1μg/mlでRTにて10分間染色した。細胞を洗浄し、Mowiol(Calbiochem)でスライド上に封入した。蛍光顕微鏡により蛍光像を可視化した。
アルカリホスファターゼおよびテロメラーゼ活性は、APキットおよびTRAPEZE(商標)キット(Chemicon)を用いて製造業者の仕様書に従って行った。
核型を分析するため、hES細胞を10μg/mlデメコルチン(Sigma)で2時間処理し、0.05%トリプシン/EDTA(Invitrogen)で回収し、700 x rpmで3分間遠心分離した。ペレットを0.56% KCl 5 mlで再懸濁し、RTで15分間インキュベートした。遠心分離を繰り返した後、上清を除去し、細胞を再懸濁して、メタノール/酢酸(3:1)の氷冷混合物 5 mlで+4℃にて5分間固定した。細胞の固定を2回繰り返した後、細胞懸濁液を顕微鏡スライド上に乗せ、標本をギムザ改良染色液(Sigma)で染色した。この様式で調製した細胞による中期のものを、標準的なGバンド法で分析した。5/1000という数の中期展開物が明らかとなり、中期のもの63個を分析した。
hESおよびphESC細胞コロニーを機械的に凝集塊に分割し、85%ノックアウトDMEM、15%ヒト臍帯血血清、1 x MEM NEAA、1 mM Glutamax、0.055 mM β-メルカプトエタノール、ペニシリン・ストレプトマイシン(50 U/50 mg)、4 ng/ml hrbFGF(血清以外すべてInvitrogen)を含む培地中、1.5%アガロース(Sigma)で予め被覆した24ウェルプレートのウェルに入れた。ヒトEBを懸濁培養で14日間培養し、培養皿に入れて成長させるか、または懸濁状態でさらに1週間培養した。
ドナー血液、hES、phESC細胞、およびヒト新生児皮膚線維芽細胞(NSF)から、Dynal製Dynabeads DNA Direct Blood(Invitrogen)を用いてゲノムDNAを抽出した。HLAタイピングは、製造業者の仕様書に従って、対立遺伝子特異的配列プライマー(PCR-SSP、Protrans)を用いてPCRにより行った。HLAクラスI遺伝子(HLA A*、B*、Cw*)は、A*01-A*80、B*07-B*83、Cw*01-Cw*18領域を規定するPROTRANS HLA A* B* Cw*を用いてタイピングした。HLAクラスII遺伝子(HLA DRB1*、DRB3*、DRB4*、DRB5*、DQA1*、DQB1*)は、DRB1*01-DRB1*16(DR1-DR18)、DRB3*、DRB4*、DRB5*領域を規定するPROTRANS HLA DRB1*、およびDQB1*02-DQB1*06(DQ2-DQ9)、DQA1*0101-DQA1*0601領域を規定するPROTRANS HLA DQB1* DQA1*を用いて解析した。PCR増幅は:94℃で2分;94℃で10秒、65℃で1分の10サイクル;94℃で10秒、61℃で50秒、72℃で30秒の20サイクルで達成した。増幅産物は2%アガロースゲルで検出した。
血液、卵丘細胞、phESC、およびNSFから、フェノール/クロロホルム抽出法によりゲノムDNAを単離した。Affimetrix Mapping 50K Hind 240 Array(Affimetrix GeneChip Mapping 100Kキットの一部)を用いて、白人対象4名から得られたこれらのDNA試料の遺伝子型を同定した。データセットは当初、57,244個の2成分性SNPマーカーを含んでいた。このマーカー数は、ゲノム試料の等価性を同定するためおよびヘテロ接合性を試験するために必要な数よりも多いため、常染色体22本のうち15本(第1〜15染色体)を選択した。無作為抽出中に所与の染色体に関してマーカーが選択されない、または単一のマーカーしか選択されないという可能性を減らすため、短い7本の染色体は除いた。マーカー1,459個を、Relcheck(バージョン0.67、著作権(著作権) 2000 Karl W. Broman、Johns Hopkins University、GNU一般公有使用許諾バージョン2(1991年6月)の下で許可される)によって解析した。
Li et al. (J Biol Chem (2002) 277(16):13518-13527)の記載する通りに、全核酸を調製した。Tri試薬(Sigma)を用いて、またはQiagen(カリフォルニア州、バレンシア)によるRNA調製キットを用いて、細胞からRNAおよびDNAを抽出した。
血液、hES細胞、およびNSFから、フェノール/クロロホルム抽出によりゲノムDNAを単離し、HinfI制限酵素(Fermentas)で消化し、0.8%アガロースゲルに負荷した。電気泳動した後、変性DNAをサザンブロッティングによりナイロン膜(Hybond N、Amersham)に転写し、32P標識(CAC)5オリゴヌクレオチドプローブとハイブリダイズさせた。Cronex増感スクリーンを用いてX線フィルム(Kodak XAR)上に膜を曝露した後、データを解析した。
血液ドナーDNAと幹細胞DNAとの間でミニサテライト遺伝子座に関して対立遺伝子同一性を決定するため、11の多型部位((1) 3'アポリポタンパク質B超可変ミニサテライト遺伝子座(3'ApoB);(2) D1S80(PMCT118)超可変ミニサテライト遺伝子座(D1S80);(3) D6S366;(4) D16S359;(5) D7S820;(6) ヒトフォンウィルブランド因子遺伝子超可変ミニサテライト遺伝子座II(vWFII);(7) D13S317;(8) ヒトフォンウィルブランド因子遺伝子超可変ミニサテライト遺伝子座(vWA);(9) CFS-1受容体遺伝子のヒトc-fms癌原遺伝子マイクロサテライト遺伝子座(CSF1PO);(10) ヒト甲状腺ペルオキシダーゼ遺伝子マイクロサテライト遺伝子座(TPOX);および(11) ヒトチロシン水酸化酵素遺伝子マイクロサテライト遺伝子座(TH01))を、PCR遺伝子型同定により解析した。上記の多型部位に関して決定された公知の集団(すなわち、ロシア人および白人-アメリカ人集団)の対立遺伝子頻度を、試験試料(すなわち、hES、NSF、およびドナー血液DNA)におけるこれらの部位の対立遺伝子頻度と比較した。染色体位置、Genbank遺伝子座および遺伝子座定義、反復配列データ、対立遺伝子ラダー範囲、VNTRラダーサイズ範囲、他の公知の対立遺伝子、対立遺伝子サイズ、PCR手順、および解析された開示集団の11のミニサテライト遺伝子座に関する対立遺伝子頻度結果を以下に提供する。
染色体位置:2p23-p23
Genbank遺伝子座および遺伝子座定義:APOB、アポリポタンパク質B(Ag(x)抗原を含む)非翻訳領域
反復配列5'-3':
対立遺伝子ラダーサイズ範囲(塩基):450+10+2プライマー+連結
VNTRラダーサイズ範囲(反復数、Ludwig et al, 1989による):30、32、34、36、38、40、42、44、46、48、50、52
他の公知の対立遺伝子(反復数):25、27、28、31、33、35、37、39、41、43、45、47、49、51、53、54、55
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):36/36
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、1分
伸長およびプライマー連結 60℃、2分
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:1p35-36
Genbank遺伝子座および遺伝子座定義:ヒトD1S80およびMCT118遺伝子
反復配列5'-3':
対立遺伝子ラダーサイズ範囲(塩基):387-762
VNTRラダーサイズ範囲(反復数):16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、34、35、36、37、40、41
他の公知の対立遺伝子(反復数):13、14、15、38、39、>41
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):18/29
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 60℃、30秒
伸長 72℃、45秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:6q21-qter
Genbank遺伝子座および遺伝子座定義:該当なし
対立遺伝子ラダーサイズ範囲(塩基):150-162
STRラダーサイズ範囲(反復数):12、13、15
他の公知の対立遺伝子(反復数):10、11、14、16、17
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):13/14
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、1分
伸長およびプライマー連結 60℃、2分
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:16q24-qter
Genbank遺伝子座および遺伝子座定義:該当なし
反復配列5'-3':(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):264-304
STRラダーサイズ範囲(反復数):5、8、9、10、11、12、13、14、15
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):11/12
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃、30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:7q11.21-22
Genbank遺伝子座および遺伝子座定義:該当なし
反復配列5'-3':(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):215-247
VNTRラダーサイズ範囲(反復数):6、7、8、9、10、11、12、13、14
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):9/11
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃、30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:12p13.3-12p13.2
Genbank遺伝子座および遺伝子座定義:HUMvWFII、ヒトフォンウィルブランド因子遺伝子
反復配列5'-3':(ATCT)n/(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):154-178
STRラダーサイズ範囲(反復数):9、11、12、13
他の公知の対立遺伝子(反復数):8、10、14、15
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):13/13
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、1分
伸長およびプライマー連結 60℃、2分
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:13q22-q31
Genbank遺伝子座および遺伝子座定義:該当なし
反復配列5'-3':(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):165-197
STRラダーサイズ範囲(反復数):8、9、10、11、12、13、14、15
他の公知の対立遺伝子(反復数):7
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):8/8
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃、30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:12p12pter
Genbank遺伝子座および遺伝子座定義:HUMVWFA31、ヒトフォンウィルブランド因子遺伝子
反復配列5'-3':(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):139-167
STRラダーサイズ範囲(反復数):14、16、17、18
他の公知の対立遺伝子(反復数):11、12、13、15、19、20、21
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):16/16
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、1分
伸長およびプライマー連結 60℃、2分
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:5q33.3-34
Genbank遺伝子座および遺伝子座定義:HUMCSF1PO、ヒトc-fms癌原遺伝子
反復配列5'-3':(AGAT)n
対立遺伝子ラダーサイズ範囲(塩基):295-327
STRラダーサイズ範囲(反復数):7、8、9、10、11、12、13、14、15
他の公知の対立遺伝子(反復数):6
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):9/10
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃ 30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:2p25.1-pter
Genbank遺伝子座および遺伝子座定義:HUMTPOX、ヒト甲状腺ペルオキシダーゼ遺伝子
反復配列5'-3':(AATG)n
対立遺伝子ラダーサイズ範囲(塩基):224-252
STRラダーサイズ範囲(反復数):6、7、8、9、10、11、12、13
他の公知の対立遺伝子(反復数):なし
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):8/9
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃ 30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
染色体位置:5q33.3-34
Genbank遺伝子座および遺伝子座定義:HUMTHO1、ヒトチロシン水酸化酵素遺伝子
反復配列5'-3':(AATG)n
対立遺伝子ラダーサイズ範囲(塩基):179-203
STRラダーサイズ範囲(反復数):5、6、7、8、9、10、11
他の公知の対立遺伝子(反復数):9.3
Promega K562 DNA(登録商標)対立遺伝子サイズ(反復数):9.3/9.3
PCR手順:
サーマルサイクラー:DNA Technology Ltd.、ロシア
最初のインキュベーション: 95℃、2分
30サイクルのサイクリング:
変性 94℃、45秒
プライマー連結 64℃、30秒
伸長 72℃ 30秒
伸長段階: 72℃、5分
保持段階: 4℃、無制限
本方法によるhES細胞は、胚性幹細胞に典型的な多くの特徴:細胞質脂肪体、低い細胞質/核比、および明白に識別可能な核小体を示す。hES細胞コロニーは、インビトロ受精後に導出されたヒト胚性幹細胞に関して以前に報告された形態と類似の形態を示す。細胞は、アルカリホスファターゼ(図1A)、オクタマー結合転写因子4 mRNA(Oct-4)(図1B)、時期特異的胚抗原1(SSEA-1)(図1C)、時期特異的胚抗原3(SSEA-3)(図1D)、時期特異的胚抗原4(SSEA-4)(図1E)、腫瘍拒絶抗原1-60(TRA-1-60)(図1F)、腫瘍拒絶抗原1-81(TRA-1-81)(図1G)に関して免疫反応陽性であり、時期特異的胚抗原1(SSEA-1)(図1C)(マウス胚性幹細胞では陽性であるが、ヒトでは陽性ではない)に関して陰性であった。テロメラーゼ活性は複製不死性と相関する場合が多く、典型的に生殖細胞、癌細胞、および幹細胞を含む種々の幹細胞で発現し、大部分の体細胞型には存在しない。3カ月のインビトロ増殖後に本方法によって調製した細胞は、その未分化形態を維持し、高レベルのテロメラーゼ活性を示した(図2A)。細胞の多能性は胚様体の形成によりインビトロで調べ(図2B、2C)、Gバンド核型分析から、細胞が正常なヒト46XX核型を有することが示される(図2D)。
phESCおよび関連ドナー由来のDNA試料を同定するデータベースS1
DNA試料は以下のように番号付けした:1-ヒト新生児皮膚線維芽細胞;2-phESC-7株ドナー;3-phESC-7株;4-phESC-1株;5-phESC-1株;6-phESC-3株;7-phESC-4株;8-phESC-5株;9-phESC-6株;10-phESC-6株ドナー;11-phESC-3〜phESC-5株ドナー;および12-phESC-1株ドナー。
結果から、1対(試料4-5)のみが一卵性(MZ)双生児であると同定されたことが示される。他の10対(試料2-3、4-12、5-12、6-7、6-11、7-8、7-11、8-11、9-10)は完全同胞であると同定され、他の組み合わせの対はすべて非関連であると同定された。出力中のIBS欄は、対が同定され、0、1、または2対立遺伝子状態同一を共有するマーカーの数を示す(遺伝子型同定に誤差のない理想的な条件下におけるMZ双生児では、すべてのマーカーがIBS=2に位置しなくてはならない)。出力はP(観察されたマーカー|所与の関係)を直接示していないが、類似性の尺度として、LODスコア‐log10{P(観察されたマーカー|推定される関係/P(観察されるマーカー/最大尤度が得られ、よってコールが作成された関係)}を示す。LODスコアが小さいほど、2つの試料間の推定される関係の可能性が低いことを示す。
データベースS2 phESC(「pC」と略す)株のヘテロ接合性
結果から、導出されたphESC株のヘテロ接合性が示され、関連ドナー遺伝子型との比較により遺伝子型の変化が示される。ドナーゲノムのヘテロ接合性部分の一部は、phESCにおいてホモ接合性になっていた。染色体-染色体番号;RS ID-dbSNPデータベースにおけるRS番号;塩基対-Affimetrix GeneChipにより記録されている塩基対距離;白人における頻度A-白人集団におけるA対立遺伝子の頻度。
Claims (12)
- ヒト多能性幹細胞を作製する方法であって、
a) i) 卵母細胞を高O2圧でイオノフォアと接触させる段階、およびii) 卵母細胞を低O2圧下でセリン・スレオニンキナーゼ阻害剤と接触させる段階を含む、未受精のヒト卵母細胞を単為生殖的に活性化する段階であって、卵母細胞が一倍体または二倍体であり、かつ父性刷り込みを欠いている、段階;
b) 段階(a)の、一倍体または二倍体でありかつ父性刷り込みを欠いている活性化卵母細胞を、胚盤胞が形成されるまで低O2圧で培養する段階であって、胚盤胞の細胞が一倍体または二倍体であり、かつ父性刷り込みを欠いている、段階;
c) 胚盤胞をフィーダー細胞層に移し、移した胚盤胞を高O2圧下で培養する段階;
d) 段階(c)の胚盤胞の栄養外胚葉から内部細胞塊(ICM)を機械的に単離する段階;ならびに
e) 段階(d)のICMの細胞をフィーダー細胞層上で培養し、該ICMの細胞の多能性状態を維持する段階を含み、
段階(e)の培養段階を高O2圧下で行う方法。 - 約2% O2〜約5% O2のO2濃度を含む気体混合環境でのインキュベーションにより低O2圧を維持する、請求項1記載の方法。
- 気体混合環境が約5% CO2および約90% N2〜93% N2をさらに含む、請求項2記載の方法。
- 約5% CO2および約20% O2を含む気体混合環境でのインキュベーションにより高O2圧を維持する、請求項1記載の方法。
- イオノフォアがイオノマイシンおよびA23187からなる群より選択される、請求項1記載の方法。
- セリン・スレオニンキナーゼ阻害剤がスタウロスポリン、2-アミノプリン、スフィンゴシン、および6-ジメチルアミノプリン(DMAP)からなる群より選択される、請求項1記載の方法。
- 培地がヒト臍帯血清を含む、請求項1記載の方法。
- フィーダー細胞層がヒト線維芽細胞を含む、請求項1記載の方法。
- 線維芽細胞が出生後ヒト皮膚線維芽細胞である、請求項8記載の方法。
- 凍結保存した未受精の卵母細胞または単為生殖体からヒト多能性幹細胞を作製する方法であって、
(a) 未受精の卵母細胞または単為生殖体の細胞質に凍結保存剤をマイクロインジェクションする段階;
(b) 未受精の卵母細胞または単為生殖体を極低温貯蔵温度まで凍結して、卵母細胞または単為生殖体を休眠状態に入らせる段階;
(c) 未受精の卵母細胞または単為生殖体を休眠状態で貯蔵する段階;
(d) 未受精の卵母細胞または単為生殖体を融解する段階;
(e) i) 卵母細胞を高O2圧でイオノフォアと接触させる段階、およびii) 卵母細胞を低O2圧下でセリン・スレオニンキナーゼ阻害剤と接触させる段階を含む、段階(d)の未受精の卵母細胞を単為生殖的に活性化する段階であって、卵母細胞が一倍体または二倍体であり、かつ父性刷り込みを欠いている、段階;
(f) 段階(d)の一倍体または二倍体の単為生殖体または段階(e)の一倍体または二倍体の未受精卵母細胞を、胚盤胞が形成されるまで低O2圧で培養する段階であって、単為生殖体または卵母細胞が父性刷り込みを欠いている、段階;
(g) 胚盤胞の栄養外胚葉から内部細胞塊(ICM)を単離する段階;ならびに
(h) 段階(g)のICMの細胞をフィーダー細胞層または細胞外マトリックス(ECM)基質上で培養し、該ICMの細胞の多能性状態を維持する段階を含み、
培養段階(h)を高O2圧下で行う方法。 - フィーダー細胞がヒト供給源に由来する、請求項10記載の方法。
- 凍結保存剤が(i) 糖を含み、(ii) 哺乳動物細胞膜に関して実質的に非透過性であり、かつ(iii) 卵母細胞または単為生殖体が一時的に休眠状態で貯蔵され、活性化状態に実質的に回復され得るように、卵母細胞または単為生殖体の生存率を維持する、請求項10記載の方法。
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US20030129745A1 (en) * | 1999-10-28 | 2003-07-10 | Robl James M. | Gynogenetic or androgenetic production of pluripotent cells and cell lines, and use thereof to produce differentiated cells and tissues |
US8647873B2 (en) | 2004-04-27 | 2014-02-11 | Viacyte, Inc. | PDX1 expressing endoderm |
ES2743202T3 (es) * | 2005-10-27 | 2020-02-18 | Viacyte Inc | Endodermo de intestino proximal dorsal y ventral que expresa PDX1 |
CA2658813A1 (en) * | 2006-07-24 | 2008-01-31 | International Stem Cell Corporation | Synthetic cornea from retinal stem cells |
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