JP2016513654A - 脱細胞化された臓器及び組織を伴うマイクロ粒子及び内皮細胞の使用 - Google Patents
脱細胞化された臓器及び組織を伴うマイクロ粒子及び内皮細胞の使用 Download PDFInfo
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Abstract
Description
本願は、2013年3月15日に出願された米国特許出願第61/790,118号明細書の出願日の利益を主張するものであり、その開示は参照により本明細書に援用される。
組織工学は、細胞、足場、及び可溶性介在物質の組み合わせを移植することにより、損傷又は罹患した組織及び臓器の修復又は再生を追求する、急速に成長している分野である。現在の幹細胞分化及び初代細胞培養は、一般に、二次元(2D)培養細胞条件下で達成される。このシステムは、特定の細胞集団を拡大できるものの、機能的な細胞表現型を保持し、高密度の細胞培養及び長期の初代細胞機能又は分化細胞機能を支援する能力は限定される。例えば、特定の細胞療法に必要な多数の初代細胞の利用可能性が限定されるのに対し、特定の系統に分化する能力を保持しながら幹細胞の数を大幅に拡大することは可能である。幹細胞の運命(例えば分化)のインビボ又はインビトロでの制御は、従来、主として遺伝的及び分子的な介在物質(例えば増殖因子や転写因子)に帰属している。幹細胞及び前駆細胞が分化する結果、系統又は組織に特異的な遺伝子発現を有する細胞が得られるが、分化後の細胞は、インビトロ又はインビボでの応用に必要な機能特性に欠けていることがある。
これまでの研究によれば、3Dの結合組織細胞は、2D培養とは非常に異なる挙動をする(Cukierman et al., Science, 294:1708 (2001))。例えば、平らな基質上で線維芽細胞を培養すると、インビボでは発生しない極性が誘発される。更に、3D組織由来のマトリックス内で線維芽細胞その他の細胞型を培養した場合、インビボで見られる複合体に似たインテグリン含有焦点接着複合体が数分以内に形成されるのに対し、2D培養や単純な3DのI型コラーゲンゲル又はマトリゲルでは、ごく原始的な接着複合体しか形成されない。適切な増殖因子により受容体シグナリングが活性化され、ECMを変化させる独自のECM構成要素及び因子の合成が急速(5分以内)に開始するには、このような接着複合体が必要とされる(Cukierman et al., 2001; Abbott, Nature, 424:870 (2003))。加えて、ECM培養における細胞は、組織由来のマトリックスに自己分泌増殖因子を堆積させるが、これは、標的細胞に増殖因子を適切に提示するために必要であり得るプロセスである。このような因子は、主として、2D培養における培地に分泌される。
脱細胞化は一般に、以下のステップを含む。固形臓器(例えばその血管形成構造)又は固形組織の安定化、固形臓器又は固形組織の脱細胞化、固形臓器又は固形組織の再生及び/又は中和、固形臓器の洗浄、臓器表面に残存するDNAの分解、臓器又は組織の殺菌、及び臓器の恒常性維持。
脱細胞化プロトコル(PEG)
心臓を、100U/mlのペニシリン、0.1mg/mlのストレプトマイシン、0.25μg/mLのアムホテリシンB、1000Uのヘパリン、及び2mgのアデノカルドを含有する200mlのPBSに入れて、再循環させずに洗浄する。次に、35mlのポリエチレングリコール(PEG、1g/mL)で最長30分間、手動で再循環させながら心臓を脱細胞化する。次に、500mLのPBSで最長24時間、再循環用ポンプを使用して臓器を洗浄する。この洗浄ステップを、各回少なくとも24時間かけて少なくとも2回繰り返す。手動で再循環させながら、心臓を少なくとも1時間、35mlのDNase I(70U/mL)に曝す。再び、少なくとも24時間かけて臓器を500mlのPBSで洗浄する。
心臓を、100U/mlのペニシリン、0.1mg/mLのストレプトマイシン、0.25μg/mLのアムホテリシンB、1000Uのヘパリン、及び2mgのアデノカルドを含有する200mlのPBSに入れて、少なくとも約20分間、再循環させずに洗浄する。次に、心臓を0.05%トリプシンで30分かけて脱細胞化した後、5% Triton−X及び0.1%水酸化アンモニウムを含有する500mLのPBSを約6時間灌流させる。心臓に脱イオン水を約1時間灌流させた後、PBSを12時間灌流させる。次に、再循環用ポンプを使用して、各回24時間かけて心臓を500mLのPBSで3回洗浄する。手動で再循環させながら、心臓に35mlのDNase I(70U/mL)を1時間灌流させ、再循環用ポンプを使用して、各回少なくとも約24時間かけて、500mLのPBSで心臓を2回洗浄する。
心臓を、100U/mlのペニシリン、0.1mg/mLのストレプトマイシン、0.25μg/mLのアムホテリシンB、1000Uのヘパリン、及び2mgのアデノカルドを含有する200mLのPBSに入れて、少なくとも約20分間、再循環させずに洗浄する。再循環用ポンプを使用して、心臓を、1% SDSを含有する500mLの水で少なくとも約6時間かけて脱細胞化する。次に、心臓を脱イオン水で約1時間洗浄し、PBSで約12時間洗浄する。再循環用ポンプを使用し、各回少なくとも約24時間かけて、心臓を500mLのPBSで3回洗浄する。次に、手動で再循環させながら、心臓に35mlのDNase I(70U/mL)を約1時間灌流させ、再循環用ポンプを使用して、各回少なくとも約24時間かけて、500mLのPBSで心臓を3回洗浄する。
心臓を、100U/mlのペニシリン、0.1mg/mlのストレプトマイシン、0.25μg/mLのアムホテリシンB、1000Uのヘパリン、及び2mgのアデノカルド(アデノシン)を含有する200mLのPBSに入れて、少なくとも約20分間、再循環させずに洗浄する。次に、再循環用ポンプを使用し、少なくとも6時間かけて、5% Triton X及び0.1%水酸化アンモニウムを含有する500mLの水で心臓を脱細胞化する。次に、心臓に脱イオン水を約1時間灌流させ、続いてPBSを約12時間灌流させる。再循環用ポンプを使用し、各回少なくとも約24時間かけて、500mLのPBSを3回灌流させることにより心臓を洗浄する。次に、手動で再循環させながら、心臓に35mlのDNase I(70U/mL)を約1時間灌流させ、各回約24時間かけて、500mLのPBSで心臓を3回洗浄する。
組織切片中の筋フィラメント及び核の欠落により、脱細胞化の成否を測定できる。脈管構造の保全の成否は、組織切片を埋め込む前に2%エバンスブルーを灌流させることにより評価できる。高効率な脱細胞化が観察される条件とは、最初に、脱イオンH2Oに溶解したイオン性界面活性剤(1%ドデシル硫酸ナトリウム(SDS)、約0.03M)を用いて心臓に定常冠灌流圧で順方向に灌流させてから、非イオン性界面活性剤(1% Triton X−100)を順方向に灌流させて、SDSを除去し恐らく細胞外マトリックス(ECM)タンパク質を再生させた場合である。閉鎖した毛細血管及び小血管を通過させるため、断続的に、リン酸緩衝液を逆方向に心臓に灌流させてよい。
肝臓を摘出するため、腹部正中切開により大静脈を露出させ、切開し、マウス大動脈カニューレ(Radnoti Glass、カリフォルニア州モンロビア)を用いてカニューレ処置する。肝動脈、肝静脈、及び胆管を切除し、腹部から肝臓を慎重に除去し、無菌PBS(ハイクローン、ユタ州ローガン)中に沈めて、門脈に加わる引張り力が最小になるようにする。ヘパリン処置されたPBSを15分間灌流させた後、脱イオン水に溶解した1% SDS(インビトロジェン、カリフォルニア州カールズバッド)を2〜12時間灌流させ、脱イオン水に溶解した1% Triton−X(シグマ、ミズーリ州セントルイス)を15分間灌流させる。次に、抗生物質を含有するPBS(100U/mlのペニシリン−G(Gibco、カリフォルニア州カールズバッド)、100U/mlのストレプトマイシン(Gibco、カリフォルニア州カールズバッド)、0.25μg/mlのアムホテリシンB(シグマ、ミズーリ州セントルイス))を124時間、肝臓に連続的に灌流させる。
脱細胞化した臓器又は組織を、分化した細胞(成熟細胞又は初代細胞)、幹細胞、部分的に分化した細胞(複数の細胞型を含む)のいずれかの細胞集団と接触させる。このように、接触させる細胞は、全能性細胞、多能性(pluripotent)細胞、多能性(multipotent)細胞のいずれであってもよく、拘束細胞、非拘束細胞のどちらでもよく、単一系統細胞であってよい。接触させる細胞は、未分化細胞、部分的に分化した細胞、完全に分化した細胞のいずれであってもよい(胎仔由来の細胞を含む)。細胞には、前駆細胞、前駆体細胞が含まれ、臍帯細胞と胎生幹細胞を含む「生体」由来の幹細胞が含まれる。本発明のマトリックスに有用な細胞には、胚幹細胞(米国国立衛生研究所(NIH)の定義による。例えばワールドワイドウェブのstemcells.nih.govに掲載されている用語集を参照)及びiPS細胞が含まれる。
臓器又は組織を脱細胞化及び/又は再細胞化するためのシステム(例えばバイオリアクター)は一般に、臓器又は組織にカニューレを挿入するための少なくとも1つのカニューレ処置装置と、カニューレを通じて臓器又は組織を灌流するための灌流装置と、臓器又は組織の無菌環境を維持するための手段(例えば封じ込めシステム)とを含む。カニューレ処置及び灌流は、当技術分野において周知の手法である。カニューレ処置装置は一般に、臓器又は組織の血管、導管、及び/又は腔に導入するのに適切なサイズの中空管を含む。通常は、臓器内の1つ以上の脈管、導管、及び/又は腔にカニューレが挿入される。灌流装置には、液体(例えば細胞破壊媒体)を保持する容器と、1つ以上のカニューレを介して液体を臓器内で移動させるための機構(例えばポンプ、空気圧、重力)とが含まれ得る。脱細胞化時及び/又は再細胞化時に臓器又は組織の無菌性を維持するには、当技術分野において公知の種々の手法を使用してよく、このような手法の例として、空気流の制御と濾過、及び/又は例えば抗生物質、抗真菌剤、その他の抗菌剤を用いた灌流による不要な微生物の増殖防止が挙げられる。
灌流と浸漬の比較
図1Aは、灌流により脱細胞化されたブタ肝臓の写真を示し、図1Bと図1Cは、灌流により脱細胞化されたブタ肝臓のそれぞれ血管と実質性マトリックスのSEM写真を示す。これらの写真は、灌流により脱細胞化された臓器の脈管導管及びマトリックスの完全性を示している。他方、図2は、浸漬により脱細胞化されたラット肝臓の外観図であり、この図では、低倍率(左)と高倍率(右)の双方でマトリックスのほつれが見られる。
本発明の方法において有用な代表的粒子
本発明の方法において有用な粒子として、ナノスフェア、マイクロスフェア等のナノ粒子、マイクロ粒子が挙げられ、これらの粒子は様々な生体適合性材料で形成されてよく、生体適合性材料の例として、合成材料、生物(天然)材料、改変生物材料が挙げられ、これらの材料は分解性であっても分解性でなくてもよい。ナノ粒子又はマイクロ粒子を形成できる原材料の例として、アルギン酸塩(alignate)、ポリサッカライド、コラーゲン、デキストラン、ヒアルロン酸、ガラス、セラミック、チタン等の金属、鉄心を有する粒子、PLA、PGA、PLA/PGA、単分散メラミン樹脂粒子、ポリスチレン、ナイロン、PMMA等が挙げられるが、これらに限定されない。適切なポリマー材料の例として、ポリ(エチレンオキシド)、ポリ(プロピレンオキシド)等のポリオキシド;ポリ(エチレンテレフタレート)等のポリエステル;ポリウレタン;ポリスルホン;ポリ(ジメチルシロキサン)等のポリシロキサン;ポリスルフィド;ポリアセチレン;ポリスルホン;ポリスルホンアミド;ポリカプロラクタム、ポリ(ヘキサメチレンアジパミド)等のポリアミド;ポリイミン;ポリ尿素;ポリビニルピリジン、ポリビニルピロリジノン等の複素環ポリマー;天然ゴム、ゼラチン、セルロース等の天然素材ポリマー;ポリカーボネート;ポリ酸無水物;ポリエチレン、ポリプロピレン、エチレン−プロピレンコポリマー等のポリアルケンが挙げられるが、これらに限定されない。ポリマー材料は、例えば、化学分析又は生物学的分析における粒子の有用性を高める上で望ましい化学的部分又は生物学的部分の結合部位を提供する目的で、カルボン酸塩、エステル、アミン、アルデヒド、アルコール、ハロゲン化物等の官能基を含有していてもよい。
Claims (35)
- 哺乳動物の臓器、組織、又はその一部分の、無傷の血管床を有する再内皮化細胞外マトリックス内の毛細血管内径を維持、縮小低減、又は拡大する方法であって、
前記方法は、
哺乳動物の臓器、組織、又はその一部分の、無傷の血管床を有する脱細胞化細胞外マトリックスと、内皮細胞又は内皮細胞に分化可能な幹細胞若しくは前駆細胞の集団と、を提供し、そして
ある量の前記細胞と、ある量の生体適合性マイクロ粒子を含む第1水溶液とを前記脱細胞化細胞外マトリックスに導入すること、
を含み、
前記細胞の前記量は、前記脱細胞化細胞外マトリックスの脈管構造を再内皮化するのに有効な量であり、
前記脈管構造内を循環している時の前記マイクロ粒子の前記量は、前記マイクロ粒子が無い対応する再内皮化後の脱細胞化細胞外マトリックスと比べて、再内皮化中及び再内皮化の後、前記脈管構造内の毛細血管内径の縮小を低減し、又は前記内径を拡大させる量である、方法。 - 前記マイクロ粒子は前記毛細血管床内の流れを維持する、請求項1に記載の方法。
- 前記マイクロ粒子は生分解性である、請求項1又は2に記載の方法。
- 前記マイクロ粒子は生分解性ではない、請求項1又は2に記載の方法。
- 前記マイクロ粒子は球形又は楕円形である、請求項1〜4のいずれか一項に記載の方法。
- 前記マイクロ粒子は変形可能である、請求項1〜5のいずれか一項に記載の方法。
- 前記マイクロ粒子はポリマーで形成される、請求項1〜6のいずれか一項に記載の方法。
- 前記ポリマーは天然に存在するポリマーである、請求項7に記載の方法。
- 前記マイクロ粒子は、アルギン酸塩、ポリサッカライド、コラーゲン、デキストラン、ヒアルロン酸、ガラス、セラミック、金属、ポリ乳酸(PLA)、ポリグルタミン酸(PGA)、又はPLAとPGAのコポリマー(PLA/PGA)を含む、請求項1〜6のいずれか一項に記載の方法。
- 前記ポリマーは天然に存在しないポリマーである、請求項1〜6のいずれか一項に記載の方法。
- 前記マイクロ粒子は、カルボン酸塩、エステル、アミン、アルデヒド、又はハロゲン化物を含むように改変される、請求項1〜10のいずれか一項に記載の方法。
- 前記マイクロ粒子はタンパク質と非タンパク質のポリマーで形成される、請求項1〜11のいずれか一項に記載の方法。
- 前記マイクロ粒子の平均直径は約0.5μm〜約20μmである、請求項1〜12のいずれか一項に記載の方法。
- 前記マイクロ粒子は親水性表面を含む、請求項1〜13のいずれか一項に記載の方法。
- 前記マイクロ粒子は磁性を有する、請求項1〜14のいずれか一項に記載の方法。
- 前記マイクロ粒子はリガンドを結合させる表面改変を含む、請求項1〜15のいずれか一項に記載の方法。
- 前記マイクロ粒子はハイドロゲルを含む、請求項1又は6に記載の方法。
- 前記溶液は再内皮化の後に添加される、請求項1〜17のいずれか一項に記載の方法。
- 前記第1水溶液中の前記マイクロ粒子より平均直径が少なくとも10%大きい生体適合性マイクロ粒子を含む第2水溶液を導入することを更に含む、請求項1〜18に記載の方法。
- 前記第2水溶液中の前記マイクロ粒子より平均直径が少なくとも10%大きい生体適合性マイクロ粒子を含む第3水溶液を導入することを更に含む、請求項19に記載の方法。
- 前記第1水溶液は、1μL当たり約300,〜約500,000のマイクロ粒子を含む、請求項1〜19のいずれか一項に記載の方法。
- 前記脈管構造を、前記マイクロ粒子が無い溶液で洗浄することを更に含む、請求項1〜20のいずれか一項に記載の方法。
- 前記ナノ粒子及びマイクロ粒子が無い前記溶液は、前記マイクロ粒子を分解させる薬剤を含む、請求項22に記載の方法。
- 前記ナノ粒子及びマイクロ粒子が無い前記溶液は、温度、pH、超音波、光、又は電気エネルギーを含む、前記マイクロ粒子を分解又は除去させる外部要因と同時に施される、請求項22に記載の方法。
- 前記マイクロ粒子はポリスチレンを含む、請求項1〜7、10〜11、13〜16又は18〜24のいずれか一項に記載の方法。
- 前記マイクロ粒子はポリサッカライドを含む、請求項1〜8、10〜11、13〜16又は18〜24のいずれか一項に記載の方法。
- 前記マイクロ粒子は約5〜約20ミクロンの平均直径を有する、請求項25又は26に記載の方法。
- 前記臓器は心臓、膵臓、骨、肝臓、腎臓、又は肺である、請求項1〜27のいずれか一項に記載の方法。
- 前記細胞はiPS細胞から取得される、請求項1〜28のいずれか一項に記載の方法。
- 前記集団は、注入若しくは灌流又はこれらの組み合わせにより前記マトリックスに導入される、請求項1〜29のいずれか一項に記載の方法。
- 前記集団は初代細胞を含む、請求項1〜30のいずれか一項に記載の方法。
- 前記集団は複数の異なる細胞型を含む、請求項1〜31のいずれか一項に記載の方法。
- 前記集団はヒト胚幹細胞を含む、請求項1〜32のいずれか一項に記載の方法。
- 前記細胞と、前記灌流により脱細胞化された臓器又は組織とは同種である、請求項1〜33のいずれか一項に記載の方法。
- 前記細胞と、前記灌流により脱細胞化された臓器又は組織とは異種である、請求項1〜33のいずれか一項に記載の方法。
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