JP2017500882A - 多能性幹細胞の誘導方法および当該方法により製造された多能性幹細胞 - Google Patents
多能性幹細胞の誘導方法および当該方法により製造された多能性幹細胞 Download PDFInfo
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Abstract
Description
a)植物幹細胞または誘導された植物多能性幹細胞から、その有効成分を含む抽出物を抽出するステップ;
b)前記抽出物を成体由来細胞に注入するステップ;および
c)前記抽出物が注入された細胞を、培養過程を経て、胚性幹細胞といった万能性を持った細胞を作製するステップを含む、カスタム型多能性幹細胞を誘導する方法を提供する。
1.本明細書に係るシキミ酸、シキミ酸を含む植物抽出物、植物幹細胞抽出物またはこれらを含む組成物を製造するステップ;
2.シキミ酸、抽出物または組成物を成体由来細胞に注入するステップ;
3.前記成体由来細胞を、一般細胞培養液を使用して培養するステップ;
4.前記培養された細胞を支持細胞層のある培養条件に移して、さらに培養する段階;
5.培養された多能性幹細胞を回収するステップ;
を含むものであってよい。
1.成体由来細胞をバラした細胞とした後、再懸濁してチューブに移すステップ;
2.遠心分離後、細胞ペレットを再懸濁して水槽で反応させるステップ;
3.細胞膜透過促進化合物を添加するステップ;
4.サンプルを水槽で上下に混ぜながら反応させるステップ;
5.反応が終わったサンプルを遠心分離するステップ;
6.細胞ペレットをシキミ酸、抽出物または組成物に再懸濁するステップ;
7.ATP‐再生システムを通じて、水槽を上下に混ぜ、反応させるステップ;
8.反応後、ES細胞培地を添加して培養器で反応させるステップ;
9.洗浄後、細胞ペレットを胚性幹細胞培養培地に再懸濁させた後、ディッシュに播種(seeding)するステップ;
を含むものであってよい。
b)細胞膜透過促進化合物を成体由来細胞に処理し、前記抽出物を成体由来細胞に注入するステップ;および
c)前記抽出物が注入された細胞を、一般細胞培養液で培養した後、支持細胞(feeder cell)層のある培養条件に移してから、胚性幹細胞培養液で培養するステップを含む、カスタム型多能性幹細胞を誘導する方法を提供する。
本発明者らは、植物由来幹細胞抽出物としてカルスパウダーを使用した。本発明に使用され得るカルスパウダーには制限がなく、商業的に購入して使用してもよい。
DMEM(Dulbecco´s Modified Eagle Medium)に、10%FBS、50U/mlのペニシリン、50mg/mlのストレプトマイシンが添加された一般細胞培養培地において、37℃を維持し、5%CO2が供給される培養器で培養した。0.1%ゼラチンがコーティングされたディッシュに、植物幹細胞抽出物(カルスパウダー)が注入された成体由来細胞(ヒト由来皮膚線維芽細胞)を前記培地で培養して、最初2日後に培地を交換した。10日間毎日培地を交換し、培養した後、マイトマイシンC(MMC)が処理された支持細胞(feeder cell、STO cell)上に、1:2の比率で移した。その後、DMEM(Dulbecco´s Modified Eagle Medium)/F12に、20%KSR(Knockout serum replacement)、2mMのL‐グルタミン、0.1mMの非必須アミノ酸、0.1mMmpβ‐メルカプトエタノール、50U/mlのペニシリン、50mg/mlのストレプトマイシン、10μg/mlのbFGFが添加された培養液において、培地を毎日交換し、7日に一度の周期で新しい支持細胞上に移した。平均的に約21日目の分析に必要なカスタム型幹細胞を培養することができた。
培養された細胞を回収した後、TRIzol試薬(Invitrogen)を使用して、全RNAを分離した。逆転写‐ポリメラーゼ連鎖反応(RT−PCR)を利用してcDNAを合成した後、Nanog,Oct‐3/4および対照遺伝子であるGAPDH遺伝子に特異的なプライマーを利用して、PCRを行った。PCR産物をアガロースゲル電気泳動により分析して、これら遺伝子の発現を確認した後、図7に示した。
実施例1によるセコイアカルスパウダー20mgを1mlのDMSO溶媒に溶解させ、同様に、セコイアカルスパウダー1gを10mlのBGとEtOHを混合した溶媒に溶解させて、シキミ酸を含むセコイアカルス抽出物を製造し、これを以下の試験例において試料として使用した。
実施例4の方法によって得られたセコイア抽出物のうち、BGとEtOHが混合された溶媒に溶解されたセコイアカルス抽出物を、HPLC機械を利用して、その成分を分析した。
ヒト真皮繊維芽細胞(Neonatal human dermal fibroblasts, NHDF‐Neonatal)(CC‐2509, Lonza, USA)5×105個に、透過化バッファー(permeabilization buffer)とジギトニン(digitonin)10μg/mlを処理し、実施例4によるセコイアカルス抽出物(BGとEtOHの混合溶媒)20μg/mlおよびシキミ酸5μg/mlをそれぞれ処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。処理後3日目に、細胞を4チャンバースライド(chamber slide)に5,000個ずつ付け、その1日後である4日目に、PBSにある3.8%ホルムアルデヒド(38%パラホルムアルデヒドを希釈したもの)で固定させて、室温で10分間置いた後、oct3/4抗体(Genetex, GTX100622, x200)およびAlexa Fluor(R)488 ヤギ抗ウサギ(goat anti−rabbit)IgGを利用して免疫組織化学(Immuno‐cytochemistry)を実施し、Carl Zeiss Confocal microscope LSM510で400倍で観察してイメージ画像を得た。観察を通じて得られたイメージ画像は、図10に示した。また、OCT3/4 ICC実験の結果得られたCarl Zeiss Confocal microscopeのイメージ画像を、サンプルあたり4枚以上、平均5枚ずつ分析して、OCT3/4陽性細胞(positive cell)の比率を求め、その平均、標準偏差を求めて表2に示した。
ヒト真皮繊維芽細胞(Neonatal human dermal fibroblasts, NHDF‐Neonatal)(CC‐2509, Lonza, USA)1×106個に、シキミ酸10μM、10mMをそれぞれ処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。処理後5日目に、細胞を4チャンバースライドに5,000個ずつ付け、その3日後である8日目に、PBSにある3.8%ホルムアルデヒド(38%パラホルムアルデヒドを希釈したもの)で固定させて、室温で10分間置いた後、oct3/4抗体(Genetex, GTX100622, x200)およびAlexa Fluor(R)488 ヤギ抗ウサギ(goat anti‐rabbit)IgGを利用して免疫組織化学(Immuno‐cytochemistry)を実施し、Carl Zeiss Confocal microscope LSM510で400倍で観察して、イメージ画像を得た。観察を通じて得られたイメージ画像は、図11に示した。また、OCT3/4 ICC実験の結果得られたCarl Zeiss Confocal microscopeのイメージ画像を、サンプルあたり4枚以上、平均5枚ずつ分析して、OCT3/4陽性細胞の比率を求め、その平均、標準偏差を求めて表3に示した。
NHDF‐Neonatal(CC‐2509, Lonza, USA)5×105個に、透過化バッファー(permeabilization buffer)とジギトニン(digitonin)10μg/mlを処理し、実施例4によるセコイアカルス抽出物(BGとEtOHの混合溶媒)20μg/mlおよびシキミ酸5μg/mlを処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。6日目に、細胞を12ウェルプレート(well plate)に5,000個ずつ付け、その5日後である11日目に、PBSにある3.8%ホルムアルデヒドで固定させて、室温で15分間置いた後、NBT/BCIP(R) ALP基質溶液(substrate solution)200μlをALPバッファー(buffer)10mlに希釈して0.5mlずつ処理し、20時間後にOlympus CKX41光学顕微鏡で40倍で観察した。観察を通じて得られた結果は、図12に示した。
NHDF‐Neonatal(CC‐2509, Lonza, USA)1×106個に、シキミ酸10μM、10mMをそれぞれ処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。5日目に、細胞を6ウェルプレートに100,000個ずつ付け、その7日後である12日目に、PBSにある3.8%ホルムアルデヒドで固定させて、室温で15分間置いた後、NBT/BCIP(R) ALP基質溶液200μlをALPバッファー10mlに希釈して0.5mlずつ処理し、20時間後にOlympus CKX41光学顕微鏡で40倍で観察した。観察を通じて得られた結果は、図13に示した。
NHDF‐Neonatal(CC‐2509, Lonza, USA)5×105個に、透過化バッファー(Permeabilization buffer)とジギトニン(digitonin)10μg/mlを処理し、0.4μmフィルターで濾過した実施例4によるセコイアカルス抽出物(BGとEtOHの混合溶媒)100ppm、200ppmと、DMSO溶液20ppmを処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。これを継代培養してから10日目に、細胞を60mmプレートに200個ずつ付けた後、23日目に、氷の上でアイス‐コールド(ice‐cold)PBSで洗浄し、−20度で保管したアイス‐コールド(ice‐cold)メタノールで細胞を10分間固定した。エタノール原液(Ethanol stock solution)にある1%クリスタルバイオレット(crystal violet)を、PBSに1/10で希釈して実験溶液(working solution)を作成した後、これを細胞に5〜10分間処理して染色した後、PBSで4回洗浄し、写真撮影をした。定量分析のために、50%エタノール、40%DW、10%酢酸で構成された溶離バッファー(elution buffer)を準備した後、5分間細胞に処理して溶出させた。その後、96ウェルプレートに200μlずつ移して、580nmで吸光度を測定した。写真撮影による結果は、図14に示した。そして、吸光度測定による結果は、陰性対照群を基準とした倍数の結果として、図15に示した。
また、真皮細胞の繊維芽細胞の増殖を顕著に促進することに照らして、本発明に係るセコイア抽出物は、皮膚再生を促進する効果を示すということを確認することができる。
NHDF‐Neonatal(CC‐2509, Lonza, USA)1×106個に、シキミ酸10μM、50μM、100μM、1mM、10mMをそれぞれ処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。これを継代培養してから5日目に、細胞を60mmプレートに200個ずつ付けた後、17日目に、氷の上でアイス‐コールド(ice‐cold)PBSで洗浄し、−20度で保管したアイス‐コールド(ice‐cold)メタノールで細胞を10分間固定した。エタノール原液(Ethanol stock solution)にある1%クリスタルバイオレット(crystal violet)を、PBSに1/10で希釈して実験溶液を作成した後、これを細胞に5〜10分間処理して染色した後、PBSで4回洗浄し、写真撮影をした。定量分析のために、50%エタノール、40%DW、10%酢酸で構成された溶離バッファーを準備した後、5分間細胞に処理して溶出させた。その後、96ウェルプレートに200μlずつ移して、580nmで吸光度を測定した。写真撮影による結果は、図16に示した。そして、吸光度測定による結果は、陰性対照群を基準にした倍数の結果として、図17に示した。
96ウェルプレートに、NHDF‐Neonatal(CC‐2509, Lonza, USA)を2,000個ずつ付けた後、その翌日に、実施例4によるセコイアカルス抽出物(BGおよびEtOH溶媒)20μg/mlおよびシキミ酸5μg/mlを処理した。何の処理もしなかったNHDF‐Neonatalを陰性対照群として設定した。これを7日間培養し(7日目にコンフルエンシー(Confluency)が90%以下になるように)、その6日後に、WST‐1を10μlずつ処理し、450nmで吸光度を測定した。陰性対照群(negative control)サンプルを基準とした倍数での結果を、グラフで図18に示した。
シキミ酸または実施例4によるセコイアカルス抽出物40μg、ビタミンE 9mg、ビタミンC 9mg、パーム油2mg、植物性硬化油8mg、黄蝋4mgおよびレシチン9mgを混合し、通常の方法に従って混合して軟質カプセル充填液を製造する。1カプセルあたり400mgずつ充填して、軟質カプセルを製造する。そして、前記とは別途に、ゼラチン66重量部、グリセリン24重量部およびソルビトール液10重量部の比率でソフトカプセルシートを製造し、前記充填液を充填させて、本発明に係る組成物400mgが含有された軟質カプセルを製造する。
シキミ酸または実施例4によるセコイアカルス抽出物40μg、ビタミンE 9mg、ビタミンC 9mg、ガラクトオリゴ糖200mg、乳糖60mgおよび麦芽糖140mgを混合し、流動層乾燥機を利用して顆粒した後、糖エステル(sugar ester)6mgを添加する。これら組成物500mgを、通常の方法で打錠して、錠剤を製造する。
シキミ酸または実施例4によるセコイアカルス抽出物40μg、ビタミンE 9mg、ビタミンC 9mg、ブドウ糖10g、クエン酸0.6gおよび液状オリゴ糖25gを混合した後、精製水300mlを加えて、各ボトルに200mlずつとなるように充填する。ボトルに充填した後、130℃で4〜5秒間殺菌してドリンク剤を製造する。
シキミ酸または実施例4によるセコイアカルス抽出物40μg、ビタミンE 9mg、ビタミンC 9mg、無水結晶ブドウ糖250mgおよび澱粉550mgを混合し、流動層造粒機を使用して顆粒に成形した後、包に充填して顆粒剤を製造する。
下記表4に記載された組成に従い、通常的な方法で注射剤を製造した。
下記表5に記載された組成に従い、通常的な方法で柔軟化粧水を製造した。
下記表6に記載された組成に従い、通常的な方法で栄養化粧水を製造した。
下記表7に記載された組成に従い、通常的な方法で栄養クリームを製造した。
下記表8に記載された組成に従い、通常的な方法でマッサージクリームを製造した。
下記表9に記載された組成に従い、通常的な方法でパックを製造した。
下記表10に記載された組成に従い、通常的な方法で健康食品を製造した。
下記表11に記載された組成に従い、通常的な方法で健康飲料を製造した。
下記表12に記載された組成に従い、通常的な方法で、本明細書の実施例2による多能性幹細胞を含む注射剤を製造した。
Claims (19)
- シキミ酸;シキミ酸を含む植物抽出物;シキミ酸を含む植物幹細胞抽出物;またはこれらのうち一つ以上を含む組成物を、成体由来細胞に処理することを含む、幹細胞の製造方法。
- 植物幹細胞抽出物は、逆分化された多能性植物幹細胞の抽出物である、請求項1に記載の方法。
- 製造方法は、シキミ酸、抽出物または組成物を成体由来の細胞に注入するステップ;および、シキミ酸、抽出物または組成物が注入された細胞を培養するステップを含む、請求項1に記載の方法。
- シキミ酸を含む植物抽出物は、セコイアデンドロン(Sequoiadendron giganteum)、キショウブ(Iris pseudoacorus)、キクイモ(Helianthus tuberosus)、アオトウヒ(Picea pungens)、シロトウヒ(Picea glauca)、シルバートップアッシュ(Eucalyptus sieberiana)、ユーカリプタス・レグナンス(Eucalyptus regnans)、ベイスギ(Thuja plicata)、ナツメヤシ(Red Ceda, Phoenix dactylifera)、ダリア(Dahlia variabilis)、エゾノコリンゴ(Malus baccata)、セイヨウナシ(Pyrus communis)、コムギ(Triticum)、アカマツ(Pinus densifloraa)、クロマツ(Pinus thunbergii)、シキミ(Illicium anisatum)、タイサンボク(Magnolia grandiflora)、ドクダミ(Houttuynia cordata)、ユキノシタ(Saxifraga stolonifera)、テルミナリア・アルジュナ(Terminalia arjuna)、マスチックノキ(Pistacia lentiscus)、ゴールデンカラント(Ribes aureum)、コンフリー(Symphytum officinalis)、ホワイトコホシュ(Actaea pachypoda)、シログキウリノキ(Alangium salvifollium)、イチョウ(Gingko biloba)、ベラトラム・バリッド(Veratrum viride)、オニナベナ(Dipsacus laciniatus)、アガスタキ(Agastache urticifolia)、オオグルマ(Inula helenium)、セイヨウオトギリソウ(Hypericum spp)、マルバツユクサ(Commelina bengalensis)、ギムネマ(糖殺草)(Gymnema sylvestris)、訶子(Terminalia chebula)、アメリカシキミ(Illicium floridanum)、シキミ科(Illicium diffengri)、紅茴香(Illicium henryi)、八角茴香(Illicium verum)、窄叶紅茴香(Illicium lanceolatum)、シキミ科(Illicium pachyphyllum)、シキミ(Illicium anisatum)、シキミ(Illicium religiosum)、ヘミデスムス・インディカス(Hemidesmus indicus, Sarvia)、シスタス・インカヌス(Cistus incanus)、ホソバキンゴジカ(Sida acuta)、インテレクトツリー(Celastrus paniculata)、トゲバンレイシ(Glycosmis muricata)、ナツシロギク(Tanacetum parthenium, Pyrethrum)、パンコムギ(Triticum aestivum)、ヒペリカム(Hypericum dolabriforme)、ディプサクス・ピロスス(Dipsacus pilosus)、ミズオトギリ(Triadenum walteri)、ヒペリカム・フロンドサム(Hypericum flondosum)、およびテルミナリア・パリド(Terminalia pallid)抽出物からなる群から選択された複数の抽出物をさらに含むものである、請求項1に記載の方法。
- 植物幹細胞抽出物は、カルス抽出物である、請求項1に記載の方法。
- 植物幹細胞は、セコイア幹細胞を利用し、詳しくは、セコイアは、セコイアデンドロン(Sequoiadendron giganteum)である、請求項1に記載の方法。
- 組成物は、その組成物の総体積を基準として、シキミ酸を10μM〜30mMの濃度で含むか、または、抽出物を0.001μg/ml〜2mg/mlの濃度で含む、請求項1に記載の方法。
- シキミ酸、抽出物または組成物の注入前に、前記成体由来細胞に細胞膜透過促進物質を処理するステップをさらに含む、請求項3に記載の方法。
- 前記細胞膜透過促進化合物は、ストレプトリジンOまたはジギトニンである、請求項8に記載の方法。
- シキミ酸、抽出物または組成物が注入された成体由来細胞を、支持細胞層に移して、さらに培養するステップをさらに含む、請求項3に記載の方法。
- 前記支持細胞は、STO細胞である、請求項10に記載の方法。
- 請求項1〜11のいずれか1項の方法によって製造された幹細胞。
- 有効成分として、請求項12に記載の幹細胞を含む、組成物。
- 成体由来細胞は、組成物が投与される個体から由来した細胞であり、幹細胞は、前記個体に対する特異的なカスタマイズ型幹細胞である、請求項13に記載の組成物。
- 組成物は、細胞治療剤である、請求項14に記載の組成物。
- シキミ酸、シキミ酸を含む植物抽出物、またはシキミ酸を含む植物幹細胞抽出物を有効成分として含む、幹細胞活性化用、皮膚細胞増殖用、皮膚再生用または抗老化用組成物。
- 組成物は、その組成物の総体積を基準として、シキミ酸を10μM〜30mMの濃度で含むか、または、植物抽出物もしくは植物幹細胞抽出物を0.001μg/ml〜2mg/mlの濃度で含む、請求項16に記載の組成物。
- 組成物は、薬学組成物または化粧品組成物である、請求項16または17に記載の組成物。
- シキミ酸を含有する植物抽出物は、請求項4に記載の植物抽出物である、請求項16または17に記載の組成物。
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