JP6847080B2 - 皮膚美白またはしわ改善用組成物 - Google Patents
皮膚美白またはしわ改善用組成物 Download PDFInfo
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- JP6847080B2 JP6847080B2 JP2018138790A JP2018138790A JP6847080B2 JP 6847080 B2 JP6847080 B2 JP 6847080B2 JP 2018138790 A JP2018138790 A JP 2018138790A JP 2018138790 A JP2018138790 A JP 2018138790A JP 6847080 B2 JP6847080 B2 JP 6847080B2
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Description
1)幹細胞を培養培地に培養した後、無血清および無抗生剤培地で継代培養する段階;
2)細胞培養上清を回収する段階;
3)回収した細胞培養上清を遠心分離する段階;および
4)エキソソームを分離および精製する段階;によって製造されうるが、これに限定されない。
前記具体例による幹細胞の分化および脂肪組織再生用組成物は、脂肪細胞の分化に関連する脂肪細胞の遺伝情報、タンパク質、成長因子を含有しているエキソソームを含む。これにより、分化のための複雑かつ多様な成長因子を追加しなくてもよいので、幹細胞の分化に効果的に応用が可能である。本発明の脂肪細胞に分化されている幹細胞由来のエキソソームにより、幹細胞が脂肪細胞に分化されて生体内に適用されるとき脂肪組織の再生に有利な効果が発揮される。本発明の脂肪細胞に分化されている幹細胞由来のエキソソームは、細胞由来物質として生体適合して、既存の細胞治療剤の副作用を最小化することができ、エキソソーム自体がキャリアの役割をすることができ、これに担持した成分を人体に容易に適用することができるので、幹細胞の分化誘導剤、組織再生用注射剤、美容目的のフィラー、組織工学用製剤などに適用することができる。
<1−1>エキソソーム(exosome)の分離
脂肪細胞に分化されている幹細胞からエキソソームを分離するために、幹細胞を分化培地で培養することにより、脂肪細胞への分化を誘導した。脂肪細胞への分化が行われることは、幹細胞が徐々に肥大しながら細胞質に脂肪滴(Lipid droplet)が生じることで確認された。分化されている幹細胞を無血清培地に交換し、48時間維持した後、細胞培養上清を回収した。回収した細胞培養上清を300xgで10分間遠心分離して細胞を除去し、2,000xgで30分間遠心分離して細胞の分泌物を除去した。その後、分子量3,000のフィルターが装着された遠心分離チューブ(molecular weight cut off=3000、amicon tube)を用いて、5000xgで60分間遠心分離をして濃縮した。濃縮後、得られた上清は、エキソソーム分離試薬(exosome isolation reagent)と1:0.5の割合で混合し、4℃で1日保管した。その後、10,000xgで60分間遠心分離によりエキソソーム沈殿物を得た後、分子量3,000のフィルター(Exosome spin column)を介して濾過し、リン酸緩衝食塩水(Phosphate−buffered saline、PBS)で洗浄した。洗浄したエキソソーム沈殿物は、10,000xgで60分間遠心分離した後、リン酸緩衝食塩水に再懸濁した(図2)。
実施例1−1から分離したエキソソームを透過電子顕微鏡(transmission electron microscope)とナノ粒子分析器(dynamic light scattering)を用いてサイズおよび形状を確認し、特定タンパク質を検出するウェスタンブロット(western blot)を用いてエキソソーム表面タンパク質を確認した。
脂肪細胞に分化されている幹細胞由来のエキソソームおよび増殖する幹細胞由来のエキソソーム内に存在する脂肪関連の生体活性因子を分析するために、マイクロアレイ(microarray)を用いた。マイクロアレイは、抗原抗体反応を介して行われ、レーザースキャナー(GenePix 4000B)により蛍光(Streptavidin−Cy3)の発現程度を測定した。
エキソソームを用いて、幹細胞の脂肪細胞への分化を誘導するために、増殖する幹細胞培養培地由来のエキソソームおよび脂肪細胞に分化されている幹細胞由来のエキソソームのそれぞれを含む培地組成物を用いた。前記培地組成物は、エキソソーム30、50、100μg/mLの濃度を幹細胞培養培地に追加して使用した。前記培地組成物を、培養されたヒト脂肪由来幹細胞(hASCs)にそれぞれ処理した後、前記培地組成物を3日に1回、14日間交換した。陽性対照群は、5%ウシ胎児血清(fetal bovine serum)、1μMデキサメタゾン(dexamethasone)、1μg/mLインスリン(insulin)、100μMインドメタシン(indomethacin)、0.5mM 3−イソブチル−1−メチルキサンチン(3−isobutyl−1−methylxanthine)が含まれたDMEM高濃度グルコース(Dulbecco’s Modified Eagle’s Medium high glucose)培地で培養された幹細胞を使用した。もう一つの陽性対照群は、増殖する幹細胞由来のエキソソームを処理した幹細胞を使用した。その後、14日間、脂肪細胞への分化が誘導された幹細胞について顕微鏡とオイルレッドO染色(Oil−red O staining)を用いて、細胞形態および分化するかどうかを分析した。
前記実施例1−1により脂肪細胞に分化されている幹細胞由来のエキソソームが包接されたリポソームを製造した。具体的には、常温(15℃)でレシチン3重量%を、前記脂肪細胞に分化されている幹細胞由来のエキソソーム0.01重量%が含まれた水相に分散させた後、超臨界二酸化炭素を用いて、逆ミセル(reverse micelle)エマルジョン(水相/低温工程二酸化炭素)を形成させた。次に前記反応を中止し、超臨界二酸化炭素を減圧気化させて超臨界二酸化炭素相を除去し、前記脂肪細胞に分化される幹細胞由来のエキソソームが包接された低温工程リポソーム懸濁液を得た。このとき、反応工程の温度は4℃以下で進行した。
脂肪細胞に分化されている幹細胞由来のエキソソームを生体内に注入した時の脂肪組織の再生効果を確認するために、増殖する幹細胞由来のエキソソームおよび脂肪細胞に分化されている幹細胞由来のエキソソームをそれぞれコラーゲン/メチルセルロースハイドロゲルに担持した。
<2−1>ヒト脂肪由来幹細胞からエキソソームの分離
ヒト脂肪由来幹細胞を継代(passage)7まで増殖させる過程でエキソソームを分離した。つまり、増殖するヒト脂肪由来幹細胞からエキソソームを分離した。
実施例2−1のヒト脂肪由来幹細胞由来のエキソソーム(Stem−Exo)、ヒト皮膚角質細胞由来のエキソソーム(K−Exo)およびヒト皮膚線維芽細胞由来のエキソソーム(F−Exo)を透過電子顕微鏡(transmission electron microscope)とナノ粒子分析器(dynamic light scattering)とを使用してサイズおよび形状を確認した。
ヒト脂肪由来幹細胞由来のエキソソーム(Stem−EXO)とヒト皮膚角質細胞由来のエキソソーム(K−EXO)およびヒト皮膚線維芽細胞由来のエキソソーム(F−EXO)内に存在するシワ改善、美白、皮膚再生に関連する生体活性因子を比較分析するために、マイクロアレイ(microarray)分析を実施した。マイクロアレイ分析は、抗原抗体反応を介して行われ、レーザースキャナー(GenePix 4000B)により蛍光(Streptavidin−Cy3)の発現程度を測定した。
ヒト脂肪由来幹細胞由来のエキソソームがヒト皮膚線維芽細胞の移動に及ぼす影響を調べるために、増殖するヒト脂肪由来幹細胞由来のエキソソーム(Stem−EXO)とヒト皮膚角質細胞由来のエキソソーム(K−EXO)およびヒト皮膚線維芽細胞由来のエキソソーム(F−EXO)をそれぞれ含む培地組成物を用いた。前記培地組成物は、Stem−EXOは、10、30、50μg/mLの濃度でDMEM無血清培養培地に追加して準備し、K−EXOとF−EXOは、それぞれ50μg/mLの濃度でDMEM無血清培地に追加して準備した。陽性対照群として10%の血清を含むDMEM培地を使用し、陰性対照群としてDMEM無血清培地を使用した。ヒト皮膚線維芽細胞は、緑色蛍光染色(green fluorescence dye)で標識した後、24ウェルプレート(well plate)にそれぞれ1×105細胞/ウェル(well)で分注し、培養培地(DMEM containing 10%fetal bovine serum、1%penicillin/streptomycin)で72時間培養した。培養後、細胞が付着したプレート(plate)の底の中心を滅菌されたピペットチップ(yellow tip)を用いて人為的に一定の間隔の傷(wound)をつくり、エキソソームが含まれた前記培地組成物のそれぞれを細胞に処理した。
ヒト脂肪由来幹細胞由来のエキソソームがヒト皮膚線維芽細胞のコラーゲン合成に及ぼす影響を調べるために、増殖する幹細胞培養培地由来のエキソソーム(Stem−EXO)、ヒト皮膚角質細胞由来のエキソソーム(K−EXO)またはヒト皮膚線維芽細胞由来のエキソソーム(F−EXO)をそれぞれ含む培地組成物を用いた。前記培地組成物は、Stem−EXOは、10、30、50μg/mLの濃度でDMEM無血清培養培地に追加して準備し、K−EXOとF−EXOは、それぞれ50μg/mLの濃度でDMEM無血清培地に追加して準備し、陰性対照群としてDMEM無血清培地を使用した。ヒト皮膚線維芽細胞は、48ウェルプレート(well plate)にそれぞれ5×104細胞/ウェル(well)で分注し、培養培地(DMEM containing 10%fetal bovine serum、1%penicillin/streptomycin)で72時間培養した後、リン酸緩衝食塩水で細胞を洗浄し、エキソソームが含まれた前記培地組成物のそれぞれを細胞に処理した。
ヒト脂肪由来幹細胞由来のエキソソーム(Stem−EXO)と対照群として、ヒト皮膚角質細胞由来のエキソソーム(K−EXO)およびヒト皮膚線維芽細胞由来のエキソソーム(F−EXO)の美白効果をマウスメラノーマに対するメラニン生成抑制の程度により判断した。前記メラノーマ細胞は、マウス黒色腫に由来する細胞であり、メラニンという黒色色素を分泌する細胞である。メラノーマ細胞を96ウェルプレート(well plate)に1×105の濃度で分注して細胞を付着させた後、Stem−EXO、K−EXO、F−EXOがそれぞれ含有された培地で培養培地を交換し、3日間培養した。3日後、培地はすべて回収し、4,500rpmで10分間遠心分離した後、405nmで吸光度を測定し、細胞外に放出されたメラニンの量を計算した。プレート(Plate)についている細胞は、トリプシン(Trypsin−EDTA)処理をして取り除いた後、細胞数を測定し、その後遠心分離して細胞を回収した。細胞をPBSで1回洗浄した後、遠心分離して細胞ペレットを得、ここに10%DMSO(dimethyl sulfoxide)が含まれている1N NaOH(sodium hydroxide)溶液を1mL添加して80℃で2時間メラニンを溶かした後、96ウェルプレート(wellplate)に入れ、405nmで吸光度を測定した。測定された吸光度を用いてメラニンを定量し、試料のタンパク質濃度で正規化(normalize)して合成されたメラニンの濃度を測定した。
前記実施例2−1によって、増殖するヒト脂肪由来幹細胞由来のエキソソームが包接されたリポソームを製造した。
前記実施例2−7の方法で得られた、増殖する幹細胞由来のエキソソームが包接されたリポソームを用いて、下記の表4のような組成で柔軟化粧水(スキンローション)を製造した。
前記実施例2−7の方法で得られた、増殖する幹細胞由来のエキソソームが包接されたリポソームを用いて、下記の表5のような組成で栄養化粧水(ローション)を製造した。
[1]脂肪細胞に分化されている幹細胞由来のエキソソームを有効成分として含有する脂肪細胞への分化誘導または脂肪組織再生用組成物。
[2]前記脂肪細胞に分化されている幹細胞は、骨髄幹細胞、臍帯血幹細胞または脂肪由来幹細胞である、[1]に記載の脂肪細胞への分化誘導または脂肪組織再生用組成物。
[3]前記骨髄幹細胞、臍帯血幹細胞または脂肪由来幹細胞は、ヒト、動物または植物由来の幹細胞である、[2]に記載の脂肪細胞への分化誘導または脂肪組織再生用組成物。
[4]前記エキソソームは、前記脂肪細胞への分化誘導または脂肪組織再生用組成物1mLあたり1〜150μgの濃度で幹細胞に処理されるものである、[1]に記載の脂肪細胞への分化誘導または脂肪組織再生用組成物。
[5][1]ないし[3]のいずれかに記載の脂肪細胞への分化誘導または脂肪組織再生用組成物を含む化粧料組成物。
[6][1]ないし[3]のいずれかに記載の脂肪細胞への分化誘導または脂肪組織再生用組成物を含む脂肪細胞への分化誘導用培地組成物。
[7][1]ないし[3]のいずれかに記載の脂肪細胞への分化誘導または脂肪組織再生用組成物;およびハイドロゲルを含む注射剤。
[8]幹細胞由来のエキソソームを有効成分として含有する皮膚美白、しわ改善、または皮膚再生用化粧料組成物。
[9]前記幹細胞は、骨髄幹細胞、臍帯血幹細胞または脂肪由来幹細胞である、[8]に記載の皮膚美白、しわ改善、または皮膚再生用化粧料組成物。
[10]前記骨髄幹細胞、臍帯血幹細胞または脂肪由来幹細胞は、ヒト、動物または植物由来の幹細胞である、[9]に記載の皮膚美白、しわ改善、または皮膚再生用化粧料組成物。
[11]前記エキソソームは、皮膚美白、しわ改善、または皮膚再生用化粧料組成物1mLあたり1〜150μgの濃度で含有されるものである、[8]に記載の皮膚美白、しわ改善、または皮膚再生用化粧料組成物。
[12]前記化粧料は、スキンローション、スキンソフナー、スキントナー、アストリンゼン、ローション、ミルクローション、モイスチャーローション、栄養ローション、マッサージクリーム、栄養クリーム、モイスチャークリーム、ハンドクリーム、ファンデーション、エッセンス、栄養エッセンス、パック、石鹸、クレンジングフォーム、クレンジングローション、クレンジングクリーム、ボディローション、ボディクレンザー、洗顔剤、トリートメント、美容液、美容パック、軟膏剤、ゲル剤、リニメント剤、液剤、パッチ、およびスプレー剤から構成された群から選択されたいずれかの剤形である、[8]に記載の皮膚美白、しわ改善、または皮膚再生用化粧料組成物。
Claims (4)
- 増殖中の脂肪由来幹細胞からエキソソームを抽出する段階と、前記抽出されたエキソソームを有効成分として含有させる段階と、を含む、皮膚美白、またはしわ改善用の化粧料組成物(但し、幹細胞の培養上清を有効成分として含む化粧料組成物、幹細胞の培養上清粉末を有効成分として含む化粧料組成物及び幹細胞の条件培地(stem cell-conditioned medium)を有効成分として含む化粧料組成物を除外する。)の製造方法であって、
前記増殖中の脂肪由来幹細胞から抽出されたエキソソームは、TIMP−1、アンギオゲニンおよびアンジオポエチン−1を含む、化粧料組成物の製造方法。 - 前記脂肪由来幹細胞は、ヒトまたは動物由来の幹細胞である、請求項1に記載の製造方法。
- 前記エキソソームは、皮膚美白、またはしわ改善用化粧料組成物1mLあたり1〜150μgの濃度で含有されるものである、請求項1に記載の製造方法。
- 前記化粧料は、スキンローション、スキンソフナー、スキントナー、アストリンゼン、ローション、ミルクローション、モイスチャーローション、栄養ローション、マッサージクリーム、栄養クリーム、モイスチャークリーム、ハンドクリーム、ファンデーション、エッセンス、栄養エッセンス、パック、石鹸、クレンジングフォーム、クレンジングローション、クレンジングクリーム、ボディローション、ボディクレンザー、洗顔剤、トリートメント、美容液、美容パック、軟膏剤、ゲル剤、リニメント剤、液剤、パッチ、およびスプレー剤から構成された群から選択されたいずれかの剤形である、請求項1に記載の製造方法。
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EP3189828B1 (en) | 2020-07-29 |
CN111773173B (zh) | 2024-03-22 |
CN111773173A (zh) | 2020-10-16 |
EP3189828A1 (en) | 2017-07-12 |
AU2015343845B2 (en) | 2018-11-08 |
JP6683700B2 (ja) | 2020-04-22 |
RU2759508C1 (ru) | 2021-11-15 |
CN118161444A (zh) | 2024-06-11 |
CN107106613B (zh) | 2021-07-06 |
CN107106613A (zh) | 2017-08-29 |
BR112017007892A2 (pt) | 2018-01-23 |
ES2831298T3 (es) | 2021-06-08 |
RU2019131867A3 (ja) | 2020-02-28 |
US10071050B2 (en) | 2018-09-11 |
JP2021020968A (ja) | 2021-02-18 |
EP3453382B1 (en) | 2020-08-12 |
RU2017116138A3 (ja) | 2018-12-07 |
CN118161529A (zh) | 2024-06-11 |
RU2017116138A (ru) | 2018-12-07 |
US20170209365A1 (en) | 2017-07-27 |
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