JP4897199B2 - 新血管新生の誘導による内因性の心筋組織の再生 - Google Patents
新血管新生の誘導による内因性の心筋組織の再生 Download PDFInfo
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Description
心筋梗塞の治癒は、梗塞組織の減少に応答してポンプ機能を増大するために、生存可能な筋細胞が梗塞外周部で代償性肥大を受ける必要があることにより、複雑である(1、2)。これは、肥大した筋細胞のアポトーシスによる減少、初期の梗塞領域の膨張、進行性のコラーゲン置換、および心不全によって特徴づけられる心臓再造形と呼ばれるプロセスを開始する(3-6)。本発明者らは、最近、内因性の毛細管ネットワークは、細胞の生存のために必要とされる代償性の灌流の増加をもたらすことができないので、肥大した心臓筋細胞がアポトーシスを受けるという仮説を提唱した(7)。
本発明は、心筋細胞の減少を含む被検体の心臓の障害を治療する方法であって、前記被検体の心臓内で心筋細胞増殖を引き起こすために有効な薬剤の量を被検体に投与することを含み、これにより前記障害を治療する方法を提供する。
(a)心筋細胞のペルオキシレドキシンをコードするmRNAの量を定量することと;
(b)心筋細胞のビタミンD3アップレギュレートタンパク質-1をコードするmRNAの量を定量することと;および、
(c)ペルオキシレドキシンをコードするmRNAの量:ビタミンD3アップレギュレートタンパク質-1のmRNAをコードする量の比を決定することとを含み、被検体において、低い比は、アポトーシスに対して心筋細胞が高い感受性であることを示し、高い比は、アポトーシスに対して心筋細胞が低い感受性であることを示す方法を提供する。
本明細書に使用されるものとして、「VEGF」は、血管内皮成長因子として定義される。「VEGF-R」は、血管内皮増殖因子受容体として定義される。「FGF」は、線維芽細胞成長因子として定義される。「IGF」は、インスリン様成長因子として定義される。「SCF」は、幹細胞因子として定義される。「G-CSF」は、顆粒球コロニー刺激因子として定義される。「M-CSF」は、マクロファージコロニー刺激因子として定義される。「GM-CSF」は、顆粒球マクロファージコロニー刺激因子として定義される。「MCP」は、単球化学誘引物質タンパク質として定義される。
1つの態様において、第2の薬剤は、特にビタミンD3アップレギュレートタンパク質-1(VDUP-1)mRNAの翻訳を阻害するアンチセンス・オリゴヌクレオチドである。
(a)心筋細胞のペルオキシレドキシンをコードするmRNAの量を定量することと;
(b)心筋細胞のビタミンD3アップレギュレートタンパク質-1をコードするmRNAの量を定量することと;および、
(c)ペルオキシレドキシンをコードするmRNAの量:ビタミンD3アップレギュレートタンパク質-1のmRNAをコードする量の比を決定することとを含み、被検体において、低い比は、アポトーシスに対して心筋細胞が高い感受性であることを示し、高い比は、アポトーシスに対して心筋細胞が低い感受性であることを示す方法を提供する。
(a)心筋細胞のペルオキシレドキシンタンパク質の発現を定量することと;
(b)心筋細胞のビタミンD3アップレギュレートのタンパク質-1発現を定量することと;および、
(c)ペルオキシレドキシンタンパク質の発現:ビタミンD3アップレギュレートタンパク質-1の発現の比を決定することとを含み、被検体において、低い比は、アポトーシスに対して心筋細胞が高い感受性であることを示し、高い比は、アポトーシスに対して心筋細胞が低い感受性であることを示す方法を提供する。
CXCケモカインは、内皮前駆体細胞の心臓への遊走を調節する。
本発明者らは、LAD結紮したヌードラットのモデルにおける心筋梗塞を使用して、ヒト内皮前駆細胞の虚血組織への走化性およびその後の血管形成の誘導を媒介したCXC受容体-リガンド相互作用のインビボにおける役割を調査した。図1aに示すように、G-CSF動員によって得られるDiIラベルしたヒトCD34+細胞(98%>CD34純度、6〜12%のCD117bright内皮前駆細胞を含む)は、静脈内注射の後に、梗塞心筋において選択的に検出されたが、偽操作したラット由来の心筋では検出されなかった。ラットCinc(ヒトIL-8およびGro-αのラット相同体)に対する、またはこれらのプロ血管形成のケモカインのCXCR1もしくはCXCR2のヒト表面受容体に対する遮断mAbsの同時投与により、対照抗体と比較して、48時間において40〜60%までヒト骨髄に由来するCD34+細胞の心筋への輸送を減少した(p<0.01)、図1b。2週まででは、ヒトCD34+細胞を受けているラットは、塩類溶液を受けているラット(図1c)と比較して、梗塞ベッドの微少血管分布の有意な増大を示し、これは、抗CXCR1/2 mAbsを同時投与したときに、50%まで減少した。本発明者らは、CD34+細胞の血管形成性の(vasculogenic)性質は、少数のCD117bright血管芽細胞画分(7)の枯渇後になくなることを示しているので、これらの結果は、虚血組織への血管芽細胞の遊走を調節することによって、CXCケモカインがこれらの部位で血管形成の発生に影響を及ぼすことを示す。対照的に、非梗塞心臓に1.0μg/mlのIL-8またはSDF-1を直接的に心臓内注射すると、48時間においてヒトCD34+細胞による心筋の浸潤を2.3および2.5倍に増大させた(両者ともp<0.01)図1d、血管形成は、2週においてこれらの条件下で観察されなかった。合わせると、これらの結果は、ケモカインで誘導される梗塞ゾーンへの遊走に続き、成熟した内皮細胞への内皮前駆細胞の分化、および血管形成の誘導は、さらなる因子を必要とし、まだ未決定であるが、これが虚血条件下で生じることを示す。
LAD冠動脈結紮により、静脈内に注射されたヒト内皮前駆細胞の虚血心筋部位への輸送を生じるが、これはラット骨髄へのヒト細胞の分布の増大も伴った。図2aに示すように、2×106個のヒトCD34+細胞の静脈内注射後の2〜14日において、LAD結紮したラット由来の骨髄は、正常ラット由来の骨髄と比較して、5〜8倍高いレベルのヒトCD117bright内皮細胞性前駆細胞を含んだ、p<0.001。本発明者らは、虚血血清と共に2日間培養すると、CD34+CD117brightヒト内皮細胞性前駆細胞の増殖を4〜5倍まで増大することを以前に示しているので(7)、これはおそらく、虚血血清中の因子の増殖性効果によるものである。骨髄へ能動的に循環するCD34+細胞の遊走は、骨髄間質細胞によって構成的に産生されるSDF-1によって促進されるので(31)、本発明者らは、虚血ラット骨髄に対するヒトCD34+CD117bright内皮細胞性前駆細胞の分布が、SDF-1/CXCR4の相互作用を含むかどうかを調査した。図2bに示すように、ヒトCXCR4またはラットSDF-1のいずれかに対するmAbsの同時投与により、抗CD34対照抗体と比較して、静脈内投与した虚血ラット骨髄にヒト内皮前駆細胞の遊走を有意に阻害した(両者ともp<0.001)。さらに、ヒトCXCR4またはラットSDF-1のいずれかに対するmAbsの同時投与により、CD34+ヒト内皮細胞性前駆細胞の虚血ラット心筋への輸送を、それぞれ24%および17%までに増大した(両者ともp<0.001)、図2c。
次に、本発明者らは、筋細胞アポトーシスに対して血管芽細胞数、心筋の新血管新生、および保護の間の関係を調査した。LAD結紮の2日後の動物には、G-CSFで動員されたCD34+ヒト細胞を静脈内に注射し、種々の割合のCD117bright内皮細胞性前駆体細胞(103、105、105プラス抗CXCR4 mAb、2×105、および2×105プラス抗CXCR4 mAb)で再構成した。同数のDiIラベルしたヒト細胞を、それぞれの細胞集団を注入して48時間後に梗塞ゾーンで検出した。データ示さず。2週における新血管新生の誘導は、それぞれ3〜6または>6の近接する内皮裏打ち細胞を有するものとして定義される中型および大型のサイズの毛細血管の定量分析を行うことによって測定した。中型の毛細血管は、0.020mm+0.002の平均内腔直径を有したが、大型のサイズの毛細血管は、0.053mm+0.004の平均内腔直径を有した(p<0.001)。特に、大型の内腔毛細血管は、細動脈(これは、ラット起源の2〜3の平滑筋細胞を含む薄層によって区別することができる)と大きさが重複する(これは、デスミンおよびラットMHCクラスI mAbsによるポジティブ染色法によって決定される)。図3a-cに示すように、2×105の内皮細胞性前駆細胞を受けている群および105の内皮前駆細胞プラス抗CXCR4 mAbを受けているものは、両者ともその他の群と比較して、1.7倍高い数の中型の毛細血管を示した(p<0.01)。2×105の内皮細胞性前駆細胞を受けている群では、加えて、103または105の内皮細胞性前駆細胞を受けている群と比較して、3.3倍高い数の大型の内腔毛細血管を示し(p<0.01)、および105の内皮前駆細胞プラス抗CXCR4 mAbを受けている群と比較して、2倍高い数の大型の内腔毛細血管を示した(p<0.01)。図3dに示すように、最も高濃度の内皮前駆細胞(2×105)と共に抗CXCR4 mAbを同時投与すると、大型の内腔毛細血管の増殖のさらに23%の増大を生じた。より顕著には、1.0μg/mlのSDF-1を心臓内に直接毛細血デリバリーした後に、2×105の内皮前駆細胞を静脈内に注射したときは、梗塞心臓においてさらに2倍の毛細血管の増加があった(p<0.01)。IL-8の心臓内のデリバリー後には、同様の梗塞周囲の毛細血管数の増加が見られなかったので、本発明者らは、これらの結果が、虚血ラット心臓内の内因性のIL-8濃度は、インビボで血管芽細胞CXCR1/2受容体を飽和させるために十分だったが、SDF-1の心臓内注射では、骨髄と心臓の間のSDF-1発現のバランスの変化を生じ、従って、虚血心臓への血管芽細胞の転送を生じたことを示すものであると解釈する。
次に、本発明者らは、長期の心筋機能に対する、虚血心筋へのヒト内皮前駆細胞輸送の数の増大の効果を検査し、これを静脈内注射の15週間後における、左心室駆出率(LVEF)の改善および収縮末期の左心室領域(LVAs)の減少の程度として定義した、図4aおよびb。塩類溶液を単独で受けているラットと比較して、103または105個の内皮細胞性前駆細胞を受けている群では、これらのパラメータの改善は観察されなかった。対照的に、105個の内皮前駆細胞プラス抗CXCR4 mAbを受けているラットでは、22+2%のLVEFの平均回復および24+4%のLVAsの平均減少という、これらのパラメータの有意な改善を示した(両者とも、p<0.001)。より顕著なことに、2×105個の内皮細胞性前駆細胞を受けていうる群では、34+4%のLVEFの平均回復および37+6%のLVAsの平均減少(両者とも、p<0.001)、または両方のパラメータのさらに50%の改善を有した。両群の動物は、初期の心筋細胞のアポトーシスに対して同様の保護レベルであると共に、2週において同程度の中型の毛細血管を含む新血管新生を示したので、これらの結果は本発明者らにとって非常に驚くべきものであった。これは、2×105のヒト内皮細胞性前駆細胞を受けているラットのさらなる機能の長期改善は、大型のサイズの毛細血管の初期発生に関与し、かつ筋細胞アポトーシスに対する保護とは異なる機構で媒介されることを示唆した。
筋細胞肥大および核倍数性の増大は、一般に虚血、損傷、および過負荷に対する主要な哺乳類の心臓応答であると考えられてきたが(1、2)、最近の観察では、ヒト心筋細胞が傷害に応答して、増殖および再生する能力を有することが示唆された(18、19)。したがって、本発明者らは、2×105個のヒト内皮細胞性前駆細胞の注射後に観察される心機能の相加的な改善は、心筋細胞増殖および/または再生の誘導に関与するかどうかを調査した。2×105個のヒト内皮前駆細胞を受けているLAD結紮ラットの2週後のラットでは、MHCクラスI分子の発現によって決定される多くのラット起源の心筋細胞の「フィンガー」を示し、梗塞周囲領域から梗塞ゾーン内に拡張した。同様の拡張は、103および105個の内皮細胞性前駆細胞を受けている動物では、あまり見られず、塩類溶液を受けているものでは、非常にまれであった。図4cに示すように、2×105個のヒト内皮細胞性前駆細胞を受けている動物の梗塞外周における心筋細胞の島は、DNA活性を有するラット筋細胞を高頻度で含んでおり、これは、心筋細胞特異的なトロポニンIおよびラットKi-67に対して反応性のmAbsによって二重染色することによって決定された。対照的に、塩類溶液を受けている動物では、梗塞ゾーン内に、線維芽細胞形態およびラットKi-67との反応性を有するがトロポニンIを有さない細胞が高頻度で存在した。2×105個のヒト内皮細胞性前駆細胞を受けているラットの梗塞周囲領域において、細胞周期を進行している心筋細胞の数は、梗塞から遠い部位のもの(ここでは、筋細胞のDNA活性が偽操作をしたラットと少しも異ならなかった)よりも40倍高かった。図4dに示すように、2×105個のヒト内皮細胞性前駆細胞を受けている動物は、梗塞外周において、非梗塞心臓において見いだされるものよりも20倍高い細胞サイクリング心筋細胞数を有し(1.19+0.2%対0.06+0.03%、p<0.01)および塩類溶液を受けているLAD結紮された対照の同じ領域よりも3.5倍高かった(1.19+0.2%対0.344+0.1%、p<0.01)。梗塞心臓に1.0μg/mlのSDF-1を直接的に心臓内にデリバリーした後に、2×105個のヒト内皮細胞性前駆細胞を静脈内注射した時に、梗塞外周の細胞サイクリング心筋細胞の数は、2×105個のヒト内皮細胞性前駆細胞の単独の静脈内注射と比較して、さらに1.9倍まで増大された(図4e、p<0.01)。したがって、SDF-1の心臓内注射を2×105個のヒト内皮前駆細胞の静脈内注射と組み合わせると、2週において、塩類溶液を受けているLAD結紮された対照と比較して、細胞サイクリング心筋細胞のほぼ8倍の累積的増加を生じ、心エコー図法によって決定すると、2×105個の内皮細胞性前駆細胞の単独の静脈内注射と比較して、4倍以上優れたLVEF改善に変化した(図4f、p<0.01)。抗CXCR4 mAbの同時投与により、2.8倍までLVEF改善を増大し(p<0.01)、一方でIL-8の心臓内注射では、相加的な利益を与えなかった。
PAI-1を阻害する触媒核酸は、ヒト血管芽細胞依存的な心筋細胞再生を増大する。
本発明者らは、PAI-1の発現を阻害することができる触媒核酸(E2と命名)によって誘導される新血管新生が、心筋細胞再生と関係する可能性があるかどうかを調査した。E2単独の注射では、新血管新生を増加するにもかかわらず、心筋細胞再生を誘導しなかった。E2注射を静脈内にデリバリーしたヒト内皮前駆細胞と組み合わせると、心筋細胞再生の程度を塩類対象よりも7.5倍高いレベルに著しく増大した(p<0.01)。スクランブルされたDNA対照酵素(EO)は、このような効果を有さなかった。さらに、E2単独では心筋機能を改善しないのに対して、E2をヒト内皮前駆細胞と組み合わせて2週における左室駆出率の回復によって決定すると、内皮前駆細胞単独での心臓機能の回復のほぼ2倍のポジティブな効果を生じた。これらの結果は、梗塞後に心機能を改善させる主要な機構として心筋細胞再生が重要であることを強調する。E2をヒト内皮前駆細胞と組み合わせると、いずれかのアプローチを単独で使用するよりも、梗塞外周で62%多い数の大型の毛細血管の生じ、これらの結果は、PAI-1発現を阻害するストラテジーなどの相乗的なアプローチを用いて、血管芽細胞で誘導される心筋細胞再生および心機能の改善を最適化し、直接または血管芽細胞依存的なプロセスのいずれかを介して新血管新生を増大することができることを示す。
本発明者らは、心筋の新血管新生が、筋細胞増殖を引き出すために必要とされるシグナルを誘導し、これを模倣する治療的な介入により、虚血またはその他の発作の発症によって損傷を受けた心臓の回復および再生に顕著な意味を有し得ると仮定した。
サブトラクティブ・ハイブリダイゼーションによって、本発明者らは、タンパク質VDUP1のmRNA発現が、急性の虚血後の心臓において有意に増大されることを見いだした。VDUP1は、サイトゾルタンパク質チオレドキシンTRXに結合することが示されており、これは、サイトゾルのチオール-ジスルフィド状態を維持するように機能する。TRXの還元型に対する結合によって、VDUP1は、還元されたTRXが、NADPH依存性酵素TRXレダクターゼによって触媒される可逆的な酸化還元反応を受ける能力を妨げる。これは、サイトゾルおよびミトコンドリアの過剰な活性酸素の産生による細胞のアポトーシスを生じる。
G-CSFは、GM-CSFよりも強力な心筋梗塞後の新血管新生の誘導因子である。図15(a)に示すように、左前下行(LAD)冠動脈結紮によって誘導される心筋梗塞の2日後に開始して4日間、10μg/kgでヒトG-CSFを皮下に注射したラットでは、塩類溶液処理した対照と比較して、2週後において約7.5倍高い数の梗塞周囲領域の大型直径の血管を示した(p<0.01)。同じ投与計画で投与したラットGM-CSFは、あまり有効でなかったが、なおも対照動物よりも4倍多い数の大型内腔血管を誘導した。
抗CXCR4抗体の静脈内投与は、心筋の新血管新生を増大し、急性の梗塞後の心機能を改善する。G-CSFが骨髄エレメントの動員を引き起こす主要な機構は、骨髄常在性の幹細胞上のケモカイン受容体CXCR4とそのリガンドのSDF-1との間の相互作用の妨害を介する。G-CSFは、CXCR4のN末端の切断およびセリンプロテアーゼの蓄積の両方を誘導し、SDF-1を直接切断して不活性化する。同様の機構が、心筋の新血管新生および心機能の改善に対するG-CSF投与の効果の原因であるたかどうかを検査するために、本発明者らは、LAD結紮の48時間後にモノクロナル抗CXCR4抗体を静脈内に投与することによって、CXCR4-SDF1の相互作用を妨害する効果を調査した。図17(a)に示すように、抗体投与の2週後において、抗CXCR4 mAbを受けている動物は、塩類溶液または抗CXCR2mAbを受けている対照動物と比較して、梗塞周囲領域の新血管新生の2倍の増大を示した。さらに、図17(b)に示すように、抗CXCR4処理した動物は、2週において、10%の駆出率の平均回復を示したが、抗CXCR2 mAbを受けているものでは、8%の心機能の平均減少を有した(p<0.05)。これらのデータは、観察されたG-CSF投与の効果が骨髄におけるCXCR4相互作用を妨害して、内皮前駆細胞を末梢循環に動員し、かつ虚血心筋に誘導することができ、ここで、生じる新血管新生が心機能の改善を生じることによって生じるという概念を支える。
SDF-1 mRNAの発現は、急性の虚血心筋の初期には誘導されず、その遅発型の誘導はGM-CSFによって阻害される。次に、本発明者らは、GM-CSFの効果が、急性の虚血心筋における走化性のシグナルを増大することなどの、G-CSF処理単独で見られるアプローチを増大することができるストラテジーを同定しようとした。CD34+骨髄幹細胞の走化性は、CD34+細胞上のCXCR4受容体とCXCケモカインSDF-1との間の相互作用によって調節されるので、本発明者らは、SDF-1 mRNAの発現が、急性の虚血心筋において誘導されるかどうかを調査した。図18に示すように、心筋のSDF-1 mRNAの相違は、非虚血対照と比較して、実験動物のLAD結紮の48時間後には観察されなかった。梗塞の2週間後までに、心筋のSDF-1 mRNAの発現は、塩類溶液処理した対照と比較して、3.3倍に増大した(p<0.01)。本発明者らは、このSDF-1の遅延性の産生は、マクロファージなどの細胞を浸潤させることによる生成を最も反映する可能性があると解釈した。対照的に、全身GM-CSF投与では、2週において約4.5倍のSDF-1 mRNA発現の阻害を伴い、実際に非虚血対照よりも低いレベルになった。SDF-1は、内皮前駆細胞の強力な走化因子であるので、これらのデータは、全身GM-CSF投与により、SDF-1などの走化性のリガンドの減少した心筋発現によって、内皮前駆体の最適以下の心筋ホーミングを生じるであろうことを示唆した。
サイトカインで動員されるヒトCD34+細胞の精製および特性付け:単一ドナーの白血球フェレーシス(leukopheresis)産物は、組換えG-CSF10mg/kg(Amgen CA)で4日間毎日sc処理したヒトから得た。ドナーは、同種の幹細胞移植体のために、骨髄動員、回収、および単離の標準的な施設内手順を受けている健康な個々であった。単核細胞をFicoll-Hypaqueによって分離し、高度に精製したCD34+細胞(>98%陽性)を抗CD34モノクローナル抗体(mAb)で被覆した磁気ビーズ(Miltenyi Biotech, CA)を使用して得た。精製したCD34細胞を、CD34およびCD117に対するフルオレッセイン結合mAbs(Becton Dickinson, CA)、AC133(Miltenyi Biotech, CA)、CD54(Immunotech, CA)、CD62E(Bio Source, MA)、VEGFR-2、Tie-2、vWF、eNOS、CXCR1、CXCR2およびCXCR4(全てSanta Cruz Biotech, CA)で染色し、FACScan(Becton Dickinson, CA)を使用して4色パラメーター蛍光によって解析した。また、CD34発現について陽性のものを選択した細胞をフィコエリトリン(PE)結合抗CD117 mAb(Becton Dickinson, CA)で染色し、Facstar Plus(Becton Dickinson)およびPEフィルターを使用して明るい蛍光および暗い蛍光のものをソートした。GATA-2の細胞内染色は、Pharmingen Cytofix/Cytoperm(商標)キットを使用して、10μlのCD117およびCD34表面抗原(Becton Dickinson, CA)に対する蛍光色素結合mAbsと共に氷上で30分間インキュベートして、各々の明るい蛍光および暗い蛍光を発する細胞群から1,000,000細胞を透過させることによって行った250μlのCytofix/Cytoperm(商標)溶液に4度Cで20分間再懸濁した後、細胞をGATA-2(Santa Cruz Biotech, CA)またはIgG対照に対する蛍光色素ラベルmAbと共に4度Cで30分間インキュベートし、3-パラメータのフローサイトメトリーによって解析した。
体群と比較して、HLAクラスI陽性細胞の比率のフローサイトメーター解析およびRT-PCR解析によって行った。新血管形成および心筋の生存戸および機能に対する効果についての研究のためには、G-CSF動員後に単一のドナーから得た2.0×106個のDiIラベルされたヒトCD34+細胞を103、105、または2.0×105個の免疫精製したCD34+CD117bright細胞と共に再構成し、LAD結紮の48時間後に、CXCR4に対する阻害活性が既知のmAbの存在下または非存在下において、ラット尾静脈に注射した。各群は、6〜10匹のラットからなった。組織学的および機能的な研究は、2週および15週に行った。
is, Missouri)。次いで、アビジン-ビオチン複合体(Vector Laboratories, Burlingame, CA)をさらに30分間添加して、筋細胞をDAB溶液混合物(Sigma, Saint Louis, Missouri)に5分照射に続いて褐色に視覚化した。組織切片は、200×の拡大率で顕微鏡で検査した。梗塞周囲部位およびこの部位の遠位の両方において、それぞれの200×の視野内で、領域につき少なくとも250細胞を含み、かつ累積的に組織の1mm2に近づけた4つの領域を検査した。組織の縁で染色された細胞は計数しなかった。結果は、検査したそれぞれの部位でのmm2あたりのアポトーシス筋細胞の平均数として表した。
1. Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. AmJ Physiol 272, H220-6 (1997).
2. Kellerman S, Moore JA, Zierhut W, Zimmer HG, Campbell J, Gerdes AM. Nuclear DNA content and nucleation patterns in rat cardiac myocytes from different models of cardiac hypertrophy. J Mol Cell Cardiol 24,497-505 (1992).
3. Colucci, W. S. Molecular and cellular mechanisms of myocardial failure. Am. J. Cardiol. 80(11A), 15L-25L (1997).
4. Ravichandran, L. V. and Puvanakrishnan, R. In vivo labeling studies on the biosynthesis and degradation of collagen in experimental myocardial myocardial infarction. Biochem. Intl. 24,405-414 (1991).
5. Agocha, A. , Lee, H. W. , Eghali-Webb, M. Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of TGF-beta, thyroid hormone, angiotensis II and basic fibroblast growth factor. J. Mol. Cell. Cardiol. 29,2233-2244 (1997).
6. Pfeffer, J. M. , Pfeffer, M. A,, Fletcher, P. J., Braunwald, E. Progressive ventricular remodeling in rat with myocardial infarction. Am. J. Physiol. 260, H1406-414 (1991).
7. Kocher, AA, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived endothelial progenitor cells prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7,430-6(2001).
8. Kennedy, M. et al. A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386,488-493 (1997).
9. Choi, K. , Kennedy, M. , Kazarov, A. , Papadimitriou, Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125,725-732 (1998).
10. Elefanty, A. G. , Robb, L. , Birner, R. , Begley, C. G. Hematopoietic-specific genes are not induced during in vitro differentiation of scl-null embryonic stem cells. Blood 90,1435-1447 (1997).
11. Labastie, M. C. , Cortes, F. , Romeo, P. H. , Dulac, C., Peault, B. Molecular identity of hematopoietic precursor cells emerging in the human embryo. Blood 92,3624-3635 (1998).
12. Rafii S, et al. Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood 84, 10-19 (1994).
13. Shi, Q. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 92,362-367 (1998).
14. Lin, Y. , Weisdorf, D. J. , Solovey, A. , Hebbel, R. P. Origins of circulating endothelial cells and endothelial outgrowth from blood. J. Clin. Invest. 105,71-77 (2000).
15. Asahara, T. et al. Isolation of putative progenitor cells for endothelial angiogenesis. Science 275, 964-967 (1997).
16. Takahashi, T. et al. Ischemia-and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5,434-438 (1999).
17. Kalka, C. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc. Natl. Acad. Sci. USA 97, 3422-3427 (2000).
18. Kajstura J, Leri A, Finato N, di Loreto N, Beltramo CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA 95, 8801-8805 (1998).
19. Beltrami AP, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344,1750-7 (2001).
20. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1: 27 (1995).
21. Strieter, RM. et al. Interleukin-8: a corneal factor that induces neovascularization. Am. J. Pathol. 141,1279-1284 (1992).
22. Murdoch C, Monk PN, Finn A. Cxc chemokine receptor expression on human endothelial cells. Cytokine 11,704-12 (1999).
23. Koch, AE. et al. Interleukin-8 (IL-8) as a macrophage-derived mediator of angiogenesis. Science, 258: 1798-1801 (1992).
24. Strieter, RM, et al The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J. Biol. Chem. 270,27348-27357 (1995).
25. Angiolillo, AL, et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182,155-62 (1995).
26. Feil C, Augustin HG. Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusin) under the control of autocrine activity and exogenous cytokines. Biochem Biophys Res Commun 247,38-45 (1998).
27. Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393,591-594 (1998).
28. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L. The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood 91,4523-30 (1998).
29. Imai, K. et al. Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenior cells to bone marrow. Br J Haematol 106,905-11 (1999).
30. Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283,845-88 (1999).
31.Voermans C, Gerritsen WR, von dem Borne AE, van der Schoot CE. Increased migration of cord blood-derived CD34+ cells, as compared to bone marrow and mobilized peripheral blood CD34+ cells across uncoated or fibronectin-coated filters. Exp. Hematol. 27,1806-14 (2000).
32. Janowska-Wieczorek, A. et al. Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34+ cells and their transmigration through reconstituted basement membrane. Blood 93,3379-3390(1999).
33. Heymans, S. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat. Med. 5,1135-1142 (1999).
34. Luca M, Huang S, Gershenwald JE, Singh RK, Reich R, Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol 151,1105-1113 (1997).
35. Masure, S. , Proost, P. , Van Damme, J., Opdenakker, MD. Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8. Eur. J. Biochem. 198,391-398 (1991).
36. Hart, P. H. et al. Activation of human monocytes by granulocyte-macrophage colony-stimulating factor: increased urokinase-type plasminogen activator activity. Blood 77,841-848 (1991).
37. Stacey, K. J. , Fowles, L. F. , Colman, M. S., Ostrowski, M. C. , Hume, D. A. Regulation of urokinase-type plasminogen activator gene transcription by macrophage colony-stimulating factor. Mol. Cell. Biol. 15,3430-3441 (1995).
38. Pei, X. H. et al. G-CSF increases secretion of urokinase-type plasminogen activator by human lung cancer cells. Clin. Exp. Metastasis 16,551-558 (1998).
39. Semerad, CL, et al. A role for G-CSF receptor signalling in the regulation of hematopoietic cell function but not lineage commitment or differentiation. Immunity 11,153-161 (1999).
40. Nagasawa, T, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382,635-638 (1996).
41. Rempel SA, Dudas S, Ge S, Gutierrez JA. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6,102-11 (2000).
42. Globerson, A. Hematopoietic stem cells and aging. Exp. Gerontol. 34,137-146 (1999).
43. de la Rubia, J., Diaz, M. A. , Verdeguer, A. , et al. Donor age-related differences in PBPC mobilization with rHuG-CSF. Transfusion 41,201-205 (2001).
44. Leferovich JM, et al. Heart regeneration in adult MRL mice. Proc Natl Acad Sci USA 98,9830-9835 (2001).
45. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB. Growth factors can influence cell survival through effects on glucose metabolism. Mol Cell Biol 21,5899-5912 (2001).
46.Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, and Dimmeler S. Akt-dependent phosphorylation ofp21Cipl regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol 21,5644-5657 (2001).
47. Tomita S, et al. Autologous transplantation of bone marrow cells improves damaged heart function.
48. Orlic D, et al. Bone marrow cells regenerate infarcted myocardium. Nature 410,701-705 (2001)
49. Kehat I, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 108,407-14 (2001).
50. Rossi et al. , 1992, Aids Research and Human Retroviruses 8,183.
51. Hampel et al. , EP0360257
52. Hampel and Tritz, 1989 Biochemistry 28,4929.
53. Hampel et al. , 1990 Nucleic Acids Res. 18,299.
54. Perrotta and Been, 1992 Biochemistry 31,16.
55. Guerrier-Takada et al. , 1983 Cell 35,849.
56. Forster and Altman, 1990 Science 249,783.
57. Saville and Collins, 1990 Cell 61,685-696.
58. Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88,8826-8830.
59. Guo and Collins, 1995 EMBO J. 14,368.
60. Cech et al. , U. S. Pat. No. 4,987, 071.
61. MatzuraO, Wennborg A (1996) RNAdraw: an integrated program for RNA secondary structure calculation and analysis under 32-bit Microsoft Windows. Comput Appl
Biosci 12: 247-9.
62. Santoro SW, Joyce GF (1997) A general purpose RNA- cleaving DNA enzyme. Proc Natl Acad Sci USA 94: 4262-6.
63. Santoro SW, Joyce GF (1998) Mechanism and utility of an RNA-cleaving DNA enzyme. Biochemistry 37: 13330-42.
64. MacLellan WR and Schneider MD. Genetic dissection of cardiac growth control pathways Annu. Rev. Physiol. 2000.62 : 289-320.7.
65. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G(1)-phase progression. Genes Dev. 1999; 13: 1501-1512.
66. Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol. 1996,148 : 291-300.
67. Hill MF, Singal PK. Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction. Circulation 1997 96: 2414-20.
68. Li, Y. , Jenkins, C. W. , Nichols, M. A. and Xiong, Y. (1994) Cell cycle expression and p53 regulation of thecyclin-dependent kinase inhibitor p21. Oncogene, 9, 2261-2268
69. Steinman, R. A. , Hoffman, B. , Iro, A. , Guillouf, C. , Liebermann, D. A. andEl-Houseini, M. E. (1994) Induction of p21(WAF1/CIP1) during differentiation. Oncogene, 9,3389-3396
70. Halevy, O., Novitch, B. G. , Spicer, D. B. , Skapek, S. X. , Rhee, J. , Hannon, G. J. , Beach, D. and Lassar, A. B. (1995) Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science, 267,1018-1021.
71. Andres, V. and Walsh, K. (1996) Myogenin expression, cell cycle withdrawal and phenotypic differentiation are temporally separable events that precedes cellfusion upon myogenesis. J. Cell Biol. , 132,657-666.
72. Tsurimoto, T. PCNA Binding Proteins. Frontiers in
Bioscience, 4: 849-858,1999.
73. Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R. Cleavage ofp21cipl/wafl and p27 kipl mediates apoptosis in endothelial cells through activation of cdk2: role of a caspase cascade. Mol Cell. 1998 ; 1: 553-563.
74. Adachi S, et al. Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes Circ Res. 88: 408,2001.
75. Ichijo H, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275: 90-94 (1997).
76. Tobiume, K. , Inage, T. , Takeda, K. , Enomoto, S., Miyazono, K. and Ichijo, H. (1997) Molecular cloning and characterization of the mouse apoptosis signal-regulating kinase 1. Biochem. Biophys. Res. Commun. , 239,905-910.
77. Asada M, Yamada T, Ichijo h, Delia D, Miyazono K, Fukumuro K, and Mizutani S Apoptosis inhibitory activity of cytoplasmicp21Cipl/WAF1 in monocytic differentiation. EMBO J, 18: 1223-1234,1999.
78. Saitoh H, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17: 2596-2606,1998.
79. Nishiyama A, et al. Identification of Thioredoxin-binding Protein-2/Vitamin D3 Up-regulated Protein 1 as a Negative Regulator of Thioredoxin Function and Expression. J Biol Chem, 31,21645-21650, 1999.
80. Junn E, et al. Vitamin D3 Up-Regulated Protein Mediates Oxidative Stress Via Suppressing the Thioredoxin Function. J Immunol. 164: 6287-6295,2000.
81. Holmgren, A. (1985) Annu. Rev. Biochem. 54,237-271.
82. Chae, H. Z. , Chung, S. J. & Rhee, S. G. (1994) J. Biol. Chem. 269,27670-27678.
83. Netto, L. E. S. , Chae, H. Z., Kang, S. , Rhee, S. G. & Stadtman, E. R. (1996) J. Biol. Chem. 271, 15315-15321.
84. Chae, H. Z. , Uhm, T. B. & Rhee, S. G. (1994) Proc. Natl. Acad. Smultifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product. Proc. Natl Acad Sci, USA. 96,12333-12338, 1999.
88. Siow, R. C. M. , et al. (1995) FEBS Lett. 368,239-242.
89. Prosperi, M. , Ferbus, D. , Karczinski, I. & Goubin, G. (1993) J. Biol. Chem. 268,11050-11056.
90. Sauri, H. , Butterfield, L., Kim, A. & Shau, H. (1995) Biochem. Biophys. Res. Commun. 208,964-969.
91. Ishii T et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biological Chem 2000, 275: 16023-16029
92. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keapl represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan1sol3 (1) : 76-86.
93. Lee, J-M, et al.Phosphatidylinositol 3-Kinase, Not Extracellular Signal-regulated Kinase, Regulates Activation of the Antioxidant-Responsive Element in IMR-32 Human Neuroblastoma Cells J. Biol. Chem., 276: 20011-20016,2001.
94. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem. 2001 276: 18399-406.
95. Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR. Role of NRF2 in Protection Against Hyperoxic Lung Injury in Mice. Am J Respir Cell Mol Biol 2002,26 : 175-182.
96. Kumuda C. Das, Paula M. B. Pahl, Xiao-Ling Guo, and Carl W. White. Induction of Peroxiredoxin Gene Expression by Oxygen in Lungs of Newborn Primates. Am. J. Respir. Cell Mol. Biol. 2001,25 : 226-232.
97. Wen S-T, and Van Etten, RA The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes and Development, 19: 2456-2467,1997.
98. Kharbanda, S. , Yuan, Z. M. , Weichselbaum, R. & Kufe, D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 17,3309-3318 (1998).
99. Yuan ZM etal, Nature 1996 18; 382 (6588): 272-4.
100. Jost, C. A. , Marin, M. C. & Kaelin, W. J. p73 is a human p53-related protein that can induce apoptosis. Nature 389,191-194 (1997).
101. Agami, R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73 [alpha] and their collaboration to induce apoptosis Nature 399,809-813 (1999).
102. Sun X, et al. Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. J Biol. Chem. 2000,275 : 17237-17240.
103. Kumar S, et al. Targeting of the c-Abl Tyrosine Kinase to Mitochondria in the Necrotic Cell Death Response toOxidative Stress J. Biol. Chem. , 276,17281-17285, 2001.
104. Chen, K. S. andDeLuca, H. F. Isolation and characterization of a novelcDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3 JOURNAL Biochim. Biophys. Acta 1219 (1), 26-32 (1994).
105. Zhang et al. Clinical Pharmacology & Therapeutics (1995) 58(1), 44-53.
106.. Tetsuro Ishii, Ken Itoh, Junetsu Akasaka, Toru Yanagawa, Satoru Takahashil, Hiroshi Yoshida, Shiro Bannai and Masayuki Yamamoto, Carcinogenesis Vol. 21 (5): 1013-1016, (2000).
107. Das KC, Pahl PM, Guo XL, White CW, Am. J. Respir. Cell Mol.Biol., (2001), 25 (2): 226-32.
108. Immenschuh S, Iwahara S, Satoh H, Nell C, Katz N,Muller-Eberhard U. , Biochemistry (1995) 17; 34 (41): 13407-11.
109. Ken Itoh, Nobunao Wakabayashi, Yasutake Katoh, Tetsuro Ishii, Kazuhiko Igarashi, James Douglas Engel,l and Masayuki Yamamoto, Genes and Development, 13(1) : 76-86,(1999).
実験結果II
ヒト骨髄に由来する内皮細胞性前駆細胞の静脈内投与は、新血管新生を誘導し、梗塞5日後以内の心筋細胞アポトーシスを防止する。
本発明者らは、骨髄に由来する内皮前駆細胞の静脈内注射後に、48時間よりも前に持続的なLAD結紮を受たラットの心臓において、どれくらい早く新血管新生を発生するかを決定しようとした。G-CSF動員によって得たDiIラベルしたヒトCD34+細胞(>98%のCD34純度、6〜12%のCD117bright血管芽細胞を含んでいる)の静脈内注射の2日後に動物を屠殺したときに、多くのDiI陽性の間質細胞が梗塞周囲領域において見られたが、定義されたDiIを発現する血管の構造を同定することはできなかった、データ示さず。対照的に、ヒトCD34+細胞の注入の5日後に屠殺した動物は、梗塞周囲領域に多くのDiI陽性の血管構造を示し、塩類溶液を受けているラットと比較して、3.5倍高い毛細血管数であった、図21(a)(p<0.01)。5日目における微少血管分布の増大(トロポニンIおよびTUNELの二重陽性によって定義される)は、塩類溶液を受けている対照と比較して、梗塞周囲領域のアポトーシス心筋細胞の数の3.3倍間での低下を伴った、図21(b)(p<0.01)。合わせると、これらのデータは、骨髄由来の血管芽細胞が、虚血心筋の毛細血管において成熟した、機能的なネットワークに分化および組織化する血管形成プロセスは、2〜5日かかることを示す。
本発明者らは、急性の虚血後の成人心臓にまれに生じることが示されている、サイクリング心筋細胞の検出のために、5日目に屠殺した実験動物および対照動物に由来する心臓組織を免疫組織化学および共焦点顕微鏡観察によって検査した。成熟したトロポニン陽性のサイクリング心筋細胞は、梗塞の5日後の対照または実験動物のいずれにおいても検出されなかったが、ヒト骨髄由来CD34+細胞を受けている動物では、梗塞周囲領域にラット起源の小さな、サイクリング細胞(ラットKi67に特異的なモノクローナル抗体に定義される)の多くのクラスターを示した、図22(a)。これらの細胞は、心筋細胞特異的なトロポニンI(心筋細胞分化のマーカー)に陰性であったが、αサルコメア・アクチンに陽性に染色し、これらが心筋細胞系統の未熟な細胞であることを示した。サイクリング心筋細胞前駆体の同様のクラスターは、塩類溶液を注入した対照動物では見られなかった。
実験の心筋梗塞において誘導されたHBP23の発現のインビボの関連性を調査するために、LAD結紮の48時間後のラットに、HBP23 DNA酵素またはスクランブルされた対照のいずれかの心筋内の注射と共に、ヒト骨髄由来する内皮細胞性前駆細胞を静脈内に注射した。図25(a)に示すように、HBP2 3DNA酵素は、ヒト骨髄血管芽細胞による新血管新生の誘導に対して効果を有さなかった。注入の5日後に屠殺すると、ヒト内皮前駆体を受けたラットは、HBP23 DNA酵素またはスクランブルされた対照が同時注入されたかどうかに関係なく、塩類の対照と比較して、心筋の毛細血管の密度の増大を示した。対照的に、HBP23 DNA酵素の注射では、新血管新生の抗アポトーシスの効果、図25(b)および心機能の改善、図25(c)がなくなったが、スクランブルされた対照ではなくならなかった。ヒト内皮前駆細胞を受け、かつ心筋の新血管新生を示す動物の中で、HBP23 DNA酵素で処理すると、1.7倍高いレベルの心筋細胞アポトーシス(p<0.01)、および心機能の38%平均の悪化(p<0.01)を生じた(心エコー図法によって評価される)。加えて、HBP23 DNA酵素は、心筋細胞前駆体の増殖/再生に対して著しい効果を及ぼした。Ki67およびαサルコメアアクチンを発現する小さなラット細胞の梗塞周囲のクラスターは、スクランブルされたコントロールDNAと共に血管芽細胞を受けている動物では容易に検出されたのに対して、HBP23 DNA酵素を受けている動物においては、いずれも同定されなかった。これらの結果は、血管芽細胞依存的な新血管新生は、心筋細胞をアポトーシスから保護し、ペルオキシレドキシン遺伝子産物によって調節される経路を経た常在心筋細胞系統前駆体の増殖/再生を誘導することを明らかに示す。
この研究において、本発明者らは、血管芽細胞由来のヒト骨髄による虚血心筋における新血管新生は、梗塞周囲領域の成熟した心筋細胞のアポトーシスに対する保護および同じ部位における心筋細胞前駆体の刺激の両方を生じて、細胞周期に入り、増殖し、再生したことを示した。さらに、本発明者らは、血管芽細胞依存的な新血管新生が心筋細胞の生存および自己再生を調節する機構は、酸化的ストレス(ペルオキシレドキシン)に伴う、抗アポトーシスおよびプロ増殖性の経路に関与する遺伝子の少なくとも1つのファミリーに関与するようにみえることを示した。酸素による緊張状態(oxigen tension)は、ポジティブにペルオキシレドキシン遺伝子の発現を調節するが(17)、HBP mRNA発現に対する血管芽細胞を媒介した新血管新生のポジティブな効果がこれだけで説明されるかどうかは、明らかでない。ペルオキシレドキシンmRNAの発現は、プロテインキナーゼCデルタによって誘導されるので(25)、骨髄血管芽細胞は、FGF-1などの、プロテインキナーゼCデルタ活性化および結果的に細胞生存を調節する細胞外シグナルの供与源であるかもしれない(26)。
サイトカインで動員されるヒトCD34+細胞の精製および特性付け。単一ドナーの白血球フェレーシス(leukopheresis)産物は、組換えG-CSF10mg/kg(Amgen CA)で4日間毎日sc処理したヒトから得た。ドナーは、同種の幹細胞移植体のために、骨髄動員、回収、および単離の標準的な施設内手順を受けている健康な個体であった。単核細胞をFicoll-Hypaqueによって分離し、高度に生成したCD34+細胞(>98%陽性)を抗CD34モノクローナル抗体(mAb)で被覆した磁気ビーズ(Miltenyi Biotech, CA)を使用して得た。精製したCD34細胞を、CD34およびCD117に対するフルオレッセイン結合mAbs(Becton Dickinson, CA)、AC133(Miltenyi Biotech, CA)、CD54(Immunotech, CA)、CD62E(Bio Source, MA)、VEGFR-2、Tie-2、vWF、eNOS、CXCR1、CXCR2およびCXCR4(全てSanta Cruz Biotech, CA)で染色し、FACScan(Becton Dickinson, CA)を使用して4色パラメーター蛍光によって解析した。また、CD34発現について陽性のものを選択した細胞をフィコエリトリン(PE)結合抗CD117 mAb(Becton Dickinson, CA)で染色し、Facstar Plus(Becton Dickinson)およびPEフィルターを使用して明るい蛍光および暗い蛍光のものをソートした。GATA-2の細胞内染色は、Pharmingen Cytofix/Cytoperm(商標)キットを使用して、10μlのCD117およびCD34表面抗原(Becton Dickinson, CA)に対する蛍光色素結合mAbsと共に氷上で30分間インキュベートして、各々の明るい蛍光および暗い蛍光を発する細胞群から1,000,000細胞を透過させることによって行った250μlのCytofix/Cytoperm(商標)溶液に4度Cで20分間再懸濁した後、細胞をGATA-2(Santa Cruz Biotech, CA)またはIgG対照に対する蛍光色素ラベルmAbと共に4度Cで30分間インキュベートし、3-パラメータのフローサイトメトリーによって解析した。
is, Missouri)。次いで、アビジン-ビオチン複合体(Vector Laboratories, Burlingame, CA)をさらに30分間添加して、筋細胞をDAB溶液混合物(Sigma, Saint Louis, Missouri)に5分照射に続いて褐色に視覚化した。組織切片は、200×の拡大率で顕微鏡で検査した。梗塞周囲部位およびこの部位の遠位の両方において、それぞれの200×の視野内で、領域につき少なくとも250細胞を含み、かつ累積的に組織の1mm2に近づけた4つの領域を検査した。組織の縁で染色された細胞は計数しなかった。結果は、検査したそれぞれの部位でのmm2あたりのアポトーシス筋細胞の平均数として表した。
1. MacLellan WR and Schneider MD. Genetic dissection of cardiac growth control pathways Annu. Rev. Physiol. 2000. 62: 289-320.
2. Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol 272, H220-6 (1997).
3. Kellerman S, Moore JA, Zierhut W, Zimmer HG, Campbell J, Gerdes AM. Nuclear DNA content and nucleation patterns in rat cardiac myocytes from different models of cardiac hypertrophy. J Mol Cell Cardiol 24,497-505 (1992).
4. Colucci, W. S. Molecular and cellular mechanisms of myocardial failure. Am. J. Cardiol. 80 (11A), 15L-25L(1997).
5. Ravichandran, L. V. and Puvanakrishnan, R. In vivo labeling studies on the biosynthesis and degradation of collagen in experimental myocardial myocardial infarction. Biochem. Intl. 24,405-414 (1991).
6. Agocha, A. , Lee, H. W. , Eghali-Webb, M. Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of TGF-beta, thyroid hormone, angiotensis II and basic fibroblast growth factor. J. Mol. Cell. Cardiol. 29, 2233-2244 (1997).
13. Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol. 148,291-300(1996)..
14. Hill MF, Singal PK. Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction. Circulation 96,2414-20 (1997).
15. Cesselli D, et al. Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89, 279-86 (2001).
16. Chae, H. Z. , Chung, S. J. & Rhee, S. G. Thioredoxin-dependent peroxide reductase from yeast. J. Biol. Chem. 269,27670-27678 (1994).
17. Das KC, Pahl PM, Guo X-L, and WhiteCW. Induction of peroxiredoxin gene expression by oxygen in lungs of newbornprimates. Am. J. Respir. Cell Mol. Biol. , 25,226-232, 2001.
18. Holmgren, A. Thioredoxin. Annu. Rev. Biochem. 54, 237-271 (1985).
19. Sun X, et al. Activation of the cytoplasmicc-Abl tyrosine kinase by reactive oxygen species. J Biol. Chem. 275,17237-17240 (2000).
20. Kumar S, et al. Targeting of the c-Abl tyrosine kinase to mitochondria in the necrotic cell death response to oxidative stress. J. Biol. Chem. 276,17281-17285 (2001).
21. Wen S-T, and Van Etten, RA. The PAG gene product, a stress-induced protein with antioxidant properties, is an AblSH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes and Development 19, 2456-2467 (1997).
22. Breaker, R. R. Making catalyticDNAs. Science 290, 2095-2096 (2000).
23. Khachigian, L. M. CatalyticDNAs as potential therapeutic agents and sequence-specific molecular tools to dissect biological function. J Clin Invest 106,1189-1195 (2000).
24. Zuker, M. On finding all suboptimal foldings of an RNA molecule. Science 244,48-52 (1989).
25. Li B, Ishii T, Choon Ping Tan CP, Soh JW, and Goff SP. Pathways of induction of Peroxiredoxin I expression in osteoblasts. Roles of p38 mitogen-activated protein kinaseand protein kinase c. J. Biol. Chem. , 277,12418-12422 (2002).
26. Wert MM and Palfrey HC. Divergence in the anti-apoptotic signalling pathways used awareness by nerve growth factor and basic fibroblast growth factor(bFGF) in PC12 cells: rescue by bFGF involves protein kinase Cd. Biochem. J. 352: 175-182 (2000).
27. Chae, H. Z. , Chung, S. J. & Rhee, S. G. J. Biol. Chem. 269,27670-27678 (1994).
28. Kwon, S. J. , Park, J. , Choi, W., Kim, I. H. & Kim, K. Biochem. Biophys. Res. Comm. 201,8-15 (1994).
29. Kang, S. W. , Baines, I. C. & Rhee, S. G. J. Biol. Chem. 273,6303-6311 (1998).
30. Wen S-T, and Van Etten, RA. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes and Development 19, 2456-2467 (1997).
31. Kharbanda, S. , Yuan, Z. M. , Weichselbaum, R. and Kufe, D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 17,3309-3318 (1998).
32. Yuan ZM, Huang Y, Whang Y, Sawyers C, Weichselbaum R, Kharbanda S, and Kufe D. Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature 382,272-4 (1996).
33. Anversa P and Nadal-Ginard B. Myocyte renewal and ventricular remodelling Nature 415,240-243 (2002).
Claims (15)
- 心筋細胞の減少を含む被検体の心臓の障害を治療する薬剤であって、前記被検体の心臓内で心筋細胞増殖を引き起こすために有効な量のCXCケモカインまたはCXCケモカインをコードする遺伝子を含み、これにより前記障害を治療する薬剤:
ここにおいて、前記ケモカインが間質由来因子-1、IL-8、またはGro-Alphaであり、前記薬剤は心筋内投与のためのものである。 - 前記薬剤が、間質由来因子−1である、請求項1に記載の薬剤。
- 前記間質由来因子−1が、間質由来因子−1αまたは間質由来因子−1βである、請求項2に記載の薬剤。
- 冠内投与のための、請求項1から3の何れか1項に記載の薬剤。
- ステント、足場(scaffold)を経て、または緩効性製剤としての投与のための、請求項1から4の何れか1項に記載の薬剤。
- 第2の薬剤をさらに含む、請求項1から5の何れか1項に記載の薬剤。
- 前記第2の薬剤がGM-CSF、G-CSF、IL-8、またはGroファミリーケモカインである、請求項6に記載の薬剤。
- 循環器病、鬱血性心不全、心筋梗塞、心筋虚血症または心筋症の治療のための、請求項1から7の何れか1項に記載の薬剤。
- 心筋梗塞の治療のための、請求項1から7の何れか1項に記載の薬剤。
- 前記薬剤が、70kgのヒト被験者に対して10mlの最大体積で、0.2〜5μg/mlの間のCXCケモカインを含む、請求項1から9の何れか1項に記載の薬剤。
- 前記薬剤の投与により心機能の改善がもたらされる、請求項1から10の何れか1項に記載の薬剤。
- 前記心機能の改善が、駆出率の改善によって決定される、請求項11に記載の薬剤。
- 前記薬剤がCXCケモカインを含む、請求項1に記載の薬剤。
- 前記薬剤が、CXCケモカインをコードする遺伝子を含む、請求項1に記載の薬剤。
- 心筋細胞の減少を含む被検体の心臓の障害を治療する薬剤であって、前記被検体の心臓内で心筋細胞増殖を引き起こすために有効なCXCケモカインを発現する細胞を含み、これにより前記障害を治療する薬剤:
ここにおいて、前記ケモカインが間質由来因子-1、IL-8、またはGro-Alphaであり、前記薬剤は心筋内投与のためのものである。
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Families Citing this family (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7351421B2 (en) * | 1996-11-05 | 2008-04-01 | Hsing-Wen Sung | Drug-eluting stent having collagen drug carrier chemically treated with genipin |
US7291597B2 (en) * | 2000-04-06 | 2007-11-06 | Franco Wayne P | Growth factor therapy mobilization of stem cells into the peripheral blood |
US7288521B2 (en) | 2000-04-06 | 2007-10-30 | Franco Wayne P | Growth factor therapy mobilization of stem cells into the peripheral blood |
US7166280B2 (en) * | 2000-04-06 | 2007-01-23 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic heart disease |
US20100303769A1 (en) * | 2000-04-06 | 2010-12-02 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic heart disease |
JP5414958B2 (ja) * | 2000-06-05 | 2014-02-12 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | ヒト骨髄由来内皮前駆細胞の同定、及び虚血性傷害後の心筋細胞の機能を改善するためのヒト骨髄由来内皮前駆細胞の使用 |
US20030199464A1 (en) * | 2002-04-23 | 2003-10-23 | Silviu Itescu | Regeneration of endogenous myocardial tissue by induction of neovascularization |
US20050271639A1 (en) * | 2002-08-22 | 2005-12-08 | Penn Marc S | Genetically engineered cells for therapeutic applications |
GB2424273B (en) * | 2002-11-14 | 2007-06-27 | Univ Nottingham | Method for preparing tumour marker protein |
US7470538B2 (en) * | 2002-12-05 | 2008-12-30 | Case Western Reserve University | Cell-based therapies for ischemia |
WO2004052177A2 (en) * | 2002-12-05 | 2004-06-24 | Case Western Reserve University | Cell-based therapies for ischemia |
SG148197A1 (en) * | 2003-11-21 | 2008-12-31 | Asubio Pharma Co Ltd | Method for proliferating cardiomyocytes |
US20050232905A1 (en) * | 2004-03-26 | 2005-10-20 | Yeh Edward T | Use of peripheral blood cells for cardiac regeneration |
JP2007536935A (ja) * | 2004-05-14 | 2007-12-20 | ベクトン・ディキンソン・アンド・カンパニー | 間葉幹細胞の無血清増殖のための細胞培養環境 |
JP5269411B2 (ja) * | 2004-06-21 | 2013-08-21 | ザ クリーブランド クリニック ファウンデーション | 幹細胞をホーミングさせるためのccrリガンド |
EP1776453B1 (en) * | 2004-08-13 | 2009-02-25 | Medtronic, Inc. | Isolation of endothelial progenitor cell subsets and methods for their use |
KR20120088865A (ko) | 2004-08-27 | 2012-08-08 | 각고호우징 게이오기주크 | 세포내 미토콘드리아를 지표로 이용하는 심근 세포의 선별 방법 |
KR20130100225A (ko) * | 2004-09-24 | 2013-09-09 | 안지오블라스트 시스템스 인코퍼레이티드 | 간엽 전구세포의 증식 및/또는 생존성 증강 방법 |
WO2006060779A2 (en) * | 2004-12-03 | 2006-06-08 | Case Western Reserve University | Novel methods, compositions and devices for inducing neovascularization |
US8999944B2 (en) | 2005-01-20 | 2015-04-07 | University Of Rochester | Thioredoxin interacting protein (TXNIP) as regulator of vascular function |
US8236772B2 (en) * | 2005-09-16 | 2012-08-07 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of modulating angiogenesis and screening compounds for activity in modulating angiogenesis |
US20110076255A1 (en) | 2005-11-07 | 2011-03-31 | Pecora Andrew L | Compositions and methods for treating progressive myocardial injury due to a vascular insufficiency |
US8637005B2 (en) | 2005-11-07 | 2014-01-28 | Amorcyte, Inc. | Compositions and methods of vascular injury repair |
EP1951864B1 (en) * | 2005-11-07 | 2014-05-07 | Amorcyte, Inc. | Compositions and methods of vascular injury repair |
TW200734462A (en) | 2006-03-08 | 2007-09-16 | In Motion Invest Ltd | Regulating stem cells |
US8574848B2 (en) * | 2006-09-13 | 2013-11-05 | Oncimmune Ltd. | Immunoassay methods |
EP2068897A1 (en) * | 2006-10-03 | 2009-06-17 | Medtronic, Inc. | Endothelial progenitor cell compositions and neovascularization |
US7696309B2 (en) | 2006-10-23 | 2010-04-13 | The Brigham And Women's Hospital, Inc. | Protease resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
WO2008085229A2 (en) * | 2006-11-15 | 2008-07-17 | Arteriocyte Inc. | Cell-based therapies for treating liver disease |
ES2520044T3 (es) * | 2007-03-30 | 2014-11-11 | The Cleveland Clinic Foundation | SDF-1 para su uso en el tratamiento de trastornos vasculares periféricos isquémicos |
CA2709398C (en) | 2007-12-14 | 2017-11-07 | The Cleveland Clinic Foundation | Use of stromal cell-derived factor 1 for promoting wound healing |
WO2009126659A1 (en) | 2008-04-07 | 2009-10-15 | Kalobios Pharmaceuticals, Inc. | Neutralization of gm-csf for the treatment of heart failure |
JP2011521908A (ja) * | 2008-05-09 | 2011-07-28 | デューク ユニバーシティ | チオレドキシンが細胞における一酸化窒素放出を調節するという知見に基づく疾患の治療法 |
US20120058105A1 (en) * | 2008-06-27 | 2012-03-08 | Martin Kean Chong Ng | Method of treatment of vascular complications |
US9572817B2 (en) | 2008-07-04 | 2017-02-21 | The Heart Research Institute Ltd. | Use of androgens for vascular regeneration and endothelial repair |
GB0814302D0 (en) * | 2008-08-05 | 2008-10-01 | Coretherapix Slu | Compounds and methods |
WO2010065601A1 (en) * | 2008-12-03 | 2010-06-10 | Amorcyte, Inc. | Infarct area perfusion-improving compositions and methods of vascular injury repair |
WO2010138180A2 (en) * | 2009-05-26 | 2010-12-02 | The University Of Vermont And State Agriculture College | Compositions and methods for cardiac tissue repair |
CA2772610C (en) | 2009-08-28 | 2018-01-23 | The Cleveland Clinic Foundation | Sdf-1 delivery for treating ischemic tissue |
US20110177091A1 (en) * | 2009-12-08 | 2011-07-21 | Gollnick Sandra O | Inhibition of Tumor Angiogenesis by Inhibition of Peroxiredoxin 1 (PRX1) |
US9050291B2 (en) * | 2009-12-08 | 2015-06-09 | Health Research Inc. | Methods and compositions using peroxiredoxin 1 (PRX1) as an adjuvant |
WO2011081229A1 (ko) * | 2009-12-29 | 2011-07-07 | 이화여자대학교 산학협력단 | 혈관신생 억제용 약제학적 조성물 |
SG10201501353YA (en) * | 2010-02-25 | 2015-04-29 | Abt Holding Co | Modulation of angiogenesis |
US9308277B2 (en) | 2010-02-25 | 2016-04-12 | Mesoblast International Sàrl | Protease-resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
JP2014513727A (ja) | 2011-05-16 | 2014-06-05 | ジェンザイム・コーポレーション | Cxcr4拮抗薬の使用 |
WO2012170495A1 (en) | 2011-06-07 | 2012-12-13 | Provasculon, Inc. | Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1 |
AR087364A1 (es) | 2011-07-29 | 2014-03-19 | Pf Medicament | Anticuerpo anti-cxcr4 y su uso para la deteccion y dianostico de canceres |
AR087363A1 (es) | 2011-07-29 | 2014-03-19 | Pf Medicament | Uso del anticuerpo i-3859 para la deteccion y diagnostico de los canceres |
CN102382127A (zh) * | 2011-09-23 | 2012-03-21 | 复旦大学 | 特异性促进心肌细胞发生增殖的心肌小分子化合物及其应用 |
WO2013070734A1 (en) | 2011-11-07 | 2013-05-16 | Chaudhry Hina W | Methods of cardiac repair |
US10072247B2 (en) * | 2012-10-05 | 2018-09-11 | Samsung Life Public Welfare Foundation | Composition comprising ischemic serum for promoting activation of stem cell and method for promoting activation of stem cell |
US9585915B2 (en) * | 2014-01-23 | 2017-03-07 | Emory University | Polypeptide hydrogels and uses related thereto |
US11491480B2 (en) | 2014-06-13 | 2022-11-08 | Children's Medical Center Corporation | Products and methods to isolate mitochondria |
US9375406B2 (en) * | 2014-09-30 | 2016-06-28 | Taigen Biotechnology Co., Ltd. | Substituted pyrimidines for mobilizing cells expressing a type 4 CXC chemokine receptor |
JP6839393B2 (ja) * | 2015-04-09 | 2021-03-10 | リジェンコア, インコーポレイテッド | 心組織を修復するための心外膜由来パラクリン因子 |
US11433136B2 (en) | 2015-12-18 | 2022-09-06 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
CN105602888A (zh) * | 2016-01-12 | 2016-05-25 | 温州医科大学附属第一医院 | 一种内皮祖细胞快速扩增体系 |
AU2017208013B2 (en) * | 2016-01-15 | 2022-12-01 | Beth Israel Deaconess Medical Center, Inc. | Therapeutic use of mitochondria and combined mitochondrial agents |
WO2018106738A1 (en) | 2016-12-05 | 2018-06-14 | Massachusetts Institute Of Technology | Brush-arm star polymers, conjugates and particles, and uses thereof |
CA3047167A1 (en) | 2016-12-15 | 2018-06-21 | Talengen International Limited | Method for treating and preventing atherosclerosis and complications thereof |
TWI677348B (zh) | 2016-12-15 | 2019-11-21 | 大陸商深圳瑞健生命科學研究院有限公司 | 一種改善心臟病變的方法 |
CN110114079A (zh) | 2016-12-15 | 2019-08-09 | 泰伦基国际有限公司 | 一种预防和治疗肥胖症的方法和药物 |
SG11201908624SA (en) | 2017-04-12 | 2019-10-30 | Magenta Therapeutics Inc | Aryl hydrocarbon receptor antagonists and uses thereof |
WO2019028094A1 (en) * | 2017-08-01 | 2019-02-07 | Temple University-Of The Commonwealth System Of Higher Education | EXOSOMES DERIVED FROM CORTICAL BONE STEM CELLS WHICH CAN INCREASE CARDIAC FUNCTION AFTER CARDIAC INJURY |
EP3704232A1 (en) | 2017-10-31 | 2020-09-09 | Magenta Therapeutics, Inc. | Compositions and methods for the expansion of hematopoietic stem and progenitor cells |
JP2021503008A (ja) | 2017-10-31 | 2021-02-04 | マジェンタ セラピューティクス インコーポレイテッドMagenta Therapeutics, Inc. | 造血幹細胞および前駆細胞移植療法のための組成物および方法 |
MX2020005878A (es) | 2017-12-06 | 2020-10-07 | Magenta Therapeutics Inc | Pautas posológicas para la movilización de células madre y progenitoras hematopoyéticas. |
US11260079B2 (en) | 2017-12-06 | 2022-03-01 | Magenta Therapeutics, Inc. | Dosing regimens for the mobilization of hematopoietic stem and progenitor cells |
US10058573B1 (en) | 2017-12-06 | 2018-08-28 | Magenta Therapeutics, Inc. | Dosing regimens for the mobilization of hematopoietic stem cells |
WO2019136159A1 (en) | 2018-01-03 | 2019-07-11 | Magenta Therapeutics Inc. | Compositions and methods for the expansion of hematopoietic stem and progenitor cells and treatment of inherited metabolic disorders |
WO2019168685A1 (en) * | 2018-02-27 | 2019-09-06 | Cytori Therapeutics, Inc. | Improvement of endothelial cell function |
CN109589339A (zh) * | 2018-12-26 | 2019-04-09 | 山西医科大学 | 人子宫内膜内皮祖细胞在改善损伤心肌细胞上的应用 |
US20230192784A1 (en) * | 2019-07-30 | 2023-06-22 | Victor Chang Cardiac Research Institute | KLF Induced Cardiomyogenesis |
WO2021087406A1 (en) | 2019-11-01 | 2021-05-06 | Magenta Therapeutics, Inc. | Dosing regimens for the mobilization of hematopoietic stem and progentor cells |
EP4143302A1 (en) | 2020-04-27 | 2023-03-08 | Magenta Therapeutics, Inc. | Methods and compositions for transducing hematopoietic stem and progenitor cells in vivo |
WO2022197776A1 (en) | 2021-03-16 | 2022-09-22 | Magenta Therapeutics, Inc. | Dosing regimens for hematopoietic stem cell mobilization for stem cell transplants in multiple myeloma patients |
CN117919400B (zh) * | 2024-03-22 | 2024-05-28 | 再少年(北京)生物科技有限公司 | iPS诱导定向分化的成内皮祖细胞和抗体联合治疗心脑血管疾病 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001094420A1 (en) * | 2000-06-05 | 2001-12-13 | The Trustees Of Columbia University In The City Of New York | Identification and use of human bone marrow-derived endothelial progenitor cells to improve myocardial function after ischemic injury |
WO2002009650A2 (en) * | 2000-07-31 | 2002-02-07 | New York Medical College | Methods and compositions for the repair and/or regeneration of damaged myocardium |
WO2002016416A2 (en) * | 2000-08-22 | 2002-02-28 | The Brigham And Women's Hospital, Inc. | Diagnosis and treatment of cardiovascular conditions |
Family Cites Families (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
US4476301A (en) | 1982-04-29 | 1984-10-09 | Centre National De La Recherche Scientifique | Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon |
US5550111A (en) | 1984-07-11 | 1996-08-27 | Temple University-Of The Commonwealth System Of Higher Education | Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof |
US4987071A (en) | 1986-12-03 | 1991-01-22 | University Patents, Inc. | RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods |
US5276019A (en) | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US5264423A (en) | 1987-03-25 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US5188897A (en) | 1987-10-22 | 1993-02-23 | Temple University Of The Commonwealth System Of Higher Education | Encapsulated 2',5'-phosphorothioate oligoadenylates |
US4924624A (en) | 1987-10-22 | 1990-05-15 | Temple University-Of The Commonwealth System Of Higher Education | 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof |
EP0406309A4 (en) | 1988-03-25 | 1992-08-19 | The University Of Virginia Alumni Patents Foundation | Oligonucleotide n-alkylphosphoramidates |
US5278302A (en) | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
CA1340323C (en) | 1988-09-20 | 1999-01-19 | Arnold E. Hampel | Rna catalyst for cleaving specific rna sequences |
US5194599A (en) | 1988-09-23 | 1993-03-16 | Gilead Sciences, Inc. | Hydrogen phosphonodithioate compositions |
US5008284A (en) | 1989-02-15 | 1991-04-16 | E. R. Squibb & Sons, Inc. | Method of reducing pre- and post-ischemic myocardial arrhythmias and fibrillation |
EP0483247A4 (en) * | 1989-07-21 | 1992-12-09 | Washington University | Recombinantly produced human membrane cofactor protein (mcp) |
US5399676A (en) | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5721218A (en) | 1989-10-23 | 1998-02-24 | Gilead Sciences, Inc. | Oligonucleotides with inverted polarity |
WO1991008231A1 (en) | 1989-11-29 | 1991-06-13 | Brigham And Women's Hospital | [Ala IL-8]77 AS A LEUKOCYTE ADHESION INHIBITOR |
US5177198A (en) | 1989-11-30 | 1993-01-05 | University Of N.C. At Chapel Hill | Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5321131A (en) | 1990-03-08 | 1994-06-14 | Hybridon, Inc. | Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling |
US5061620A (en) * | 1990-03-30 | 1991-10-29 | Systemix, Inc. | Human hematopoietic stem cell |
IE912365A1 (en) * | 1990-07-23 | 1992-01-29 | Zeneca Ltd | Continuous release pharmaceutical compositions |
US5177196A (en) | 1990-08-16 | 1993-01-05 | Microprobe Corporation | Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof |
US5672697A (en) | 1991-02-08 | 1997-09-30 | Gilead Sciences, Inc. | Nucleoside 5'-methylene phosphonates |
JP2697495B2 (ja) | 1991-06-19 | 1998-01-14 | 富士レビオ株式会社 | アルデヒド誘導体 |
US5571799A (en) | 1991-08-12 | 1996-11-05 | Basco, Ltd. | (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response |
US5476925A (en) | 1993-02-01 | 1995-12-19 | Northwestern University | Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups |
GB9304618D0 (en) | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Chemical compounds |
US5599703A (en) | 1993-10-28 | 1997-02-04 | The United States Of America As Represented By The Secretary Of The Navy | In vitro amplification/expansion of CD34+ stem and progenitor cells |
JPH07166906A (ja) * | 1993-12-14 | 1995-06-27 | Nissan Motor Co Ltd | 燃料カットと点火時期変更による加速スリップ制御装置 |
US5625050A (en) | 1994-03-31 | 1997-04-29 | Amgen Inc. | Modified oligonucleotides and intermediates useful in nucleic acid therapeutics |
US5824784A (en) * | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
DE4442665A1 (de) | 1994-11-30 | 1996-06-05 | Gruenenthal Gmbh | Chimäre Proteine mit fibrinolytischen und thrombinhemmenden Eigenschaften |
US6506770B1 (en) * | 1996-06-06 | 2003-01-14 | Anormed, Inc. | Antiviral compounds |
US5980884A (en) * | 1996-02-05 | 1999-11-09 | Amgen, Inc. | Methods for retreatment of patients afflicted with Hepatitis C using consensus interferon |
US6110889A (en) | 1996-06-14 | 2000-08-29 | Board Of Regents, The University Of Texas System | Peptide tumor cell growth inhibitors |
JP3866800B2 (ja) * | 1996-08-29 | 2007-01-10 | 東菱薬品工業株式会社 | アポトーシス関連疾患の予防及び/又は治療薬 |
US5980887A (en) * | 1996-11-08 | 1999-11-09 | St. Elizabeth's Medical Center Of Boston | Methods for enhancing angiogenesis with endothelial progenitor cells |
JP2001507354A (ja) * | 1996-12-20 | 2001-06-05 | クリエイティブ バイオモレキュールズ,インコーポレイテッド | 局所的モルフォゲンまたは形態形成処理された筋形成前駆体細胞による哺乳動物心筋層の処置 |
US6248878B1 (en) | 1996-12-24 | 2001-06-19 | Ribozyme Pharmaceuticals, Inc. | Nucleoside analogs |
US6251666B1 (en) | 1997-03-31 | 2001-06-26 | Ribozyme Pharmaceuticals, Inc. | Nucleic acid catalysts comprising L-nucleotide analogs |
CN1068517C (zh) * | 1997-04-04 | 2001-07-18 | 北京万业经贸发展公司 | 2(3)叔丁基-4-羟基茴香醚在制备防治组织器官损伤性疾病药物中的应用 |
DE69806244T2 (de) | 1997-05-27 | 2002-11-07 | Unichema Chemie Bv | Fettsäuren-oligomere |
GB9716656D0 (en) * | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
EP0897980A3 (en) | 1997-08-20 | 2002-04-17 | Smithkline Beecham Corporation | CXCR4B: A human splice variant of CXCR4 chemokine receptor |
US5880090A (en) * | 1997-09-19 | 1999-03-09 | The Hope Heart Institute | Treatment of vascular graft implants with G-CSF |
DK1019082T4 (da) | 1997-10-02 | 2008-10-27 | Max Planck Gesellschaft | Fremgangsmåde til moduleringen af neovaskularisering og/eller væksten af kollaterale arterier og/eller andre arterier fra forudeksisterende arteriolære forbindelser |
CN1290353A (zh) | 1997-10-06 | 2001-04-04 | 阿克丘拉斯有限公司 | 用于切除组织的方法和设备 |
AU2559799A (en) | 1998-01-22 | 1999-08-09 | Genentech Inc. | Antibody fragment-polymer conjugates and humanized anti-il-8 monoclonal antibodies and uses of same |
AU2469299A (en) | 1998-01-23 | 1999-08-09 | Cornell Research Foundation Inc. | Purified populations of stem cells |
IL138075A0 (en) | 1998-02-27 | 2001-10-31 | Univ Pennsylvania | Vaccines, immunotherapeutics and methods for using the same |
WO1999045775A1 (en) * | 1998-03-09 | 1999-09-16 | St. Elizabeth's Medical Center | Compositions and methods for modulating vascularization |
AU4696899A (en) | 1998-06-19 | 2000-01-05 | General Hospital Corporation, The | Modulating platelet function |
US20020107196A1 (en) | 1998-07-21 | 2002-08-08 | Smithkline Beecham Corporation | Method for inducing chemotaxis in endothelial cells by administering stromal cell derived factor-1alpha |
US6124131A (en) * | 1998-08-25 | 2000-09-26 | The Johns Hopkins University School Of Medicine | Mutant hypoxia inducible factor-1 HIF-1 |
US20060057722A1 (en) | 1999-03-30 | 2006-03-16 | Myocardial Therapeutics, Inc. | Conditioned medium of autologous or allogenic progenitor cells for angiogenesis treatment |
CA2368677C (en) | 1999-03-30 | 2012-07-10 | Ran Kornowski | Intramyocardial injection of autologous bone marrow |
US20060051334A1 (en) | 1999-03-30 | 2006-03-09 | Myocardial Therapeutics, Inc. | Injection of bone marrow-derived conditioned medium for angiogenesis |
WO2001013031A2 (en) | 1999-08-13 | 2001-02-22 | Chiron Corporation | Dose of an angiogenic factor and method of administering to improve myocardial blood flow |
US7547674B2 (en) | 2001-06-06 | 2009-06-16 | New York Medical College | Methods and compositions for the repair and/or regeneration of damaged myocardium |
WO2002020847A2 (en) * | 2000-09-08 | 2002-03-14 | The Regents Of The University Of California | Gene and sequence variation associated with lipid disorder |
AU2001286221B2 (en) | 2000-09-13 | 2006-09-28 | Chugai Seiyaku Kabushiki Kaisha | Remedies for ischemic diseases |
AU2002235168A1 (en) | 2000-11-05 | 2002-05-15 | University Of Florida | Targeting pluripotent stem cells to tissues |
IL146970A0 (en) | 2001-12-06 | 2002-08-14 | Yeda Res & Dev | Migration of haematopoietic stem cells and progenitor cells to the liver |
US20030199464A1 (en) | 2002-04-23 | 2003-10-23 | Silviu Itescu | Regeneration of endogenous myocardial tissue by induction of neovascularization |
US7178755B2 (en) * | 2003-07-30 | 2007-02-20 | Lincoln Global, Inc | Retainer ring for wire package |
US7220407B2 (en) | 2003-10-27 | 2007-05-22 | Amgen Inc. | G-CSF therapy as an adjunct to reperfusion therapy in the treatment of acute myocardial infarction |
-
2002
- 2002-04-23 US US10/128,738 patent/US20030199464A1/en not_active Abandoned
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001094420A1 (en) * | 2000-06-05 | 2001-12-13 | The Trustees Of Columbia University In The City Of New York | Identification and use of human bone marrow-derived endothelial progenitor cells to improve myocardial function after ischemic injury |
WO2002009650A2 (en) * | 2000-07-31 | 2002-02-07 | New York Medical College | Methods and compositions for the repair and/or regeneration of damaged myocardium |
WO2002016416A2 (en) * | 2000-08-22 | 2002-02-28 | The Brigham And Women's Hospital, Inc. | Diagnosis and treatment of cardiovascular conditions |
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