JP2021522824A - 間葉系間質細胞エキソソーム処置単球およびそれらの使用 - Google Patents
間葉系間質細胞エキソソーム処置単球およびそれらの使用 Download PDFInfo
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Abstract
Description
本出願は、2018年5月9日に出願され、「間葉系間質細胞エキソソーム処置単球およびそれらの使用」と題された米国仮出願第62/669324号について35USC§119(e)の下で利益を主張し、その内容全体は参照により本明細書に組み込まれる。
特発性肺線維症(IPF)は、100,000人年あたり0.5から27.9の有病率を伴う、慢性進行性呼吸器疾患である。この疾患の根底にある機序の完全な理解の欠如は、成功した治療法の欠乏に貢献したかもしれない。新しく承認された2つの薬にもかかわらず、IPFは5年生存率が10%未満と致死的のままである。
本明細書では、間葉系幹細胞(MSC)エキソソームの単回静脈内(IV)用量が、少なくとも部分的に、骨髄中の単球表現型の調節および肺胞上皮細胞(AEC)アポトーシスの低減を通じて、ブレオマイシン誘発性肺線維症を元に戻すことが示された。さらに、MSCエキソソームで処置された単球は、肺線維症を有する対象に投与された場合、この疾患に対して治療的に有効であった。
添付の図面は、縮尺どおりに描かれることを意図したものではない。図面において、様々な図に図示される同一またはほぼ同一の各構成要素は、同様の数字で表されている。明確にするために、すべての構成要素がすべての図面において標識されているわけではない。特許または出願ファイルは、カラーで実行された少なくとも1つの図面を含有する。カラー図面(単数または複数)を伴うこの特許または特許出願公報のコピーは、請求および必要な費用の支払いに応じて、米国特許庁によって提供されるだろう。図面中:
本開示は、間葉系間質細胞(本明細書において「間葉系幹細胞」または「MSC」としても互換的に称される)エキソソーム(本明細書において「Mex」とも称される)が、対象へ投与(例として、全身的に)される場合、骨髄中の単球表現型を調整し得、炎症促進性単球の代わりに、調節性の単球の、より大きな亜集団を生じるという知見に、少なくとも部分的に基づく。さらに、in vitroにおいてMSCエキソソームで処置された単球(例として、骨髄由来単球)は、肺線維症を有する対象へ投与される場合、線維性肺における治療効果を有する。
特発性肺線維症(IPF)は、慢性進行性呼吸器疾患であり、その根底にある機序は、不完全に理解されており、今のところ有効な処置を欠く。肺線維症の予防における間葉系間質細胞(MSC)処置での有望な結果に拘わらず、細胞治療の限界は、無細胞治療を非常に望ましいものにし続ける。IPF以外の前臨床モデルにおいて、MSC細胞外ベシクル(EV)またはより具体的には、MSCセクレトームから単離されたエキソソーム(MEx)は、治療用ベクターとして、作用することが示されてきた。IPFにおけるMExの効果、およびそれらの作用機序(MOA)は、未知である。
方法:ヒト骨髄MSCから単離されたエキソソーム(MEx)は、気管内ブレオマイシンの滴下後0または7日に、成体C57BL/6マウスへ注入された。肺および骨髄由来の単球(BMDMo)は、組織学的、遺伝子発現またはサイトメトリー分析のために、7日および14日目に採取された。
ブレオマイシン曝露と同時またはその7日後のMEx処置は、肺線維症およびコラーゲン沈着を実質的に予防した。MEx処置は、炎症を鈍化させ、肺中の古典的(Ly6C高CCR−2+ve)単球を低減させた。MExの上流効果の調査により、MExが、骨髄において、古典的単球表現型から調節性単球表現型への移行を誘発したことを明らかにした。興味深いことに、MExで前処置されたBMDMoの養子移入は、線維症を軽減するのに十分だった。加えて、MExは、肺胞上皮細胞アポトーシスを防いだ。
特発性肺線維症(IPF)は、100,000人年あたり0.5から27.9の有病率を伴う慢性進行性呼吸器疾患である(1、2)。この疾患の根底にある機序の完全な理解の欠如は、成功した治療法の欠乏に貢献したかもしれない。新しく承認された2つの薬にもかかわらず、IPFは5年生存率が10%未満と致死的のままである(3〜6)。薬理学的治療に加えて、間葉系間質細胞(MSC)などの細胞ベースの治療もまた検討されてきた(7〜9)。肺線維症の予防におけるMSC療法の有望な結果にもかかわらず、有害な免疫反応、生存の課題、予想外の生着、MSCから線維芽細胞への分化の可能性などの制限は、それにもかかわらず、無細胞療法を非常に望ましいものにし続けている(8〜10)。
動物モデル、組織学およびサイトメトリー
すべてのマウスは病原体フリーの施設で飼育され、世話をされた。すべての動物実験は、ボストンチルドレンズホスピタルアニマルコアアンドユース委員会(Boston Children’s Hospital Animal Core and Use Committee)によって承認された。10〜14週齢のC57BL/6マウス(Charles Laboratories)は、イソフルランで麻酔され、0日目に、50μlの0.9%生理食塩水(NS)中の3U/kgの用量のブレオマイシンスルファートまたはNS単独で気管内注射された。マウスは、200μlのボーラス用量のMEx(5×106のMSCによって生成されたEV、処置群)、ヒト皮膚線維芽細胞由来のエキソソーム(FEx)を投与された;(5×106のヒト皮膚線維芽細胞によって生成されたEV、最初の対照群)またはOptiPrep(商標)(イオジキサノール、IDX、1:9希釈);(ビヒクル、第2対照群)または0日目および7日目の尾静脈注射を介するNS。
エキソソームの単離、精製、および特徴付けは、これまでに記載されたとおり、OptiPrep(商標)(イオジキサノール;IDX)クッション密度浮力を用いて実行された(11)。手短に言えば、骨髄MSCまたはヒト皮膚線維芽細胞(HDF)からの濃縮馴化培地は、IDXクッションの上に浮かせられ、4℃で100,000xgで3.5時間遠心分離した。
異なるグループ間のデータは、GraphPad Prism(v6.0;GraphPad、CA、US)でのFisherのLSDテスト事後分析を伴うANOVAを用いて比較された。フローサイトメトリーデータ分析は、FlowJoソフトウェアv10.2(TreeStar、OR、US)を用いて実行された。mRNAレベルはRT−qPCRによって査定され、内因性対照と比較して表された。統計分析のために、ΔCTが用いられた。データは、平均±平均の標準誤差(SEM)として提供される。特に明記しない限り、有意性は、p<0.05閾値に関して決定された。各群で最低5匹の動物が用いられ、5%のαレベルで>90%のパワーを生み出した。
初期炎症時のMEx投与は、肺線維症を予防する
十分に確立されたブレオマイシン肺傷害モデルが、炎症性段階(0日目から8日目)とそれに続く線維化段階(9日目から32日目)によって特徴づけられた肺線維症のために、用いられた(24)。
炎症の後の段階でのMExの効果を査定するために、マウスは、ブレオマイシン投与の7日後に、MExで注射された(図7A)。予防療法実験(0日目のMEx注射)で観察されたものと同様に、炎症段階でのMExの投与は、線維症スコアの改善およびコラーゲン沈着における統計的に有意な低減をもたらした(図7B、7Cおよび7D)。したがって、MEx治療は、炎症の最後に投与された場合であっても、線維症を改善する。
ブレオマイシン肺傷害モデルにおけるMExの作用機序を調査するために、予防療法実験(0日目のMEx注射)が実行された。
ブレオマイシン障害を伴うおよびMEx治療後の免疫細胞集団の動的変化を調査するために、ブレオマイシンの投与後7日目または14日目に、全肺におけるサイトメトリー分析が実施された。AM数(CD45+veCD11b−veCD11c+ve細胞)における減少は、7日目にブレオマイシン処置マウスで見られた(図3A)。これは、Ly6C高古典的または炎症性単球(CD45+veCD11b+veMHCII−veLy6C高CCR−2+ve細胞)の数における増加と関連していた(図3B)。しかしながら、14日目に、ブレオマイシン滴下後のAMの割合は増加した(図3C)一方で、古典的単球の数は低減させられた(図3D)。MEx治療は、7日目および14日目の両方で、AMおよび単球集団の浸潤を対照群と同様のレベルまで回復させた。これらの結果は、肺傷害後、MExがAMと動員された単球集団との間の恒常性バランスを、対照マウスに見られるレベルおよび表現型と同様に、回復し得ることを示す。
ブレオマイシン曝露マウスの肺における増加した炎症性単球の所見、およびMEx治療後の正常レベルへの回復に続いて、単球の発達が骨髄(BM)において起こるという事実を考慮して(25)、MExが、BMにおける単球表現型を変更することにより免疫調整的効果を発揮してもよいことが提案された。この問題に答えるために、MExの可能性が最初に調査され、BMに浸透させた。色素標識EVは、対照マウスに静脈内注射され、注射後2、4、8および24時間で動物はサクリファイスされた。BMサイトスピンのDapi染色は、注射後8時間までのBMにおけるEVの存在を明らかにした(図9、画像は注射後2時間を表し、さらなる時点は示されていない)。
MEx治療後のBM調節性単球における増加を考慮すると、骨髄単球におけるMExの免疫調整的効果は、線維症を予防するのに十分であるかもしれず、肺のさらなる変化は、変更されたBM単球亜集団の結果であるとの仮説が立てられた。
肺胞上皮細胞アポトーシス(AEC)は、損傷した肺における線維化促進性シグナルのためのトリガーとして説明されてきた(26、27)。MExが肺傷害から保護するさらなる機序を探索するために、ブレオマイシン傷害後のアポトーシスの低減におけるMExの潜在的な役割が調査された。肺アポトーシスの程度は、対照、ブレオマイシン、およびMEx処置マウスからの肺切片におけるTunel染色を用いて、査定された。ブレオマイシン曝露群においてアポトーシスの増加が見られた一方で、アポトーシスレベルはブレオ+MExおよび対照マウスで同様であった(図5A、5B)。加えて、14日目に、全肺においてアネキシンV/PI染色が実施された。対照およびMEx処置マウスと比較して、ブレオマイシンに存在するアポトーシス(アネキシンV+/PI−)における増加が再びあった(図5C)。
この研究は、ブレオマイシン誘発性肺傷害の炎症期の導入または最後のいずれかでのヒト骨髄由来MExの単回IV用量が、線維症を著しく予防し、肺構造を回復させることを示す。MEx処置は、肺における炎症を鈍化させただけでなく、AMを回復させ、単球数を対照マウスと同様のレベルまでに動員した。先述の所見および単球の発達が骨髄(BM)で生じるという事実は、BM骨髄の特性を調査することによって、MExの上流の免疫調整的効果の調査につながった。BMにおける標識MExの可視化に加えて、BM骨髄性細胞のフローサイトメトリー分析は、MEx処置マウス中で、炎症誘発性(Ly6C高CCR−2+ve)から調節性(Ly6C低CCR−2−ve)表現型への単球亜集団におけるシフトを、明らかにした。
細胞の単離および培養
ヒト骨髄間葉系幹細胞(BMSC)は、RoosterBio(RoosterBio、MD、US)から得られた。ヒト包皮(真皮)線維芽細胞(HDF)は、組織外植片法によって樹立された(36)。BMSCおよびHDFは、培養および拡張され、ならびにさらに、これまでに記載されたとおり、さらに特徴付けられた(37)。A549肺胞上皮細胞(ATCC)は、F−12K培地(Thermo Fisher Scientific, Inc.、Waltham、MA)で培養された。
5〜10μlの細胞外小胞(EV)調製物のアリコートは、フォルムバール/カーボンコーティンググリッド(Electron Microscopy Sciences、PA、US)に15秒間吸着させられた。試料は、Whatman Grade 1濾紙(Sigma)での余分な液体の除去後、2%酢酸ウラニルで染色された。EVは、次いで、JEOL 1200EX透過型電子顕微鏡(TEM)で観察され、AMT 2k CCDカメラで画像が記録された。
エキソソームのサイズおよび濃度の分布は、これまでに記載されたとおり(37)、ナノ粒子追跡分析(NTA、NanoSight LM10 system、Malvern instruments、MA、US)を用いて決定された。
エキソソーム調製物中のタンパク質は、4〜20%ポリアクリルアミドゲル(Bio- Rad、Hercules、CA)で分離され、0.45μmPVDF膜(Millipore、MA、US)への転写が続いた。ウサギポリクローナル抗フロチリン−1および抗CD63抗体(Santa Cruz Biotech、CA、US)、およびマウスモノクローナル抗Alix抗体(Santa Cruz Biotech、CA、US)は、製造元が推奨する希釈に基づいて用いられた。
EV調製物は、5×106細胞当量に相当するようにPBSで希釈された。この用量は、対応するNTAおよびタンパク質濃度で、新生マウスにおける以前の用量計算に基づいて推定された(37)。
肺組織切片は、キシレンで脱パラフィンされ、再水和された。組織スライドは、10mMクエン酸バッファーで処置され、血清およびBSAで20分間ブロックされた。試料は、次いで、示された一次抗体であるアルギナーゼ1(Santa Cruz Biotech、CA、US);CD206(Santa Cruz Biotech、CA、US)とともに40℃で一晩インキュベートされ、次いで、二次抗体(Life technologies、MA、US)とともに20分間さらにインキュベートされ、DAPIで10分間核染色が続いた。
左肺は、製造元のプロトコル(Biocolor, Life Science Assays)に従ってコラーゲン定量化に用いられた。手短に言えば、左肺ホモジネートは、0.6%ペプシンを伴う5mlの0.5M酢酸中で4°で終夜振とうされた。1mlの色素試薬は、100μlの透明な上清に加えられ、試料は30分間ボルテックスされた。残りのペレットは、酸性塩洗浄バッファーで洗浄され、未結合のコラーゲンを除去し、pHはアルカリ化バッファーで正規化された。吸光度は、マイクロプレートリーダーにおける550nmの波長で測定された。測定されたコラーゲン含量は、標準曲線と比較され、左肺ホモジネートのmg/mlとして表された。
肺マクロファージ集団は、これまでに記載されたように(38)、フローサイトメトリーによって査定された。肺は、7日目および14日目に採取された。左肺は、小片に切断され、RPMI−1640(Invitrogen、CA、US)、コラゲナーゼIV(1.6mg/ml);およびDNAse1(50ユニット/ml)(両者ともWorthington Biochemical Corp、NJ、USより)からなる消化バッファーの5mlにおいて消化された。肺は37℃で30分間振とうされ、赤血球(RBC)はRBC溶解バッファー(Roche、IN、US)を用いて溶解された。ホモジナイズされた肺は、40μm細胞漉し器(Corning、MA、US)に通され、単一細胞懸濁液を得た。
全RNAは、TRIZOL(登録商標)(Thermo Fisher Scientific, Inc.、Waltham、MA)を製造元の指示に従って用いて、左肺から抽出された。Ccl2、Il6、TGF−β、およびアルギナーゼ1を含むPCR反応で用いられたTaqMan(登録商標)プライマーは、Invitrogenから得られた。
アネキシンV染色キット(Sigma-Aldrich、MO、US)は、全肺におけるアポトーシスを査定するために用いられた。単細胞懸濁液は、上に記載のとおり左肺から得られた。細胞は、次いで、1x結合バッファーに浮遊され、FITC結合アネキシンVおよびPI抗体で10分間染色され、即時にフローサイトメトリーによって査定された。
BMDMoは、大腿骨および脛骨を洗い流し、かつ細胞を、10%FBSで補充され、30%v/vL929−馴化培地(マクロファージコロニー刺激因子;M−CSFの供給源として)を含有するダルベッコ改変イーグル培地(DMEM)で3日間培養することにより、6〜8週齢のFVBから単離された。各プレートは、1日目および2日目にのみ、1x106のMSCまたは培地のみから生成されたMExで処置された。細胞は、3日目に採取され、PBSで2回洗浄された後、製造元のプロトコル(Life technologies)に従ってDilで染色された。BMDMoは、次いで、ブレオマイシンの気管内注入後0日目および3日目に、1:1の比率で尾静脈注射を介して投与された(1匹のマウスから単離されたBMDMoは、実験マウスに注射された)。
6から8週のFVBマウスは、i.p.ペントバルビタール注射によって安楽死させられた。気管の前壁は、21ゲージの針でカニューレ挿入され、紐で固定された。
EVは、骨髄MSCの濃縮馴化培地から100,000gで70分間ペレット化された。EVタンパク質濃度は、マイクロBCAタンパク質アッセイキット(Thermo Fisher Scientific, Inc.、Waltham、MA)を用いて決定された。EVは、製造プロトコルに従ってExoGlow-Membrane(商標)EV標識化キット(System biosciences、CA、USA)によって標識された。手短に言えば、50〜100μgのEVは、反応バッファーと標識化色素との混合物に添加され、室温で30分間インキュベートされた。フリーの非標識色素は、100,000gで70分間の2回目の超遠心分離の後、除去された。1×106のMSCの当量によって生成されたEVは、200μlのPBSにおいて希釈され、尾静脈注射を用いてC57BL/6マウスへ注射された。200μlの染色されたEVフリーSN、または希釈フリー色素は、対照として用いられた。
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当業者は、本明細書に記載の態様の多くの均等物を認識する、または日常的な実験のみを用いて確認することができるであろう。本開示の範囲は、上記の説明に限定されるものではなく、むしろ、添付の特許請求の範囲で表されるものである。
Claims (56)
- 単球表現型を調節する方法であって、単球を、単離された間葉系幹細胞(MSC)エキソソームと接触させることを含む、前記方法。
- 単球が、骨髄からのものである、請求項1に記載の方法。
- 単離されたMSCエキソソームが、MSC馴化培地から単離される、請求項1または請求項2に記載の方法。
- MSCが、ホウォートンゼリー、骨髄、または脂肪組織からのものである、請求項1〜3のいずれか一項に記載の方法。
- 単離されたMSCエキソソームが、実質的にタンパク質夾雑物フリーである、請求項1〜4のいずれか一項に記載の方法。
- 単離されたMSCエキソソームが、約50〜150nmの直径を有する、請求項1〜5のいずれか一項に記載の方法。
- 接触が、in vitroである、請求項1〜6のいずれか一項に記載の方法。
- 接触が、ex vivoである、請求項1〜6のいずれか一項に記載の方法。
- 接触が、in vivoである、請求項1〜6のいずれか一項に記載の方法。
- 接触が、少なくとも2時間である、請求項1〜9のいずれか一項に記載の方法。
- 単球が、単離されたMSCエキソソームと接触される前に炎症促進性であり、および、単離されたMSCエキソソームと接触された後に調節性である、請求項1〜10のいずれか一項に記載の方法。
- 線維性疾患を処置する方法であって、有効量の単球を、これを必要とする対象へ投与することを含み、ここで単球は、投与される前に、単離された間葉系幹細胞(MSC)エキソソームで処置される、前記方法。
- 自己免疫疾患を処置する方法であって、有効量の単球を、これを必要とする対象へ投与することを含み、ここで単球は、投与される前に、単離された間葉系幹細胞(MSC)エキソソームで処置される、前記方法。
- 単球をMSCエキソソームで処置する前に、単球を単離することをさらに含む、請求項12または請求項13に記載の方法。
- 単球が、対象から単離される、請求項14に記載の方法。
- 単球が、対象の骨髄から単離される、請求項15に記載の方法。
- 単球が、対象へ投与される前に、MSCエキソソームで少なくとも2時間処置される、請求項12〜16のいずれか一項に記載の方法。
- 単球が、全身的に投与される、請求項12〜17のいずれか一項に記載の方法。
- 単球が、静脈内注入を介して投与される、請求項18に記載の方法.
- 単球が、気管内または鼻腔内に投与される、請求項12〜18のいずれか一項に記載の方法。
- 単球が、対象へ一度投与される、請求項12〜20のいずれか一項に記載の方法。
- 単球が、対象へ複数回投与される、請求項12〜21のいずれか一項に記載の方法。
- 有効量の第二の剤を、対象へ投与することをさらに含む、請求項12〜22のいずれか一項に記載の方法。
- 第二の剤が、単離されたMCSエキソソームである、請求項23に記載の方法。
- 第二の剤が、ニンテダニブ、ピルフェニドン、抗線維化剤、免疫抑制薬、および/または抗炎症剤である、請求項23に記載の方法。
- 線維性疾患が:全身性硬化症;肝臓線維症、心臓線維症、腎臓線維症、および骨髄線維症からなる群から選択される、請求項12および14〜25のいずれか一項に記載の方法。
- 線維性疾患が、肺線維症である、請求項26に記載の方法。
- 肺線維症が、特発性肺線維症(IPF)である、請求項27に記載の方法。
- 単球が、線維性疾患に関連する炎症を低減させる、請求項12に記載のおよび12〜28のいずれか一項に記載の方法。
- 単球が、線維性疾患に関連するアポトーシスを低減させる、請求項12に記載のおよび12〜29のいずれか一項に記載の方法。
- 対象が、哺乳動物である、請求項12〜30のいずれか一項に記載の方法。
- 対象が、ヒト対象である請求項31に記載の方法。
- ヒトが、新生児、幼児、または成人である、請求項32に記載の方法。
- ヒト対象が、4週齢未満である、請求項32に記載の方法。
- ヒト対象が、4週齢から3歳である、請求項32に記載の方法。
- ヒト対象が、3〜18歳である、請求項32に記載の方法。
- ヒト対象が、成人である、請求項32に記載の方法。
- ヒト対象が、低体重で生まれる、請求項32〜37のいずれか一項に記載の方法。
- ヒト対象が、在胎37週より前に生まれた、請求項38に記載の方法。
- ヒト対象が、在胎26週より前に生まれた、請求項38に記載の方法。
- 対象が、齧歯類の動物である、請求項31に記載の方法。
- 齧歯類の動物が、マウスまたはラットである、請求項41に記載の方法。
- 単球が、単離されたMSCエキソソームで処置される前に炎症促進性であり、および、単離されたMSCエキソソームで処置された後に調節性である、請求項12〜42のいずれか一項に記載の方法。
- 単離された間葉系幹細胞(MSC)エキソソームで処置された、単球。
- 単球が、骨髄からのものである、請求項44に記載の単球。
- 単離されたMSCエキソソームが、MSC馴化培地から単離される、請求項44または請求項45に記載の単球。
- MSCが、ホウォートンゼリーまたは骨髄もしくは脂肪組織からのものである、請求項44〜46のいずれか一項に記載の単球。
- 単球が、単離されたMSCエキソソームで処置される前に炎症促進性であり、および、単離されたMSCエキソソームで処置された後に調節性である、請求項44〜47のいずれか一項に記載の単球。
- 請求項42〜48のいずれか一項に記載の単球を含む、組成物。
- 第二の剤をさらに含む、請求項49に記載の組成物。
- 医薬組成物である、請求項49または請求項50に記載の組成物。
- 薬学的に許容し得る担体をさらに含む、請求項49〜51のいずれか一項に記載の組成物。
- 請求項44〜48のいずれか一項に記載の単球または請求項49〜52のいずれか一項に記載の組成物の、線維性疾患を処置するための使用。
- 線維性疾患を処置するための医薬の製造における使用のための、請求項44〜48のいずれか一項に記載の単球または請求項49〜52のいずれか一項に記載の組成物。
- 請求項44〜48のいずれか一項に記載の単球または請求項49〜52のいずれか一項に記載の組成物の、自己免疫疾患を処置するための使用。
- 自己免疫疾患を処置するための医薬の製造における使用のための、請求項44〜48のいずれか一項に記載の単球または請求項49〜52のいずれか一項に記載の組成物。
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KR20220124817A (ko) | 2017-08-07 | 2022-09-14 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | 안전한 세포 치료제를 생성하기 위한 플랫폼 |
JP7425092B2 (ja) * | 2020-01-15 | 2024-01-30 | 富士フイルム株式会社 | 抗線維化剤、及び抗線維化作用を有する細胞外小胞の製造方法 |
US20230248773A1 (en) | 2020-07-09 | 2023-08-10 | Exo Biologics Sa | Extracellular Vesicles and Compositions Thereof |
WO2022087483A1 (en) * | 2020-10-22 | 2022-04-28 | Wisconsin Alumni Research Foundation | Use of toll-like receptor 4 agonists to treat inflammation and tissue injury |
CN115475250B (zh) * | 2022-05-26 | 2024-03-26 | 南京鼓楼医院 | 一种靶向肝星状细胞并抑制其激活的载药外泌体及其制备和应用 |
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 192, no. 3, JPN6023011846, 2015, pages 324 - 336, ISSN: 0005020646 * |
STEM CELLS, vol. 35, JPN6023011845, 2017, pages 316 - 324, ISSN: 0005020647 * |
WORLD J. GASTROENTEROL., vol. 18, JPN6023011844, 2012, pages 1048 - 1058, ISSN: 0005020648 * |
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EP3790560A4 (en) | 2022-03-30 |
CN112469423A (zh) | 2021-03-09 |
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EP3790560A1 (en) | 2021-03-17 |
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