JP2023148677A - エクソソーム分泌促進剤 - Google Patents
エクソソーム分泌促進剤 Download PDFInfo
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Abstract
Description
[1]
ローヤルゼリーを含む、間葉系幹細胞のエクソソーム分泌を促進するための、エクソソーム分泌促進剤。
[2]
上記間葉系幹細胞が脂肪由来間葉系幹細胞である、[1]に記載のエクソソーム分泌促進剤。
[3]
間葉系細胞及び/又は間葉系細胞によって分泌されるエクソソームにおける、miRNA-205-5pの含有量を向上させる、[1]又は[2]に記載のエクソソーム分泌促進剤。
[4]
[1]~[3]のいずれかに記載のエクソソーム分泌促進剤を有効成分として含む、化粧品原料、化粧品、食品組成物又は医薬組成物。
[5]
ローヤルゼリーを含む培地で間葉系幹細胞を培養する工程を含む、間葉系幹細胞由来エクソソームの製造方法。
[6]
上記間葉系幹細胞が脂肪由来間葉系幹細胞である、[5]に記載の製造方法。
[7]
分泌されたエクソソームを採集する工程をさらに含む、[5]又は[6]に記載の製造方法。
[8]
[5]~[7]のいずれかに記載の製造方法によって製造されたエクソソームを含む、組成物。
[9]
皮膚ケア用組成物である、[8]に記載の組成物。
[10]
線維芽細胞の活性化作用を有する、[8]又は[9]に記載の組成物。
[11]
上記線維芽細胞の活性化作用が、線維芽細胞増殖促進作用、創傷治癒促進作用、創傷部位への遊走促進作用、及び/又は、コラーゲン産生促進作用を含む、[10]に記載の組成物。
[12]
化粧品原料、化粧品、食品組成物又は医薬組成物である、[8]~[11]のいずれかに記載の組成物。
[13]
上記組成物が、局所用組成物である、[12]に記載の組成物。
本実施形態の間葉系幹細胞のエクソソーム分泌を促進するためのエクソソーム分泌促進剤は、ローヤルゼリーを含む。
本実施形態の間葉系幹細胞由来エクソソームの製造方法は、ローヤルゼリーを含む培地で間葉系幹細胞を培養する工程を含む。
本実施形態の間葉系幹細胞由来エクソソームは、上記間葉系幹細胞由来エクソソームの製造方法によって得られるエクソソームであり、間葉系幹細胞由来エクソソームを含む培養上清であってもよく、精製した間葉系幹細胞由来エクソソームであってもよい。本発明の一実施形態は、また、本実施形態の間葉系幹細胞由来エクソソームを含む組成物を提供する。該組成物は経口組成物であっても、局所用組成物であってもよい。
[エクソソームの粒子径及び粒子濃度の評価]
脂肪由来幹細胞(Adipose Derived Stem Cell、以下「ADSC」と略す場合がある)としてはLonza社から購入したものを使用した。1×105細胞/mLに調整したADSCをT75フラスコに播種し、ADSC培地(Lonza、MSCBM(商標登録)基本培地)中、37℃、5%CO2にて48時間前培養した。48時間後、培地に凍結乾燥ローヤルゼリー(FDRJ、山田養蜂場社、ローヤルゼリーを凍結乾燥、粉末化したもの)又は酵素処理ローヤルゼリー(EzRJ、山田養蜂場社、酵素分解ローヤルゼリーを粉末化したもの)を100μg/mLとなるように添加し、5日間培養した。5日間培養後、培地を回収し、新しく調製した同じ培地に交換してさらに5日間培養した。培養後、培地を回収し、最初の5日間培養後の回収培地と合わせた。
1×104細胞/mLに調整したADSCを96ウェルプレートに100μL/ウェルずつ播種し、上記と同様に24時間前培養した。24時間後、培地を、凍結ローヤルゼリー(FRJ、山田養蜂場社、生ローヤルゼリー)、FDRJ又はEzRJを100、200又は300μg/mL含むADSC培地(Lonza)に切り換え、72時間培養した。72時間培養後、培地を10%WST-1(タカラバイオ)含有ADSC培地に切り換え、2時間培養した。さらにその培養後、ミトコンドリアの呼吸鎖にて機能するコハク酸塩テトラゾリウム還元酵素によって、WST-1から変換されたホルマザン色素を、マイクロプレートリーダーにて450nm及び690nmにおける吸光度を測定し、吸光度に基づき、無処理のADSCの増殖率を1とした場合の、ADSCの相対増殖率を算出した。その結果を図2に示す。なお、図中のa、ab、b、cは異なる符号間で有意差があることを示している。また、aとab、bとabは同じ符号を有するため、有意差がないことを示している。
ヒト正常皮膚線維芽細胞(normal human dermal fibroblasts;以下「NHDF」という場合がある)としては、Lonza社から購入したものを使用した。1×104細胞/mLに調製したNHDFを96ウェルプレートに100μL/ウェルずつ播種し、NHDF培地(Lonza、MSCBM(商標登録)基本培地)中、37℃、5%CO2にて24時間培養した。24時間後、培地を、ADSCエクソソーム、FDRJ-ADSCエクソソーム又はEzRJ-ADSCエクソソームが、50、200、又は400ngタンパク質/mLとなるように添加したNHDF培地に切り換え、NHDFを72時間培養した。72時間培養後、培地を10%WST-1(タカラバイオ)含有NHDF培地に切り換え2時間培養した。さらにその培養後、上記[ADSCの増殖率の評価]と同様にして吸光度を測定し、吸光度に基づき、無処理のNHDFの細胞増殖率を100%とした場合のNDHFの相対増殖率(%)を算出した。結果を図3に示す。なお、図中のa、ab、bは異なる符号間で有意差があることを示している。また、aとab、bとabは同じ符号を有するため、有意差がないことを示している。
1×105細胞/mLに調整したNHDFを12ウェルプレートに1mL/ウェルずつ播種し、NHDF培地(Lonza)中、37℃、5%CO2にて24時間前培養した。24時間後、培地を実験例2と同様の各種ADSCエクソソームを、400又は800ngタンパク質/mLとなるように添加したNHDF培地に切り替え、NHDFをさらに24時間培養した。24時間培養後、NHDF培地に切り換え、細胞層に1000μLチップの先端でひっかくことで直線の創傷部位を作成した。NHDF培地で24時間培養後、創傷部位へ遊走したNHDF細胞の数を位相差顕微鏡により撮影し、図4に示す。また、ImageJにより遊走した細胞数をカウントし、無処理のNHDFの遊走活性を1とした場合の相対遊走活性を算出した。結果を図5に示す。なお、図中のa、ab、c、bc、d、eは異なる符号間で有意差があることを示している。また、aとab、cとbcは同じ符号を有するため、有意差がないことを示している。
1×105細胞/mLに調整したNHDFを12ウェルプレートに1mL/ウェルずつ播種し、NHDF培地(Lonza)中、37℃、5%CO2にて24時間前培養した。24時間後、実験例2と同様の各種ADSCエクソソームを200ngタンパク質/mLとなるように培地に添加し、さらに72時間培養した。72時間培養後、NHDF培地に切り換え72時間培養した。72時間培養後、冷PBSにより細胞を洗浄し、Collagen Quantitation Kitを用いて生成されたコラーゲン含有量を定量した。その結果を図6に示す。なお、図中のa、bは異なる符号間で有意差があることを示している。また、同じ符号間では有意差がないことを示している。
実験例1に記載した方法により調製した各種ローヤルゼリー処理ADSC及びADSCエクソソームから、RNeasy Mini Kit (Qiagen)を用いてtotalRNAを抽出した。RNA試料はBioanalyzer(Agilent Technologies)を用いて、分解を受けていないことを確認した。QIA-seq miRNA Library Kit(Qiagen)、QIA-seq miRNA NGS 96 Index IL(Qiagen)をそれぞれ用いてmiRNA-seq解析用のライブラリーを調製した。その後、直ちに次世代シーケンサーNovaSeq 6000(商標登録、Illumina)に供し、ADSC及びADSCエクソソームにおけるmiRNAプロファイルを解析した。なお、検出されたmiRNAからリード数のcount値が16未満のデータはノイズデータとして削除し、全部で94種類のmiRNAを解析対象とした。ADSC及びADSCエクソソーム中の同時差次的発現miRNAの含有量を表1に示す。表1中のmiRNAの含有量は、TPM(Transcripts per million)で表されている。また、スクリーニングされた同時差次的発現miRNAのベン図(Venn diagram)を図7及び図8に示す。
Claims (13)
- ローヤルゼリーを含む、間葉系幹細胞のエクソソーム分泌を促進するための、エクソソーム分泌促進剤。
- 前記間葉系幹細胞が脂肪由来間葉系幹細胞である、請求項1に記載のエクソソーム分泌促進剤。
- 間葉系細胞及び/又は間葉系細胞によって分泌されるエクソソームにおける、miRNA-205-5pの含有量を向上させる、請求項1又は2に記載のエクソソーム分泌促進剤。
- 請求項1~3のいずれか一項に記載のエクソソーム分泌促進剤を有効成分として含む、化粧品原料、化粧品、食品組成物又は医薬組成物。
- ローヤルゼリーを含む培地で間葉系幹細胞を培養する工程を含む、間葉系幹細胞由来エクソソームの製造方法。
- 前記間葉系幹細胞が脂肪由来間葉系幹細胞である、請求項5に記載の製造方法。
- 分泌されたエクソソームを採集する工程をさらに含む、請求項5又は6に記載の製造方法。
- 請求項5~7のいずれか一項に記載の製造方法によって製造されたエクソソームを含む、組成物。
- 皮膚ケア用組成物である、請求項8に記載の組成物。
- 線維芽細胞の活性化作用を有する、請求項8又は9に記載の組成物。
- 前記線維芽細胞の活性化作用が、線維芽細胞増殖促進作用、創傷治癒促進作用、創傷部位への遊走促進作用、及び/又は、コラーゲン産生促進作用を含む、請求項10に記載の組成物。
- 化粧品原料、化粧品、食品組成物又は医薬組成物である、請求項8~11のいずれか一項に記載の組成物。
- 前記組成物が、局所用組成物である、請求項12に記載の組成物。
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