JP6952761B2 - 組織修復のための臍帯血由来エキソソームの使用 - Google Patents
組織修復のための臍帯血由来エキソソームの使用 Download PDFInfo
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Description
創傷治癒は、4つの連続し、重複する段階:うっ血、炎症、増殖、及び組織再構築から成る動的プロセスである(Guo他、2010年)。最適な創傷治癒には、各段階中の現象が、正確に且つ規則的に発生しなければならない。プロセスにおける中断、異常(aberrancy)、又は延長は、創傷治癒の遅れや非治癒の慢性創傷に繋がり得る(Guo他、2010年)。
真性糖尿病は、慢性的高血糖を特徴とする一連の代謝障害を示す。また、若年発症糖尿病としても知られるI型真性糖尿病は、インシュリンを分泌する膵臓β細胞の自己免疫破壊から生じる。また、成人発症糖尿病としても知られるII型真性糖尿病は、過度のインスリン分泌、組織インスリン耐性、及びその後のβ細胞機能障害を特徴とする(Goutos他、2015年)。
糖尿病の人々は、急性創傷の治癒不良を示し、糖尿病性足部潰瘍等の慢性創傷に進展する傾向がある(Guo他、2010年)。
エキソソームは、殆どの種類の細胞によって分泌されるリポソーム様小胞(30〜200nm)であり、多小胞体(MVB:multivesicular body)と呼ばれる区画で分泌細胞内に形成され、次に、エンドソーム区画と原形質膜とが融合することで放出され、その結果、細胞外環境への内容物放出が生じる(Raposo及びStoorvogel、2013年)。エキソソームは、分泌細胞と刺激の種類に応じて、細胞質内容物の無作為標本ではなく、タンパク質、脂質、及びRNAの特異的なセットを含有する(Raposo及びStoorvogel、2013年; Mathivanan S.及びSimpson R.J.、2009年)。エキソソームは、エキソソームを有望な生物由来遺伝子送達システムへとプロモートする特徴の、mRNA及びmicroRNAの形をした、遺伝物質を担持する(O’Loughlin他、2012年)。
a)少なくとも1つの線維芽細胞層を含む移植材料;
b)フィブリンマトリックス及び線維芽細胞を含むゲル又は移植材料;
c)少なくとも1つの構造タンパク質のマトリックスを含む移植材料;
d)架橋コラーゲン及びグルコサミノグリカンのマトリックスを含む移植材料;
e)水中に分散された親水性ポリマのマトリックスを含むゲル、パッチ、パッド、硬膏剤、フィルム若しくは接着剤;
f)ポリウレタン膜及び/又は泡;
g)細胞外マトリックスタンパク質、アルギン酸及び水を含む製剤;又は
h)上記エキソソームを含むエアゾールを含むエアゾール容器
である。
別段に定義されない限り、本明細書で使用される全ての技術用語及び科学用語は、本発明が属する技術分野の当業者によって一般的に理解されるのと同じ意味を有する。
実施例1 虚血プレコンディショニングは、エキソソームを分泌するように臍帯血単核細胞(UCBMNC)を刺激し、該細胞の皮膚細胞に対する生理活性を高める。
UCBMNCの全画分は、Lymphoprep(登録商標)を使用して単離され、該細胞は、血液分析器を使用して特徴付けられた。凍結保存後に、該集団は、リンパ球及び単球(MNC:monocyte)を濃縮される一方で、好中球の大部分の画分は、失われる(図1A及び図1B)。エキソソームの分泌に使用されるプールは、リンパ球と単球で主に構成される。
実験手順:
エキソソームは、その全内容が本明細書に組込まれるThery C.他(2006年)に記載された分画遠心法によって精製された。
我々の結果は、エキソソームが、140nmの平均サイズ(図2A)、負のゼータ電位(−30mV)(図2B)、及び球状形態(図2C.1及び図2C.2)を有したことを示した。また、これらのエキソソームは、FACSによって分析した際、マーカCD9、CD81、及びHSC70を発現した(図2D)。
1.2.1 皮膚細胞の割合
実験手順:
皮膚細胞は、UCBMNC由来のエキソソームを取込むが、取込み速度及び程度は、細胞の種類によって異なる。皮膚細胞によるエキソソームの取込み速度の相違を示すために、エキソソームは、初めに、蛍光染料(NBD−DPPE及びSyto green)で標識された。手短に言えば、NBD−DPPE(エタノール中16μM)又はSyto Green(DMSO 中10μM)染料が、エキソソーム懸濁液(100μL;タンパク質濃度60〜70μg/mL)(DMSO及びEtOH<1%)に添加され、37℃で30分間インキュベートされた。ウシ血清アルブミン(BSA、1%、w/v)で反応をブロッキングした後に、エキソソームは、PBS(6mL)で洗浄され、遊離色素は、100,000gで1 時間、超遠心分離することによって除去された。次に、エキソソームは、PBS(100μl)に再懸濁された。この手順は、常に新鮮なエキソソームで実行された。標識されたエキソソームは、直ちに内部移行実験に使用された。
エキソソームは、内皮細胞に対して、濃度10μg/mLまでは、細胞毒性はない。(図3A)。
実験手順:
次に、我々は、共焦点顕微鏡を使用して、皮膚細胞によるエキソソームの取込み速度に関するインキュベーション時間及びエキソソーム濃度の影響を評価した(図3C)。スナップショット(図3C)は、Zeiss社製LSM710共焦点走査装置で、405及び488の励起波長、及びプランアポクロマート40x/1.4油浸対物レンズを用いて、取得された。また、動態プロファイルも、ハイコンテント顕微鏡(In Cell Analyser、GE Healthcare社)を使用して、24時間の異なる時点で細胞質強度を分析することによって、得られた。顕微鏡は、加熱恒温装置を備え、該装置は、37℃に設定され、CO2供給が5%に設定された。生細胞を顕微鏡検査する実験には、HUVEC細胞が、24時間、IBIDI(登録商標)のμ−Slide Angiogenesis プレートで成長された。Syto(登録商標) RNASelect(登録商標)で標識されたエキソソーム(1〜20g/ml)が、コンフルエントな細胞に、エキソソーム除去済み培地内で添加され、異なる時点でインキュベートされた。細胞は、PBSで2回洗浄され、実験の経過中に、FBS含有培地内に保持された。
我々の結果は、検査された3種類の細胞において、エキソソームが全細胞質に存在したことを示した。細胞質におけるエキソソームの蓄積は、接触後約16時間でピークに達した(図3D)。
実験手順:
皮膚細胞に対するエキソソームの機能的効果を判定するために、我々は、エキソソームの内部移行が、(i)虚血状態下での細胞生存、(ii)細胞増殖、(iii)細胞遊走、及び(iv)内皮管形成(図4及び図5)を誘導できたか否かを評価した。
我々の結果は、低酸素状態(Exo_Hyp)で、正常酸素圧ではない状態(Exo_Nor)で培養されたUCBMNCから単離されたエキソソームは、48時間、虚血状態で培養された内皮細胞生存を誘導するのに極めて効率的であることが示された(図4A.1〜4)。
実験手順:
UCBMNC−ExoのRNA含有量は、RNAディープシークエンシングによって特徴付けられた。2名の異なるドナーから低酸素状態と酸素正常状態で分泌されたUCBMNC−Exoが使用された。以下の方法が使用された。
我々の結果は、Exo_HypとExo_Norの両方が、miRNAの大規模プールを有する(図6A)を示した。全リードに関して、両エキソソームの30個の最も代表的なmiRNAは:hsa−miR−150−5p、hsa−miR−16−5p、hsa−miR−142−3p、hsa−miR−223−3p、hsa−let−7g−5p、hsa−miR−21−5p、hsa−let−7f−5p、hsa−miR−19b−3p、hsa−let−7a−5p、hsa−miR−26a−1−5p、hsa−miR−20a−5p、hsa−miR−181a−5p、hsa−miR−451a、hsa−miR−23a−3p、hsa−miR−342−3p、hsa−miR−191−5p、hsa−miR−103a−3p、hsa−miR−15a−5p、hsa−miR−142−5p、hsa−miR−146a−5p、hsa−miR−19a−3p、hsa−miR−15b−5p、hsa−miR−26b−5p、hsa−miR−30d−5p、hsa−miR−146b−5p、hsa−miR−106b−5p、hsa−miR−29a−3p、hsa−miR−17−5p、hsa−miR−29b−3p、及びhsa−miR−101−3pである。
実験手順:
I型真性糖尿病は、Charles River社(米国マサチューセッツ州ウィルミントン市)から購入された雄のC57BL/6マウス(10〜12週齢)にストレプトゾトシン(Sigma−Aldrich社)を腹腔内投与して誘導された。
我々の結果は、エキソソーム治療が、I型糖尿病の切除創傷の治癒を大幅に加速したこと(図7A1及びA2)を示した。創傷治癒(創傷サイズの縮小)の加速が、2日目にはもう観察され、これは、ドナー2で統計的に顕著であった。10日後に、UCBMNC−Exoの適用時に創閉鎖に関して一貫して55%の改善が、ドナーに関係無く、観察された(治療された創傷サイズは、対照のサイズの半分である)。同じ治療計画が、正常なマウスに適用され、創閉鎖の加速が、3日目から顕著になり、10日目には全体的に39%の改善を齎すことが観察された(図7A3)。
実験手順:
インビトロアッセイにおいて、内皮細胞、線維芽細胞及びケラチノサイトは、miR150−5p(5nm、miRIDIAN microRNA Human hsamiR150−5p mimic MIMAT0000082、Dharmacon、米国コロラド州ラファイエット市)、及びLipofectamine(登録商標)RNAiMAXトランスフェクション試薬(Invitrogen(登録商標))で、100μLの完全培地において、48時間(細胞生存及び管形成アッセイ)又は24時間(細胞増殖及び引掻きアッセイ)、トランスフェクトされた。
我々の結果では、miR−150−5pでトランスフェクトされた線維芽細胞は、トランスフェクトされない細胞より、72時間虚血後の生存率が高いことを示している(図8A)。内皮細胞やケラチノサイトには、同じではなかった。我々は、我々の分析を、遊走、増殖及び血管新生アッセイへと広げた。線維芽細胞ではなく、miR−150−5pでトランスフェクトされたケラチノサイトは、引掻きアッセイによって評価された際に、遊走性を改善した。増殖及び血管新生については、細胞間で、全く統計的差異が観察されなかった。
Charles River (フランス)から購入された、体重20〜30gの雄C57BL/6野生型マウス(8週齢)6匹は、麻酔され、其々が直径6mmの、5cm離間した全層に亘る切除が、各動物の背側に無菌生検パンチで付けられた。
我々の結果は、has−miR−150−5pで治療された創傷が、負のmiR対照(scramble)で治療された創傷及び非治療(PBS)創傷より速く治癒したことを示した(図8B)。
Claims (21)
- 創傷治癒のための組成物であって、前記組成物は、低酸素かつウシ胎児血清(FBS)枯渇状態の臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む、創傷治癒のための組成物。
- 創傷治癒のための組成物であって、前記組成物は、低酸素かつウシ胎児血清(FBS)枯渇状態の臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)(但し、CD34+細胞を除く)エキソソームを含む、創傷治癒のための組成物。
- 前記UCBMNCは、リンパ球、単球、好中球、好酸球、及び/又は好塩基球を含む、請求項1又は2に記載の組成物。
- 前記UCBMNCは、リンパ球、単球、好中球、好酸球、及び/又は好塩基球である、請求項1又は2に記載の組成物。
- 前記エキソソームの少なくとも1つは、以下から成る群:hsa−miR−150−5p、hsa−miR−16−5p、hsa−miR−142−3p、hsa−miR−223−3p、hsa−let−7g−5p、hsa−miR−21−5p、hsa−let−7f−5p、hsa−miR−19b−3p、hsa−let−7a−5p、hsa−miR−26a−1−5p、hsa−miR−20a−5p、hsa−miR−181a−5p、hsa−miR−451a、hsa−miR−23a−3p、hsa−miR−342−3p、hsa−miR−191−5p、hsa−miR−103a−3p、hsa−miR−15a−5p、hsa−miR−142−5p、hsa−miR−146a−5p、hsa−miR−19a−3p、hsa−miR−15b−5p、hsa−miR−26b−5p、hsa−miR−30d−5p、hsa−miR−146b−5p、hsa−miR−106b−5p、hsa−miR−29a−3p、hsa−miR−17−5p、hsa−miR−29b−3p、及びhsa−miR−101−3pから選択される1つ又は複数のmiRNAを含有する、請求項1又は2に記載の組成物。
- 前記エキソソームは、以下から成る群:hsa−miR−150−5p、hsa−miR−16−5p、hsa−miR−142−3p、hsa−miR−223− 3p、hsa−let−7g−5p、hsa−miR−21−5p、hsa−let−7f−5p、hsa−miR−19b−3p、hsa−let−7a−5p、hsa−miR−26a−1−5p、hsa−miR−20a−5p、hsa−miR−181a−5p、hsa−miR−451a、hsa−miR−23a−3p、hsa−miR−342−3p、hsa−miR−191−5p、hsa−miR−103a−3p、hsa−miR−15a−5p、hsa−miR−142−5p、hsa−miR−146a−5p、hsa−miR−19a−3p、hsa−miR−15b−5p、hsa−miR−26b−5p、hsa−miR−30d−5p、hsa−miR−146b−5p、hsa−miR−106b−5p、hsa−miR−29a−3p、hsa−miR−17−5p、hsa−miR−29b−3p、及びhsa−miR−101−3pから選択される1つ又は複数のmiRNAを濃縮され、それにより、前記エキソソームにおける前記miRNAの濃度を高める、請求項1又は2に記載の組成物。
- 前記エキソソームの少なくとも1つは、マーカCD9、CD81及び/又はHsc70を発現する、請求項1又は2に記載の組成物。
- 前記エキソソーム組成物におけるタンパク質の濃度は、0.01μg/mL〜10μg/mLである、請求項1又は2に記載の組成物。
- 化粧品として使用する、請求項1〜8のいずれか一項に記載された、臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む組成物。
- 薬物として使用する、請求項1〜8のいずれか一項に記載された、臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む組成物。
- 組織修復時に薬物として使用する、請求項10に記載の組成物。
- 皮膚組織修復時に薬物として使用する、請求項10又は11に記載の組成物。
- 切り傷、裂傷、断裂、擦過傷、剥離又は手術創の皮膚開放創の治療時に使用する、請求項10〜12のいずれか一項に記載の組成物。
- 熱傷、化学火傷若しくは放射線火傷の皮膚火傷の治療時に、及び/又はざ瘡、乾癬、酒さ、皮膚炎、湿疹、膿痂疹、間擦疹、若しくは毛包炎の皮膚の状態又は病気時に使用する、請求項10〜12のいずれか一項に記載の組成物。
- 動脈性潰瘍、静脈性潰瘍、糖尿病性潰瘍、及び褥瘡性潰瘍、手術後の潰瘍、外傷性潰瘍、口腔内潰瘍、糖尿病性足部潰瘍又は角膜潰瘍の創傷治療時に薬物として使用する、請求項10〜12のいずれか一項に記載の組成物。
- 組織修復時に予防薬として使用する、請求項1〜8のいずれか一項に記載された、臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む組成物。
- 請求項9〜16のいずれか一項に記載の組成物を含む製品であって、前記製品は、液状、粉状、噴霧状、クリーム状、ジェル状又はヒドロゲルである、製品。
- 前記組成物は、天然若しくは合成ポリマーマトリックスの担持体、パッチ又は別の医療装置によって保持される、請求項17に記載の製品。
- 請求項1〜8のいずれか一項に記載された、臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む組成物を調製するプロセスであって、該プロセスは:
a)前記UCBMNCから前記エキソソームを分離するステップ、及び
b)前記エキソソームを適当な担体に懸濁するステップを含み、
前記UCBMNCは、前記分離ステップ(a)の前に、低酸素かつウシ胎児血清(FBS)枯渇状態に曝される、プロセス。 - 前記エキソソームは、請求項5又は6のどちらかに記載された群から選択される1つ又は複数のmiRNAを濃縮される、請求項19に記載のプロセス。
- 請求項10〜16のいずれか一項に記載された、臍帯血単核細胞(UCBMNC:umbilical cord blood mononuclear cell)エキソソームを含む組成物を含む製品を調製するプロセスであって、該プロセスは:
a)請求項10〜16のいずれか一項に記載された、前記UCBMNCからの前記エキソソームを含む組成物の、b)適当な薬学上許容可能な担体との接触を促進するステップを含む、プロセス。
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US20120093885A1 (en) * | 2010-10-18 | 2012-04-19 | Northwestern University | Therapeutic vesicles |
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KR102469326B1 (ko) | 2022-11-23 |
US20200289583A1 (en) | 2020-09-17 |
CN109414459B (zh) | 2022-10-25 |
KR20180123106A (ko) | 2018-11-14 |
WO2017163132A2 (en) | 2017-09-28 |
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