JP2020092651A - 脱細胞化用界面活性剤 - Google Patents
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Abstract
Description
[1] 臓器又は組織に、炭素数8〜22の直鎖状若しくは分岐鎖状の脂肪酸又はその塩を接触させる工程を含む、該臓器又は組織を脱細胞化する方法。
[2] 前記脂肪酸又はその塩が直鎖状の飽和脂肪酸若しくは不飽和脂肪酸、又はそれらの塩を含む、[1]に記載の方法。
[3] 前記脂肪酸又はその塩がラウリン酸又はその塩を含む、[1]又は[2]に記載の方法。
[4] 前記臓器又は組織が、心臓、腎臓、肝臓、肺、膵臓、腸、筋肉、皮膚、***、食道、気管、並びにそれらの組織からなる群より選択される臓器又は組織である、[1]〜[3]のいずれかに記載の方法。
[5] 前記臓器又は組織が肺又は肺組織である、[1]〜[4]のいずれかに記載の方法。
[6] [1]〜[5]のいずれかに記載の方法により、臓器又は組織を脱細胞化する工程を含む、脱細胞化された臓器又は組織の製造方法。
[7] [6]に記載の方法で製造された脱細胞化臓器又は組織。
[8] [7]に記載の脱細胞化臓器又は組織を再細胞化する工程を含む、再細胞化された臓器又は組織の製造方法。
[9] 前記再細胞化がヒト細胞による再細胞化である、[8]に記載の方法。
[10] 炭素数8〜22の直鎖状又は分岐鎖状の脂肪酸又はその塩を含有してなる、臓器又は組織の脱細胞化剤。
本発明は、(1)臓器又は組織に、脂肪酸又はその塩を接触させる工程を含む、該臓器又は組織を脱細胞化する方法(以下「本発明の脱細胞化方法」と称することがある。)を提供する。また、本発明の脱細胞化方法を用いて、脱細胞化された臓器又は組織(以下「脱細胞化臓器等」と称することがある。)を製造する方法(以下「本発明の脱細胞化臓器等の製法」と称することがある。)を提供する。
本発明はまた、本発明の脱細胞化臓器等の製法により製造された脱細胞化臓器又は組織(以下「本発明の脱細胞化臓器等」と称することがある。)を提供する。本発明の脱細胞化臓器等は、界面活性剤としてSDSを用いた方法により製造された脱細胞化臓器等と比較して、(A)硫酸化グリコサミノグリカン(GAG)の残存量が高い、(B)少なくとも1種のその他の細胞外マトリックス(ラミニン、フィブロネクチン、コラーゲンI、コラーゲンIV)の残存量が高い、及び(C)ゲノムDNAの残存量が同程度かそれ以下である、との性質を有し得る。また、SDSを用いた方法により製造された脱細胞化臓器等と比較して、(D)VEGFの残存量が高い、及び(E)細胞を接着させた場合、該細胞の増殖能が高い、との性質を有し得る。このような性質のため、生体に移植した場合に、生体適合性が高くなり得る。
本発明はまた、本発明の脱細胞化方法により製造された臓器又は組織を再細胞化する工程を含む、臓器又は組織を再細胞化する方法、並びに該方法を用いた、再細胞化された臓器又は組織(以下「再細胞化臓器等」と称することがある。)の製造方法(以下「本発明の再細胞化臓器等の製法」と称することがある。)を提供する。
(2−1)再細胞化用細胞を含む灌流液を臓器等に灌流させる工程。
(2−2)再細胞化用細胞を含まない灌流液の灌流後、再細胞化用細胞を含む灌流液を臓器等に灌流させる工程。
(2−3)再細胞化用細胞を含まない灌流液の灌流後、灌流を停止させて再細胞化用細胞を灌流系内に導入し、培地を含む灌流液とともに臓器等に灌流させる工程。
上記再細胞化の工程は、複数回行ってもよく、この際細胞の種類を変えてもよい。
方法
1.ラット肺の採取
肺は、若い成体(3ヶ月齢)の雄のフィッシャー344ラット(Charles River、Wilmington、MA)から採取した。全ての動物実験は、長崎大学動物実験委員会の承認を得て行い、長崎大学における動物実験指針に従って行った。塩酸ケタミン(90mg/kg)、イソフルラン(3〜5%)を使用して麻酔導入を行い、気管切開して16Gカニューレを挿管後、人工呼吸管理とした。麻酔はイソフルラン(2〜3%)で維持した。ヘパリン(250U/kg)を下大静脈に穿刺注入し、胸郭を切断して肺を露出させた。肺動脈より18Gカニューレを挿入し、50 U/ml ヘパリン(Sigma)及び1 μg/mlニトロプルシドナトリウム(SNP、Fluka)を含有するPBSを肺に灌流した。灌流完了後、心臓、肺及び気管を解剖し、ひとまとめにして取り出した。
2−1.ラウリン酸カリウムを用いたラット肺の脱細胞化
新しく採取した肺組織をバイオリアクターに移し、37℃に保った。肺動脈圧を、脱細胞化プロセスを通してモニターし、20mmHg未満に保った。0.1%ラウリン酸カリウムを含むPBS又は0.15%ラウリン酸カリウムを含むPBSを脱細胞化溶液として用いた。イオン不含有PBSで30分間灌流した後、0.01%ラウリン酸カリウムを含む425 mlの脱細胞化溶液で、脈管構造を通じてさらに1〜2時間灌流した。その後0.05%ラウリン酸カリウムを含む脱細胞化溶液を同量用いて、同様に1〜2時間灌流し、ラット肺を脱細胞化した。脱細胞化肺を、425mlのイオン不含有PBSですすぎ、EDTAを含む、0.5%Triton 100mlで30分間灌流し、500mlのイオン不含有PBSで、計4回すすぎ、最後に5% ペニシリン/ストレプトマイシン(Gibco)を含む、500 mlのイオン不含有PBSですすいで滅菌することで、脱細胞化された肺(脱細胞化肺)を作製した(図1C)。この脱細胞化肺は、5% ペニシリン/ストレプトマイシンを含む、200 mlのイオン不含有PBS中に保存した。
脱細胞化溶液に含まれるラウリン酸カリウムを、ドデシル硫酸ナトリウム(SDS)に換えた脱細胞化溶液を用いて、脱細胞化工程以外は上記と同様にして脱細胞化された肺を作製した(図1B)。脱細胞化工程は、イオン不含有PBSで30分間灌流した後、0.01%SDSを含む425 mlの脱細胞化溶液で、脈管構造を通じてさらに1〜2時間灌流した。その後、0.05%SDSを含む脱細胞化溶液を同量用いて、同様に1〜2時間灌流し、最後に0.1%SDSを含む脱細胞化液を同量用いて、同様に1〜2時間灌流し、ラット肺を脱細胞化した。
SDSで脱細胞化された肺胞隔壁(図1E)は菲薄化しているが、ラウリン酸カリウムで脱細胞化された肺胞隔壁(図1F)は正常肺と同程度の厚さで微細構造が残存していた。
方法
1.走査型電子顕微鏡(SEM)解析
2%グルタルアルデヒド及び2.5%パラホルムアルデヒドを含む0.1Mカコジル酸緩衝液(EMD Biosciences、Gibbstown、NJ)を用いて、試料を室温で2時間固定し、次いでカコジル酸緩衝液ですすぎ、スライスし、エタノール勾配により脱水した。試料を、さらにヘキサメチルジシラザン中で10分間脱水し、一晩乾燥させた後、金でスパッタコーティングし、JOEL JXA-8600を用いて分析した(図1D〜Fの下図)。
4%パラホルムアルデヒドを含むPBSを用いて、試料を固定し、2%グルタルアルデヒド及び2.5%パラホルムアルデヒドを含む0.1Mカコジル酸ナトリウムで緩衝化した固定液中に室温で2時間置いた。試料を0.1Mカコジル酸ナトリウム緩衝液ですすぎ、1% 四酸化オスミウムで1時間、後固定し、次いで2%酢酸ウラニルを含むマレイン酸緩衝液(pH 5.2)でさらに1時間染色した。次に、試料をすすぎ、エタノール勾配により脱水し、エポン樹脂を浸透させ、60℃で一晩乾燥させた。硬化したブロックをLeica UltraCut UCTを用いて切断し、60nmの切片をニッケルグリッド上に収集し、2%酢酸ウラニル及びクエン酸鉛を用いて染色した。試料を、FEI Tencai Biotwin TEM上で、80kVで観察した。iTEM(オリンパス)ソフトウェア及びMorada CCDデジタルカメラを用いて、画像を撮影した(図1D〜Fの上図)。
固定、包埋された試料の脱パラフィン処置を行った後、タンパク質分解酵素処理、続いてTEバッファー(pH8.0)を使用して加熱し、賦活化処理を行った 5%BSAと 0.75%グリシンを含んだPBSを使用してブロッキング処理を行い、1時間常温で静置した。その後、抗ラミニン(abcam)、抗フィブロネクチン(abcam)、抗コラーゲンI(Novus Biologicals)、 抗コラーゲン IV(abcam)の一次抗体と4℃で一晩反応させた。標識二次抗体と5分間反応させた後、DABで発色させ、脱水、透徹、封入を行った後に画像撮影した(図4A)。
図4Aのように、免疫染色により、各種細胞外タンパク質残存が確認された。全てのタンパク質において、SDSよりラウリン酸カリウムを使用した脱細胞化法の群で強く、広範囲での染色を認めた。
方法
1.サイトカインの残存量の測定
脱細胞化肺の右下葉よりタンパク質を抽出し、Milliplex kit(Merck)を用いて、VEGFの濃度を測定した。測定はMAGPIX(登録商標)system(Merck)を使用して行い、1群あたり3個の肺について、それぞれについて3回ずつ行った。結果を図2に示す。
メーカーの説明書に従い、Quant-iT PicoGreen dsDNA assay kit(Invitrogen、Eugene、OR)を用いて、肺のDNA含有量を定量した(各群3個)。簡潔に述べると、組織試料を秤量し、凍結乾燥し、TE緩衝液で希釈し、Quant-iT PicoGreen試薬と混合した。485nmで励起して、蛍光を535nmで測定し、DNA含有量を、標準曲線を用いて定量した。結果を図3Bに示す。
3−1.硫酸化グリコサミノグリカン(GAG)の残存量の測定
コンドロイチン、デルマタン、ヘパラン及びケラタン硫酸を含む硫酸化グリコサミノグリカン(硫酸化GAG)を、Blyscan GAG assay kitを用いて定量した(各群3個)。パパインで消化した試料を、メーカーの説明書に従って測定した。簡潔に述べると、硫酸化GAGを、1,9-ジメチル-メチレンブルー色素で標識し、吸光度を650nmで測定した。結果を図3Aに示す。
抗ラミニン抗体(abcam)を使用し、免疫染色を行った(各群3個)。その後、画像解析ソフト(BZ-X Analyzer ver. BZ-H3A (Keyence))を使用し、基準信号強度以上の領域を残存部位とし、一肺胞当たりの染色領域に換算することにより、残存タンパク質の定量とした。
抗フィブロネクチン抗体(abcam)を使用し、免疫染色を行った(各群3個)。その後、画像解析ソフト(BZ-X Analyzer ver. BZ-H3A (Keyence))を使用し、基準信号強度以上の領域を残存部位とし、一肺胞当たりの染色領域に換算することにより、残存タンパク質の定量とした。
抗コラーゲンI抗体(Novus Biologicals)、抗コラーゲンIV(abcam)を使用し、免疫染色を行った(各群3個)。その後、画像解析ソフト(BZ-X Analyzer ver. BZ-H3A (Keyence))を使用し、基準信号強度以上の領域を残存部位とし、一肺胞当たりの染色領域に換算することにより、残存タンパク質の定量とした。
全てのタンパク質(ラミニン、フィブロネクチン、コラーゲンI、コラーゲンIV)において、有意差をもってSDS脱細胞化群よりラウリン酸カリウム脱細胞化群で残存タンパク質量が多かった(図4B)。
方法
1−1.脱細胞化肺の再細胞化
実施例1で作製した脱細胞化肺を培地ですすぎ、組織培養インキュベーターに移し、37℃、5%CO2の条件で培養した。新生児の上皮細胞を、約1000万個/ mlの濃縮細胞懸濁液として、気道区画に導入した。プレプレーティング工程なしで、単離直後に上皮細胞を播種した。各肺には、典型的には1億個の肺胞上皮細胞を播種し、細胞懸濁液で完全に膨張させた。細胞接着を可能にするために一晩静置培養した後、肺を、脈管構造を介して1〜4mL/minで灌流するか、又は気道を介して、10ml/minで陰圧液体呼吸を行った。肺の微小血管内皮細胞を、60cmH2Oで肺動脈、肺静脈を介して、約60万個の脂肪幹細胞と約3000万個の内皮細胞を脱細胞化肺へ播種した。播種した細胞は陰圧液体呼吸管理のもと、10%FBS及び抗生物質を含むDMEM中で、肺循環を維持しながら培養した。培養期間は、通常4〜8日間であった。
培養器内での細胞増殖に対する脱細胞化骨格の影響を観察する目的で、IncuCyteTM ZOOM Live-Cell イメージングシステム (Essen Bioscience, Ann Arbor, Mich.)を使用し、血管内皮と脂肪幹細胞の増殖状況を観察した。SDS又はラウリン酸カリウムにより作製した脱細胞骨格をそれぞれ粉砕し培地と混和した。1)培地のみ、2)培地とSDS処理した脱細胞骨格粉末、3)培地とラウリン酸カリウム処理した脱細胞骨格粉末、の三種類の培地で血管内皮細胞、脂肪幹細胞それぞれを培養し、増殖状況を72時間の経過で観察し、血管内皮と脂肪幹細胞の増殖率を比較した(各群3個)。
結果を図5に示す。血管内皮細胞、脂肪幹細胞ともにラウリン酸カリウム群、SDS群、培地群の順番に細胞の増殖が良かった。血管内皮細胞で培地環境による増殖速度の差が顕著であった。
方法
1.ヘマトキシリン・エオシン染色及び免疫染色
サンプルを10%ホルマリン中で4時間固定し、脱水し、パラフィンに包埋し、5μmの切片とした後、ヘマトキシリン・エオシン(H&E)染色を施行した。免疫染色のために、試料を脱パラフィン化し、再水和し、0.2%Triton X-100を含むPBS中で15分間すすいだ。抗原回復を、0.01Mクエン酸(pH6.0)を用いて70℃、20分間で行った。次いで、5%BSA及び0.75%グリシンを含むPBSで、切片を室温で1時間ブロッキングした。一次抗体を、ブロッキング緩衝液中で表1に示す濃度で、4℃で一晩アプライし、続いて室温で1時間、1:200希釈で二次抗体をアプライした。二次抗体として、AlexaFluor 594ロバ抗マウス抗体(life thchnologies)、及びAlexaFluor 488ロバ抗ウサギ抗体(life thchnologies)を用いた。スライドに、DAPIを含む封入剤(Vector Labs)を用いて封入し、画像をZeiss Axiovert 200M倒立蛍光顕微鏡を用いて取得した。
ラウリン酸カリウムを使用した群の方が、SDS群より肺の末梢胸膜下まで細胞が均等に生着しており、細胞の凝集も少ない。1肺胞当たりの細胞数で比較しても(各群3個)、血管内皮細胞が有意差をもって、多く生着していることがわかる。(図7,8)
方法
同一遺伝子の3ヶ月齢のオスFischer 344ラットを、肺移植のレシピエント動物として使用した。実験は、長崎大学における動物実験指針に従って実施した。レシピエント動物を麻酔し、挿管し、100%酸素の空気を送った。イソフルランの吸入により麻酔を維持し、動物をヘパリン(100 U/kg)で抗凝固剤処置した。左肺移植を、以下の標準的なげっ歯類の外科的技術により行った。簡潔に述べると、左側の開胸術を行い、左肺門を切開して左肺の動脈、静脈及び気管支を露出させた。レシピエントの生来の(native)左肺を結紮して除去した。左側の再細胞化肺を切開し、左肺の動脈、静脈を、カフ法を用いてレシピエントに吻合した。肺静脈、肺動脈の順番にデクランプし、30分間経過を観察し、肺循環が維持できているか、また肺胞出血の有無で再細胞肺血管の脆弱性の評価をおこなった。
PL群(ラウリン酸カリウム投与群)において、肺循環を確認することができたが、SDS群でははっきりとしなかった(図9)。肺血管構造の脆弱性から、肺胞出血を両群ともに認めたが、SDS群でその傾向はより顕著であった(図9)。この原因として、PL群の方が、血管内皮細胞が血管内腔を広範囲で均一に被覆しており、それもあって血栓形成性が低かったためと推察される。
Claims (10)
- 臓器又は組織に、炭素数8〜22の直鎖状若しくは分岐鎖状の脂肪酸又はその塩を接触させる工程を含む、該臓器又は組織を脱細胞化する方法。
- 前記脂肪酸又はその塩が直鎖状の飽和脂肪酸若しくは不飽和脂肪酸、又はそれらの塩を含む、請求項1に記載の方法。
- 前記脂肪酸又はその塩がラウリン酸又はその塩を含む、請求項1又は2に記載の方法。
- 前記臓器又は組織が、心臓、腎臓、肝臓、肺、膵臓、腸、筋肉、皮膚、***、食道、気管、並びにそれらの組織からなる群より選択される臓器又は組織である、請求項1〜3のいずれか1項に記載の方法。
- 前記臓器又は組織が肺又は肺組織である、請求項1〜4のいずれか1項に記載の方法。
- 請求項1〜5のいずれか1項に記載の方法により、臓器又は組織を脱細胞化する工程を含む、脱細胞化された臓器又は組織の製造方法。
- 請求項6に記載の方法で製造された脱細胞化臓器又は組織。
- 請求項7に記載の脱細胞化臓器又は組織を再細胞化する工程を含む、再細胞化された臓器又は組織の製造方法。
- 前記再細胞化がヒト細胞による再細胞化である、請求項8に記載の方法。
- 炭素数8〜22の直鎖状又は分岐鎖状の脂肪酸又はその塩を含有してなる、臓器又は組織の脱細胞化剤。
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