JP6918943B2 - 癌細胞の増殖を抑制する間葉幹細胞の製造方法 - Google Patents
癌細胞の増殖を抑制する間葉幹細胞の製造方法 Download PDFInfo
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Description
脂肪吸入術(Liposuction)によって腹部脂肪から得られたヒト脂肪組職を分離してPBSで洗浄した。組職を細く切った後、コラゲナーゼ型1(collagenase type 1)(1mg/ml)を添加したDMEM培地を用いて37℃で2時間ダイジェスト(digestion)した。PBSで洗浄した後、1000rpmで5分間遠心分離した。上澄み液は吸引し(suction)底に残ったペレットはPBSで洗浄した後、1000rpmで5分間遠心分離した。100μmメッシュでフィルタリングして屑を除去し、PBSで洗浄した後、10%FBS、2mM NAC、0.2mMアスコルビン酸を含むDMEM培地で培養した。
実施例1のビタミンCを含む培地で培養したVit.C−MSCを96−ウェル細胞培養プレートに1×104cells/plate濃度で接種した後、ひと晩培養して付着及び安定化させる。その後、RKCM−N培地である5%FBS、2mM NAC、0.2mMアスコルビン酸、0.09mMカルシウム、5ng/ml rEGF、5μg/mlインスリン及び74ng/mlヒドロコルチゾンを含むケラチノサイト−SFMにアスピリンをそれぞれ0.005mM、0.001mM、0.05mM、0.1mM、0.5mM、1mM、5mM及び10mMの濃度で添加した培地に交換した後、24時間培養した。各ウェルにcck−8(Cell Counting Kit−8、Dojindo)溶液(10μl/100μl)を添加して2時間反応させた後、Plate Reader(LonZa)を用いて450nm吸光度値を測定した。
実施例1のビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンをそれぞれ0.1mM、0.5mM、1mM及び10mMの濃度で添加したRKCM−N培地に交換して24時間培養した。
4−1:CFA(Colony forming assay)
ビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンをそれぞれ0.1mM、0.5mM及び1mMの濃度で添加したRKCM−N培地に交換して24時間培養した。その後、それぞれのアスピリン濃度別細胞300個をRKCM−N培地に混合して100mm細胞培養トレイに接種した。2〜3日ごとに培地を交換しながら10日間37℃、5%CO2で培養した。10日後、培地を除去し、0.1%クリスタルバイオレット試薬3mlを添加して10分間反応させた後、洗浄して乾燥した。形成されたコロニー数を測定し、形成能(PE)=コロニー形成個数/総接種細胞数×100%を計算した。
ビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンを0.1mM、0.5mM及び1mMの濃度で添加したRKCM−N培地に交換して24時間培養した。
5−1:脂肪細胞分化誘導
ビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンを0.1mM、0.5mM及び1mMの濃度で添加したRKCM−N培地交換して24時間培養した。その後、12ウェルプレートに2×104cellsで接種し、脂肪分化誘導培地(STEMPRO Adipogenesis differentiation Kit)で2〜3日に一度ずつ培地を交換しながら14日間培養した。
ビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンを0.1mM、0.5mM及び1mMの濃度で添加したRKCM−N培地に交換して24時間培養した。その後、12ウェルプレートに2×104cellsで接種し、骨分化誘導培地(STEMPRO Osteogenesis differentiation Kit)で2〜3日に一度ずつ培地を交換しながら21日間培養した。
6−1:乳房癌及び膵膓癌細胞
直接共培養(direct co−culture)を実施するために、実施例1のビタミンCを含む培地で培養したVit.C−MSCをT75フラスコに10%密度(0.5×106cells)でRKCM−N培地に接種した。2日後、50〜60%密度になれば、RKCM−N培地である5%FBS、2mM NAC、0.2mMアスコルビン酸、0.09mMカルシウム、5ng/ml rEGF、5μg/mlインスリン及び74ng/mlヒドロコルチゾンを含むケラチノサイト−SFM培地にそれぞれ0.5mM、1mM及び10mMの濃度でアスピリンを処理し、24時間培養した後、ASP−Vit.C−MSC(Angel−Stem cell)を回収した。
実施例6−1と同様にアスピリンを処理したVit.C−MSCであるASP−Vit.C−MSCを製造した後、癌幹細胞との直接共培養によってASP−Vit.C−MSCの坑癌効果を確認した。
7−1:乳房癌及び膵膓癌細胞
間接共培養(indirect co−culture)を実施するために、2元化細胞培養ができるトランスウェルを使い、ウェルの底に癌細胞を付着させ、ウェルの挿入膜(insert membrane)上にはVit.C−MSCを付着させた後、10%FBSが含まれたDMEM培地で5%CO2の供給及び37℃の条件の下で48時間共培養した。
2元化細胞培養ができるトランスウェルを使って癌幹細胞とVit.C−MSCの間接共培養(indirect co−culture)を実施してASP−Vit.C−MSCの坑癌効果を確認した。
実施例1のビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンをそれぞれ0.1mM、0.5mM及び1mMの濃度で添加した培地に交換して24時間培養した。その後、坑癌メカニズムに関連した遺伝子、アポトーシス及び血管新生関連遺伝子の発現を確認した。
9−1:Fas L、TRAIL及びCXCR4遺伝子発現分析による坑癌メカニズム確認
実施例1のビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンをそれぞれ0.1mM、0.5mM及び1mMの濃度で添加した培地に交換して24時間培養した。
実施例1のビタミンCを含む培地で培養したVit.C−MSCを2日間培養して付着及び安定化させた後、アスピリンをそれぞれ0.1mM、0.5mM及び1mMの濃度で添加した培地に交換して24時間培養した。
実施例7と同様な条件の下で0.5mMアスピリン含有培地で培養したVit.C−MSC(Angel−Stem cell)とMSCでNrf2、c−myc及びp21遺伝子の発現を比較した。実施例8と同様な方法でRT−PCRを遂行し、表3のプライマーを使った。
実施例10:アスピリン含有培地で培養したVit.C−MSCと間接共培養した癌細胞の遺伝子発現分析
実施例7と同様な条件の下でアスピリン含有培地で培養したVit.C−MSC(Angel−Stem cell)と癌細胞を間接共培養した後、癌細胞で遺伝子発現を分析した。遺伝子発現分析は実施例8と同様な方法で遂行した。
アスピリン含有培地で培養したVit.C−MSC(Angel−Stem cell)の癌細胞増殖抑制メカニズムを明かすために、癌細胞でアポトーシス関連因子の発現を分析した。
アスピリン含有培地で培養したVit.C−MSC(Angel−Stem cell)の癌細胞転移抑制効果を確認するために、癌細胞でOct4遺伝子の発現を分析した。Oct4プライマーは実施例9−3で使ったものと同じプライマー(表3)で分析した。
本発明は一態様において以下を提供する。
[項目1]
アスピリンを含む、改善した癌細胞増殖抑制能を有する間葉幹細胞を製造するための培地組成物。
[項目2]
ビタミンCをさらに含むことを特徴とする、項目1に記載の培地組成物。
[項目3]
5〜10%FBS及びNAC(N−acetyl Cystein)を含むDMEM又はK−SFMであることを特徴とする、項目1に記載の培地組成物。
[項目4]
カルシウム、rEGF、インスリン及びヒドロコルチゾンをさらに含むことを特徴とする、項目3に記載の培地組成物。
[項目5]
前記間葉幹細胞は、脂肪、子宮、骨髓、筋肉、胎盤、臍帯血、小便、毛嚢及び皮膚からなる群から選択された組職来由のものであることを特徴とする、項目1に記載の培地組成物。
[項目6]
前記アスピリンの濃度は0.1mM〜1mMであることを特徴とする、項目1に記載の培地組成物。
[項目7]
前記癌細胞は乳房癌、膵膓癌、神経膠腫、神経膠肉腫、逆形成性星細胞腫、髄芽細胞腫、肺癌、小細胞肺癌種、子宮頸癌、結腸癌、直膓癌、軟骨腫、咽喉癌、カポシ肉腫、リンパ管肉腫、リンパ管内皮腫、結腸直腸癌、子宮内膜癌、卵巣癌、白血病、前立腺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、精巣癌、ウィルムス腫瘍、ユーイング肉腫、膀胱癌、血管肉腫、内皮肉腫、腺癌、汗腺癌、皮脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、気管支癌、髄様癌、肥満細胞腫、中皮腫、滑膜腫、黒色腫、平滑筋腫、横紋筋腫、神経芽細胞腫、網膜芽細胞腫、乏突起膠腫、聴神経腫、血管芽細胞腫、髄膜腫、松果体腫、上衣細胞腫、頭蓋咽頭腫、上皮癌、胎生期癌、扁平上皮細胞癌、基底細胞癌、線維肉腫、粘液腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫細胞又は癌幹細胞であることを特徴とする、項目1に記載の培地組成物。
[項目8]
アスピリンを含む培地で間葉幹細胞を培養する段階を含む、改善した癌細胞増殖抑制能を有する間葉幹細胞の製造方法。
[項目9]
前記培地はビタミンCをさらに含むことを特徴とする、項目8に記載の製造方法。
[項目10]
前記培地は5〜10%FBS及びNAC(N−acetyl Cystein)を含むDMEM又はK−SFMであることを特徴とする、項目8に記載の製造方法。
[項目11]
カルシウム、rEGF、インスリン及びヒドロコルチゾンをさらに含むことを特徴とする、項目10に記載の製造方法。
[項目12]
前記間葉幹細胞はビタミンCで前処理されることを特徴とする、項目8に記載の製造方法。
[項目13]
前記間葉幹細胞は、脂肪、子宮、骨髓、筋肉、胎盤、臍帯血、小便、毛嚢及び皮膚からなる群から選択された組職来由のものであることを特徴とする、項目8に記載の製造方法。
[項目14]
前記アスピリンの濃度は0.1mM〜1mMであることを特徴とする、項目8に記載の製造方法。
[項目15]
前記癌細胞は、乳房癌、膵膓癌、神経膠腫、神経膠肉腫、逆形成性星細胞腫、髄芽細胞腫、肺癌、小細胞肺癌種、子宮頸癌、結腸癌、直膓癌、軟骨腫、咽喉癌、カポシ肉腫、リンパ管肉腫、リンパ管内皮腫、結腸直腸癌、子宮内膜癌、卵巣癌、白血病、前立腺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、精巣癌、ウィルムス腫瘍、ユーイング肉腫、膀胱癌、血管肉腫、内皮肉腫、腺癌、汗腺癌、皮脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、気管支癌、髄様癌、肥満細胞腫、中皮腫、滑膜腫、黒色腫、平滑筋腫、横紋筋腫、神経芽細胞腫、網膜芽細胞腫、乏突起膠腫、聴神経腫、血管芽細胞腫、髄膜腫、松果体腫、上衣細胞腫、頭蓋咽頭腫、上皮癌、胎生期癌、扁平上皮細胞癌、基底細胞癌、線維肉腫、粘液腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫細胞又は癌幹細胞であることを特徴とする、項目8に記載の製造方法。
[項目16]
前記培養の時間は24時間であることを特徴とする、項目8に記載の製造方法。
Claims (12)
- 0.5mM〜1mMのアスピリンとビタミンCを含む、改善した癌細胞増殖抑制能を有する間葉幹細胞を製造するための培地組成物。
- 5〜10%FBS及びNAC(N−acetyl Cystein)を含むDMEM又はK−SFMであることを特徴とする、請求項1に記載の培地組成物。
- カルシウム、rEGF、インスリン及びヒドロコルチゾンをさらに含むことを特徴とする、請求項2に記載の培地組成物。
- 前記間葉幹細胞は、脂肪、子宮、骨髓、筋肉、胎盤、臍帯血、小便、毛嚢及び皮膚からなる群から選択された組職来由のものであることを特徴とする、請求項1に記載の培地組成物。
- 前記癌細胞は乳房癌、膵膓癌、神経膠腫、神経膠肉腫、逆形成性星細胞腫、髄芽細胞腫、肺癌、小細胞肺癌種、子宮頸癌、結腸癌、直膓癌、軟骨腫、咽喉癌、カポシ肉腫、リンパ管肉腫、リンパ管内皮腫、結腸直腸癌、子宮内膜癌、卵巣癌、白血病、前立腺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、精巣癌、ウィルムス腫瘍、ユーイング肉腫、膀胱癌、血管肉腫、内皮肉腫、腺癌、汗腺癌、皮脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、気管支癌、髄様癌、肥満細胞腫、中皮腫、滑膜腫、黒色腫、平滑筋腫、横紋筋腫、神経芽細胞腫、網膜芽細胞腫、乏突起膠腫、聴神経腫、血管芽細胞腫、髄膜腫、松果体腫、上衣細胞腫、頭蓋咽頭腫、上皮癌、胎生期癌、扁平上皮細胞癌、基底細胞癌、線維肉腫、粘液腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫細胞又は癌幹細胞であることを特徴とする、請求項1に記載の培地組成物。
- 0.5mM〜1mMのアスピリンとビタミンCを含む培地で間葉幹細胞を培養する段階を含む、改善した癌細胞増殖抑制能を有する間葉幹細胞の製造方法。
- 前記培地は5〜10%FBS及びNAC(N−acetyl Cystein)を含むDMEM又はK−SFMであることを特徴とする、請求項6に記載の製造方法。
- カルシウム、rEGF、インスリン及びヒドロコルチゾンをさらに含むことを特徴とする、請求項7に記載の製造方法。
- 前記間葉幹細胞はビタミンCで前処理されることを特徴とする、請求項6に記載の製造方法。
- 前記間葉幹細胞は、脂肪、子宮、骨髓、筋肉、胎盤、臍帯血、小便、毛嚢及び皮膚からなる群から選択された組職来由のものであることを特徴とする、請求項6に記載の製造方法。
- 前記癌細胞は、乳房癌、膵膓癌、神経膠腫、神経膠肉腫、逆形成性星細胞腫、髄芽細胞腫、肺癌、小細胞肺癌種、子宮頸癌、結腸癌、直膓癌、軟骨腫、咽喉癌、カポシ肉腫、リンパ管肉腫、リンパ管内皮腫、結腸直腸癌、子宮内膜癌、卵巣癌、白血病、前立腺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、精巣癌、ウィルムス腫瘍、ユーイング肉腫、膀胱癌、血管肉腫、内皮肉腫、腺癌、汗腺癌、皮脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、気管支癌、髄様癌、肥満細胞腫、中皮腫、滑膜腫、黒色腫、平滑筋腫、横紋筋腫、神経芽細胞腫、網膜芽細胞腫、乏突起膠腫、聴神経腫、血管芽細胞腫、髄膜腫、松果体腫、上衣細胞腫、頭蓋咽頭腫、上皮癌、胎生期癌、扁平上皮細胞癌、基底細胞癌、線維肉腫、粘液腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫細胞又は癌幹細胞であることを特徴とする、請求項6に記載の製造方法。
- 前記培養の時間は24時間であることを特徴とする、請求項6に記載の製造方法。
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