JP6385976B2 - 生理活性腎臓細胞 - Google Patents
生理活性腎臓細胞 Download PDFInfo
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- JP6385976B2 JP6385976B2 JP2016080335A JP2016080335A JP6385976B2 JP 6385976 B2 JP6385976 B2 JP 6385976B2 JP 2016080335 A JP2016080335 A JP 2016080335A JP 2016080335 A JP2016080335 A JP 2016080335A JP 6385976 B2 JP6385976 B2 JP 6385976B2
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Description
本発明は、健康な個体に比べて細胞成分が欠けているが治療活性を維持している生理活性腎臓細胞集団または画分、およびそれを単離し培養する方法、ならびに、その細胞集団を必要としている対象を治療する方法に関する。さらに、本発明は、生理活性腎臓細胞集団を使ってネイティブ腎臓に対し再生効果を与える方法に関する。
慢性腎疾患(CKD)は、1,900万人を越える米国人が罹患しており、また、この疾患は、代謝障害の結果であることが多く、肥満症、糖尿病、および高血圧症を伴う。データ調査により、増加率は、高血圧症およびインスリン非依存性糖尿病(NIDDM)(同じく世界中で増えつつある2つの疾患)に続発する腎不全の発生に起因することが示されている(米国腎臓データシステム(United States Renal Data System):CKDとESRDのコスト.ed.Bethesda、MD、国立衛生研究所、国立糖尿病・消化器病・腎臓病研究所、2007 pp 223−238)。肥満症、高血圧症、および血糖コントロール不良は、全て腎障害の独立したリスク因子であることが示され、糸球体および尿細管障害を生じ、蛋白尿および他の全身的に検出可能な腎臓濾過機能の変化の原因となる(Aboushwareb、et al.、World J Urol、26:295−300、2008;Amann、K.et al.、Nephrol Dial Transplant、13:1958−66、1998)。進行の1〜3ステージのCKD患者は、生活様式の変更および根底にある病的状態の制御を目的とした薬理学的介入によって管理されるが、一方、4〜5ステージの患者は、透析および通常、降圧剤、赤血球生成促進剤(ESA)、鉄およびビタミンD補充を含む投薬計画により管理される。再生医療技術は、CKDに対する次世代の治療オプションを提供できる。国際公開第2010/056328号でPresnell、等は、単離腎臓細胞について記載しているが、これには、尿細管とエリスロポエチン(EPO)産生腎臓細胞集団、および、これらを単離、培養する方法、ならびに、その細胞集団を必要としている対象を治療する方法が含まれている。この患者集団に対し、本当の意味での、長続きのする腎臓機能の増強療法を提供し、進行を遅らせ、生活の質を改善するための新規治療パラダイムが必要である。
本発明は、生理活性腎臓細胞(BRC)の異種起源混合物、およびこれらを単離し培養する方法、ならびに本明細書記載のBRCおよび/またはBRCを播種した足場から形成したBRC含有構築物を必要としている対象を治療する方法に関する。生理活性腎臓細胞は、尿細管およびエリスロポエチン(EPO)産生腎臓細胞含有単離腎臓細胞であってもよい。BRC細胞集団は、富化尿細管およびEPO産生細胞集団を含んでもよい。BRCは、健康な個体由来腎臓細胞画分由来か、または画分それ自体であってもよい。さらに、本発明は、対応する健康な個体の腎臓細胞画分と比較して、特定の細胞成分が欠如している可能性があるが、それでも、治療特性を保持している不健康な個体から採取した腎臓細胞画分を提供する。本発明は、また、健康な個体に比較して細胞成分が欠けている治療的に活性な細胞集団を提供し、一実施形態では、この細胞集団は、種々の疾患状態の自己ソースから単離、増殖できる。
特に断らなければ、本明細書で使われる技術的および科学的用語は、本発明の属する当業者により共通に理解されているものと同じ意味を有する。Principles of Tissue Engineering、3rd Ed.(Edited by R Lanza、R Langer、& J Vacanti)、2007、は本出願で使われる多くの用語に対する一般的ガイドを当業者に提供する。当業者なら、本明細書記載のものと類似の、または等価な、本発明の実施に使用可能な多くの方法と材料に気付くであろう。実際、本発明は、記載されている方法と材料に限定されるものではない。
腎疾患の処置に使用するための、すなわち、腎臓機能の安定化および/または改善および/または再生を提供する、特異的生理活性成分または細胞型を富化した、および/または特異的不活性または望ましくない成分または細胞型を枯渇させた異種起源の単離腎臓細胞集団、およびそれらの混合物は、以前に、2009年11月12日出願の米国特許出願第12/617、721号に記載された。この特許の全内容は、参照により本明細書に組み込まれる。本発明は、健康な個体に比べて、細胞成分を欠くが、依然として、治療特性を保持している、すなわち、腎臓機能の安定化および/または改善および/または再生を行える単離腎臓細胞画分を提供する。本明細書記載の細胞集団、細胞画分、および/または細胞の混合物は、健康な個体、腎疾患の個体、または本明細書記載の対象由来であってもよい。
一態様では、本発明は、生理活性成分を富化させ、不活性または望ましくない成分を枯渇させた異種起源の腎臓細胞集団の特定の亜画分が、出発集団より優れた治療および再生結果を提供するという驚異的知見に基づいている。例えば、本発明の生理活性成分、例えば、不活性または望ましくない成分、例えば、B1およびB5が枯渇しているB2、B4、およびB3は、単独または混合して、予想外の腎臓機能の安定化および/または改善および/または再生を提供する。
ヒアルロナン(ヒアルロン酸またはヒアルロン酸塩とも呼ばれる)は、グリコサミノグリカン(GAG)であり、非硫酸化二糖ユニットの規則的反復配列、特にN−アセチルグルコサミンおよびグルクロン酸から構成される。その分子量は、400ダルトン(二糖)から百万ダルトン超までの範囲に及ぶ。それは、皮膚、軟骨、および目等、の全組織中、ならびに、成人動物の、全てではないにしても、ほとんどの体液中に可変量として認められる。それは特に初期の胚中に豊富である。ヒアルロナンにより形成された空間、および実際にGAGは、通常、細胞遊走、細胞付着中に、創傷修復、器官形成、免疫細胞接着、細胞内シグナル伝達の活性化、ならびに腫瘍転移の間に、それが何らかの役割を果たすことを可能とする。これらの役割は、ヒアルロナンへの特異的タンパク質およびプロテオグリカンの結合により媒介される。細胞の運動性および免疫細胞接着は、細胞表面受容体RHAMM(ヒアルロナン媒介運動性のための受容体;Hardwick et al.、1992)およびCD44(Jalkenan et al.、1987;Miyake et al.、1990)により媒介される。ヒアルロナンは、細胞表面の内側膜で直接合成され、合成されるにつれ、成長するポリマーが膜を通して細胞の外側へ押し出される。合成は、遺伝子ファミリーが少なくとも3つのメンバーから構成される単一タンパク質酵素、ヒアルロナン合成酵素(HAS)により媒介される。
本明細書で記載のように、本発明は、1つには、生理活性成分富化および不活性または望ましくない成分が枯渇している腎臓細胞の異種起源の集団の特定亜画分が、出発集団よりも優れた処置および再生の結果を提供するという驚くべき知見に基づいている。好ましい実施形態では、本発明の細胞集団は、B1および/またはB5細胞集団が枯渇している。例えば、下記は、B1および/またはB5を枯渇していてもよい:2つ以上のB2、B3、およびB4’の混合物;B2、B3、およびB4’富化細胞集団。
一態様では、本発明は、治療上の使用のために、腎臓細胞成分、例えば、富化細胞集団を分離し、単離する方法を提供し、この方法は、腎疾患、貧血、EPO欠乏、尿細管輸送機能欠損、および糸球体濾過機能低下の処置を含む。一実施形態では、細胞集団は新たに消化された、すなわち、機械的に、もしくは酵素的に消化された腎臓組織から、または哺乳類腎臓細胞のインビトロ異種起源培養物から単離される。
Bertram et al.の特許公開第20070276507号(参照によりその全体が本明細書に組み込まれる)に記載のように、ポリマーマトリックスまたは足場は、任意の数の所望形状に成形して、任意の数の全体系、幾何学的配置または空間の制約を満たすことができる。一実施形態では、本発明のマトリックスまたは足場は、3次元であってもよく、また、成形されて、器官または組織構造の寸法と形状に適合されてもよい。例えば、腎疾患、貧血、EPO欠乏、尿細管輸送機能欠損、または糸球体濾過機能低下の処置のためのポリマー足場の使用で、3次元(3−D)マトリックスを使用できる。種々の別々に成形された3−D足場を使用可能である。当然、ポリマーマトリックスは、異なるサイズと形状に成形して別々のサイズの患者に適合させることができる。ポリマーマトリックスは、また、別の方法で成型して、特殊ニーズの患者に適合させることができる。別の実施形態では、ポリマーマトリックスまたは足場は、生体適合性、多孔性ポリマー足場であってもよい。足場は、限定されないが、次記を含む種々の合性または天然材料から形成してもよい:連続気泡ポリ乳酸(OPLA(登録商標))、セルロースエーテル、セルロース、セルロースエステル、フッ化ポリエチレン、フェノール、ポリ−4−メチルペンテン、ポリアクリロニトリル、ポリアミド、ポリアミデイミド、ポリアクリラート、ポリベンゾオキサゾール、ポリカルボナート、ポリシアノアリールエテル、ポリエステル、ポリエステルカルボナート、ポリエーテル、ポリエーテルエーテルケトン、ポリエーテルイミド、ポリエーテルケトン、ポリエーテルスルホン、ポリエチレン、ポリフルオロオレフィン、ポリイミド、ポリオレフィン、ポリオキサジアゾール、ポリフェニレンオキシド、ポリフェニレンスルフィド、ポリプロピレン、ポリスチレン、ポリスルフィド、ポリスルホン、ポリテトラフルオロエチレン、ポリチオエーテル、ポリトリアゾール、ポリウレタン、ポリビニル、ポリフッ化ビニリデン、再生セルロース、シリコーン、尿素−ホルムアルデヒド、コラーゲン、ラミニン、フィブロネクチン、絹、エラスチン、アルギナート、ヒアルロン酸、アガロース、またはそれらの共重合体もしくは物理的混合物。足場形状は、ソフト多孔性足場としての液体ヒドロゲル懸濁液から剛直、形状保持多孔性足場までの範囲が可能である。
一態様では、本発明は、治療を必要としている対象の腎疾患、貧血、またはEPO欠乏の処置のための1つまたは複数の本明細書記載の細胞集団を有する移植可能な構築物を提供する。一実施形態では、構築物は、1つまたは複数の合性または天然生体適合性材料からなる生体適合性材料または生体材料、足場またはマトリックス、および付着および/または捕捉により足場の表面上に析出したまたは内部に包埋された1つまたは複数の細胞集団または本明細書記載の細胞の混合物で作られている。特定の実施形態では、構築物は、生体材料、および生体材料成分でコートされた、その上に析出させた、その中に析出させた、それに付着させた、その中に捕捉された、その中に包埋された、またはそれと組み合わされた、1つまたは複数の細胞集団または本明細書記載の細胞の混合物で作られている。富化細胞集団またはそれらの混合物を含むいずれかの本明細書記載の細胞集団は、マトリックスと組み合わせて使用して、構築物を形成することができる。
a)1つまたは複数の生体適合性合成高分子または天然タンパク質またはペプチドを含む生体材料;および
b)腎疾患を有する対象由来の哺乳類腎臓細胞の混合物で、1.045g/mL〜1.052g/mLの密度の単離された、尿細管細胞富化集団を含む第1細胞集団、B2、および、エリスロポエチン(EPO)産生細胞および血管細胞を含むが、糸球体細胞が枯渇している1.063g/mL〜1.091g/mLの密度の第2細胞集団、B4’を含み、これら細胞集団は、生体材料成分でコートされ、その上もしくはその中に析出し、その中に捕捉され、その中に懸濁され、その中に包埋され、および/または別の方法でそれと組み合わされている。
もう一つの態様では、本発明は、本明細書記載の富化腎臓細胞集団または富化腎臓細胞集団の混合物からの分泌産物に関する。一実施形態では、産物は、1つまたは複数の下記を含む:パラクリン因子、内分泌因子、ジャクスタクライン因子、および小胞。小胞は、1つまたは複数の次の物を含んでもよい:パラクリン因子、内分泌因子、ジャクスタクライン因子、微小胞、エキソソーム、およびRNA。分泌産物は、また、微小胞内にない産物を含んでもよく、限定されないが、パラクリン因子、内分泌因子、ジャクスタクライン因子、およびRNAが含まれる。例えば、細胞外のmiRNAは、小胞外から検出されている(Wang et al.、Nuc Acids Res 2010、1−12doi:10.1093/nar/gkq601、July 7、2010)。分泌産物は、また、細胞由来産物、例えば、細胞由来小胞、と呼ばれる。
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一態様では、本発明は、治療を必要としている対象の腎疾患、貧血、またはEPO欠乏を本明細書記載の腎臓細胞集団および腎臓細胞の混合物により処置する方法を提供する。一実施形態では、方法は、EPO産生細胞富化第1腎臓細胞集団を含む組成物を対象に投与することを含む。別の実施形態では、第1細胞集団は、EPO産生細胞、糸球体細胞、および血管細胞が富化されている。一実施形態では、第1腎臓細胞集団は、B4’細胞集団である。別の実施形態では、組成物は、1つまたは複数の追加の腎臓細胞集団をさらに含んでもよい。一実施形態では、追加の細胞集団は、EPO産生細胞が富化されていない第2細胞集団である。別の実施形態では、追加の細胞集団は、EPO産生細胞、糸球体細胞、または血管細胞が富化されていない第2細胞集団である。別の実施形態では、組成物は、また、本明細書記載の疾患または障害の処置のために、生体材料中に析出して、その上に析出して、その中に包埋されて、それによりコートされて、またはその中に捕捉されて本明細書記載の移植可能な構築物を形成する腎臓細胞集団または腎臓細胞混合物を含む。一実施形態では、細胞集団は、単独または他の細胞または生体材料、例えば、ヒドロゲル、多孔性足場、またはネイティブもしくは合成ペプチドまたはタンパク質と組み合わせて使用し、急性または慢性疾患状態の再生を刺激する。
合物は、必要としている対象に対し自己である腎臓検体由来である。一実施形態では、検体は、腎生検である。他の実施形態では、本発明の方法で使われる混合物は、非自己腎臓検体由来である。
別の態様では、本発明は、本明細書記載の細胞集団、混合物、または構築物の対象への投与または移植後のネイティブ腎臓の再生をモニタリングするための予後徴候予測方法を提供する。一実施形態では、方法は、対象由来試験検体および対照検体中のマーカー発現レベルを検出するステップを含み、対照検体に比べてより高いレベルの試験検体中のマーカーの発現は、対象のネイティブ腎臓の再生の予後徴候となる。別の実施形態では、方法は、検体中の1つまたは複数の幹細胞マーカーの発現の検出を含む。幹細胞マーカーは、Sox2;UTF1;NODAL;CD133;CD24;およびこれらの任意の組み合わせから選択できる。検出ステップは、幹細胞マーカーの発現が発現上昇しているか、または対照検体に比べ試験検体中で高いことを測定することを含んでもよく、より高いレベルの発現は、対象のネイティブ腎臓再生の予後徴候となる。もう一つの実施形態では、幹細胞マーカーのmRNA発現が検出される。他の実施形態では、mRNA発現の検出は、PCRベース方法、例えば、qRT−PCRによってもよい。インサイツハイブリダイゼーションもまた、mRNA発現の検出に使用できる。
本発明の細胞調製物および/または構築物は、単独または他の生理活性成分と組み合わせて投与できる。
本発明は、本発明のポリマーマトリックスおよび足場および関連材料、および/または細胞培地および使用説明書を含むキットをさらに含む。使用説明書は、例えば、細胞の培養または細胞および/または細胞産物の投与に関するインストラクションを含んでもよい。一実施形態では、本発明は、本明細書記載の足場およびインストラクションを含むキットを提供する。さらに別の実施形態では、キットは、マーカー発現検出用試薬、薬剤を使用するための試薬、および使用説明書を含む。このキットは、本明細書記載の細胞集団、混合物、または構築物の移植または投与後の対象のネイティブ腎臓の再生予後の測定のために使うことができる。キットは、また、本明細書記載の細胞集団、混合物、または構築物のバイオセラピューティック効力の測定に使用可能である。
本発明の方法では、商業目的で実施する場合、一般的に、再生予後の報告書または要約を作成する。本発明の方法は、本明細書記載の細胞集団、混合物、または構築物のいずれかの投与または移植の前と後の可能なコースまたは再生結果の予測を含む報告を作成することになる。この報告は、予後に関連するいずれかの指標の情報を含んでもよい。本発明の方法および報告は、データベースに報告を保存することもさらに含んでもよい。あるいは、方法は、対象に対するデータベースに記録をさらに作成することができ、記録にデータを呼び込むことができる。一実施形態では、報告は、文書による報告書であり、別の実施形態では、報告は、聴覚による報告であり、別の実施形態では、報告は電子記録である。報告は、医師および/または患者に提供されることが意図されている。報告の受領は、データおよび報告を含むサーバーコンピュータにネットワーク連結を確立すること、およびサーバーコンピュータからデータおよび報告を要求することをさらに含む。本発明により提供される方法は、また、全体または一部が自動化されてもよい。
成体雄ブタ(イノシシ)の貧血を伴う特発性進行性慢性腎疾患(CKD)の症例から、同年齢の正常なブタ腎臓組織と直接比較して細胞組成物の評価とキャラクタリゼーションを行うための、新鮮な腎臓患部組織が提供された。採取時間での腎臓組織の組織学的検査により、重篤なびまん性慢性間質性線維症および多巣性線維形成を伴う半月体形成性糸球体腎炎を特徴とする腎疾患であると確認された。臨床化学により、高窒素血症(血中尿素窒素および血清クレアチニンの上昇)、および軽度の貧血(ヘマトクリットの軽度の減少および低下したヘモグロビンレベル)である事が確認された。病気および正常の両方の腎臓組織由来の細胞が単離され、増殖されて、特性が明らかにされた。Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図1に示されるように、ゴモリのトリクローム染色により正常な腎臓組織に比較して腎臓患部組織中の線維形成が強調される(矢印で示す青色染色)。キュビリン:メガリンを発現し、受容体媒介アルブミン輸送ができる機能性尿細管細胞が、正常および病気両方の腎臓組織から増殖する。エリスロポエチン(EPO)発現細胞は、また、培養物中に存在し、複数の継代中保持され、冷凍/解凍サイクルを受ける。さらに、分子分析により、正常および患部組織の両方由来のEPO発現細胞は、インビトロの低酸素性の条件に応答し、EPOおよびvEGF等の他の低酸素調節遺伝子標的のHIF1α駆動型誘導が起こる。細胞は、コラゲナーゼ+ディスパーゼの酵素消化によりブタ腎臓組織から単離され、また、単純な機械的消化および外植片培養を行うことにより、別の実験でも単離された。継代2で、EPO発現細胞含有外植片由来細胞培養を大気(21%)および可変の低酸素性(<5%)培養の両方の条件に供し、低酸素への暴露が、EPO遺伝子発現の上昇発現の結果をもたらすのかどうかを判定する。げっ歯類培養で述べるように(実施例3を参照)、正常なブタは、酸素依存性発現およびEPO遺伝子調節を示した。驚くべきことに、CKDブタの尿毒性/貧血状態(ヘマトクリット<34、クレアチニン>9.0)にもかかわらず、EPO発現細胞は、容易に単離され、組織から増殖し、EPO遺伝子の発現は、低酸素に調節されたままであった(Presnell et al.国際公開
第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図2に示すように)。Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図3に示すように、増殖培養物中の細胞は、尿細管様構造へと自己組織化する能力を示した。Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図4に示すように、培養細胞によるFITC複合化アルブミンの受容体媒介取込を観察することにより、培養物(継代3の)中の機能的尿細管細胞の存在が確認された。緑色ドット(細い白色の矢で示す)は、取り込まれたフルオレセイン複合化アルブミンを表し、これは、尿細管細胞特異的受容体、メガリンとキュビリンにより媒介され、機能的尿細管細胞によるタンパク質の再吸収を示す。青色染色(細い白色の矢で示す)は、Hoescht染色した核である。まとめると、これらのデータは、機能的尿細管および内分泌細胞は、CKDに激しく侵されている腎臓組織であっても、ブタ腎臓組織から単離、増殖できることを示唆している。さらに、これらの知見は、CKDの処置に対する自己細胞ベースの治療薬の進展を支援する。
腎臓細胞単離:簡単に述べると、10、2週齢雄Lewisラット腎臓のバッチを市販品納入業者(Hilltop Lab Animals Inc.)から入手し、約4℃のViaspan保存培地中に入れ一晩輸送した。本明細書記載の全ステップは、生物学的安全キャビネット(BSC)中で行い、無菌を保った。腎臓を、ハンクス平衡塩類溶液(HBSS)で3回洗浄してViaspan保存培地を洗い流した。3回目の洗浄後、残っている腎臓カプセル剤、ならびに残っている全ての間質組織が除去された。また、主要腎杯を顕微解剖技術を使って取り出した。次に、腎臓を無菌のメスを使って細かく分割してスラリーにした。その後、スラリーを50mlの遠心分離機のコニカルチューブに移し、秤量した。小検体をRNA分析用に集め、無菌の無RNアーゼ1.5ml微量遠心分離機チューブ中に入れ、液体窒素中で急速凍結した。凍結するとすぐに、−80℃フリーザーに移し、分析まで保存した。10個の若齢腎臓の組織重量は、約1グラムに相当する。バッチの重量に基づいて、消化培地を、1グラムの組織当たり20mlの消化培地になるように調節した。この手続き用消化緩衝液には、4ユニットのHBSS中ディスパーゼ1(Stem Cell Tech)、5mM CaCl2(シグマ)含有300Units/mlのコラゲナーゼタイプIV(Worthington)を含めた。
養後に、密度勾配分離を行った場合は、EPO産生細胞、糸球体有足細胞、および血管細胞(「B4」)富化画分は、1.073〜1.091g/mLの密度の区分に分配された。重要なのは、培養物の低酸素性培養環境への暴露(約1時間〜約24時間の間)により、培養後に細胞の「B2」および「B4」画分への分配が高められたことである(低酸素は、採取およびステップ勾配手続きの前で、21%(大気)未満の酸素レベルとして定義される(バンド分布に対する低酸素効果についてのさらなる詳細は、実施例3で提供される))。
プロトタイプB2およびB4の分布および組成に与える酸素条件の効果を測定するために、勾配ステップの前に、異なる種由来の新規腎臓(neokidney)細胞調製物を種々の酸素条件に暴露した。ラット細胞単離および培養開始のための標準的手順を使って、上述のように、げっ歯類新規腎臓増強(NKA)細胞調製物(RK069)を形成した。21%(大気)酸素条件下で2〜3日間、全てのフラスコを培養した。培地を交換し、半分のフラスコを2%酸素に設定された酸素制御インキュベーターに再配置し、一方、残りのフラスコを追加の24時間の間、21%酸素条件に保持した。次に、上述の標準的な酵素による採取法を使って、各セットの条件から細胞を採取した。標準的手続きに従ってステップ勾配を調製し、「正常酸素圧」(21%酸素)および「低酸素性の」(2%酸素)培養物を別々に採取し、並行してステップ勾配に適用した(図2)。両条件で4バンドおよびペレットが生成されたが、勾配全体の細胞の分布は、21%と2%酸素培養バッチで異なっていた(表1)。特に、B2の収率は、低酸素で増加し、同時にB3が減少した。さらに、低酸素性培養細胞から生成された勾配中でB4特異的遺伝子(例えば、エリスロポエチン)の発現が増加した(Presnell et al.国際公開第2010/056328号の図73を参照)。
全体にわたり記載されている酵素を使った単離方法により、正常なヒト腎臓組織から尿細管および糸球体細胞を単離し、増殖した。上述の勾配方法により、尿細管細胞画分を培養後、エクスビボで富化した。Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図68に示すように、表現型特性は単離および増殖中、維持された。標識アルブミンの取込により評価された尿細管細胞機能は、また、繰り返された継代後も維持され、冷凍保存された。Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図69は、尿細管富化および尿細管枯渇集団が3Dダイナミック培養により培養される場合、尿細管マーカー、カドヘリン発現の有意な増加が尿細管富化集団で認められた。このことにより、細胞が3Dダイナミック環境で培養される場合、尿細管細胞の富化が、初期の富化を越えて維持できることが確認される。
上述の実施例2で記載の腎臓細胞の同じ培養集団をフローサイトメトリー分析に供し、前方散乱および側方散乱を調査した。小さくて、顆粒がより少ないEPO産生細胞集団は識別可能であり(8.15%)、また、フローサイトメーターの選別能力を使って、小さくて、顆粒がより少ない集団のポジティブセレクションにより分離される(Presnell et al.国際公開第2010/056328号(参照によりその全体が本明細書に組み込まれる)の図70を参照))。
腎臓細胞の未分画混合物を上述のように自己免疫性糸球体腎炎患者検体から単離した。腎臓組織から単離、増殖された腎臓細胞の特定亜集団の不偏の遺伝子型組成を決定するために、定量リアルタイムPCR(qrtpcr)分析(Brunskill et al.、前出、2008)を採用し、細胞亜画分中の細胞型特異的および経路特異的遺伝子発現パターンの差異を特定した。表6.1に示すように、HK20は、自己免疫性糸球体腎炎患者検体である。表6.2は、qRTPCR測定の結果の基づき、HK20から生成された細胞は、糸球体細胞が欠乏していることを示す。
腎臓組織から単離、増殖された腎臓細胞の特定亜集団の不偏の遺伝子型組成を決定するために、定量リアルタイムPCR(qrtpcr)分析(Brunskill et al.、前出、2008)を採用し、細胞亜画分中の細胞型特異的および経路特異的遺伝子発現パターンの差異を特定した。糸球体の大部分が破壊されている巣状分節性糸球体硬化症(FSGS)の症例由来の、ヒト調製物HK023をB4画分の糸球体細胞の存在に関し、採取時に評価した。簡単に述べると、未分画(UNFX)培養物を生成し(Aboushwareb et al.、前出、2008)、標準的生検方法を使って腎臓から採取した(4)コア生検をそれぞれ相互に独立に維持した。UNFXエクスビボでの(2)継代後、細胞を採取し、密度勾配法(実施例8のように)に供し、げっ歯類、イヌ、および他のヒト検体で行った研究に基づいて、内分泌、血管、および糸球体細胞が富化されていると解っている亜画分B4を含む亜画分を生成した。
蛍光活性化セルソーター(FACS)を使って、1つまたは複数の単離腎臓細胞を富化でき、および/または単離した1次腎臓組織から1つまたは複数の特定の腎臓細胞型を枯渇できる。
1つまたは複数の単離された腎臓細胞を富化でき、および/または1つまたは複数の特定の腎臓細胞型を単離1次腎臓組織から枯渇できる。
細胞選別または枯渇の後に、検体を集め、使用まで氷上に置く。
枯渇または選別された検体の純度をフローサイトメトリーで検証する。
本調査の目的は、ハイコンテントアナリシス(HCA)によりヒトNKA細胞の機能的特性解析を行うことにあった。ハイコンテントイメージング(HCI)は、多くの検体全体に対し、2つ以上の蛍光プローブ(多重処理)を使って、複数の細胞下イベントの同時画像処理を提供する。ハイコンテントアナリシス(HCA)は、ハイコンテントイメージングで捕捉された複数の細胞パラメーターの同時定量測定を提供する。簡単に述べると、未分画(UNFX)培養物を生成し(Aboushwareb et al.、前出、2008)、標準的生検手順を使って、進行性慢性腎疾患(CKD)および3つの非CKDヒト腎臓を含む5つのヒト腎臓から採取したコア生検とは独立に維持する。UNFXのエクスビボによる(2)継代後、細胞を採取し、密度勾配法(実施例2のように)に供し、亜画分B2、B3、および/またはB4を含む亜画分を生成する。
この調査は、治療的生理活性1次腎臓細胞亜集団で処理した5/6腎摘出ラットにおける腎臓再生の予測因子としての幹細胞および前駆細胞マーカー発現に関する。根底にあるNKA処置が腎機能を改善するメカニズムは、特徴付けられつつある。NKA処置の作用機序に関する我々の調査は、細胞−細胞シグナル伝達、生着、および線維化経路に関する。本調査は、NKA処置が、−おそらく、動員腎臓幹細胞の動員による−器官固有の再生能力をどのようしてに高めることができるかについてに焦点を絞った。我々は、NKA処置5/6NXラットで観察された生存の延長および腎機能の改善は、特定の幹細胞マーカー分子の発現に関連していると仮定する。
ラット由来1次腎臓細胞集団の単離:前述のように、ラットから1次腎臓細胞集団の単離を行った(Aboushwareb et al.、前出、2008;Presnell et al.、2009 FASEB J 23:LB143)。
ces、Piscataway NJ)を使って発色させ、ChemiDoc(登録商標)XRS分子イメージャーおよびQuantity One(登録商標)ソフトウェア(BioRad、Hercules CA)を使って可視化した。
我々は、再生結果を得る機序を解明するためのインビボ調査の設計に繋げるために、特定のエキソソーム由来miRNAと、標的細胞における機能的に関連した結果とをインビトロで関連付けるよう努めてきた。
この調査では、我々は、インビトロ細胞ベースアッセイを採用し、生理活性腎臓細胞がプラスミノーゲン活性化因子阻害剤−1(PAI−1)等のメディエーターにより線維形成を調節できると思われるパラクリン機序を調査した。
この調査では、我々は、5/6腎摘出術モデルの疾患進行のNKA媒介減弱化におけるNFκB経路の役割を調査し、また、NFκB活性化の直接調節による再生結果に対し寄与できる生理活性腎臓細胞の特性を特定することを検討した。図17Gは、TNFαによるNFkB経路の標準的活性化を示す。
ゼラチンまたはHAベースヒドロゲル上に播種した腎臓細胞集団は生存可能であり、トランスクリプトーム、プロテオミクス、セクレトームおよび共焦点免疫蛍光法アッセイにより測定して、3日間のインビトロ成熟の間、尿細管上皮機能性表現型を維持した。NKA構築物が疾患状態に影響する可能性のある機序を調べるため、CKD進行に付随する尿細管間質性線維形成に関係するTGF−βシグナル伝達経路に対する馴化培地の効果を評価した。馴化培地は、ヒト近位尿細管細胞株(HK2)中でのインビトロTGF−β−誘導上皮間葉転換(EMT)を弱めることが観察された。
生体材料:生体材料を、ビーズ(同種構成の球形状)として、または粒子(ギザギザの縁のある異種起源集団)として、調製した。Percell Biolytica(Åstorp、スエーデン)により製造されたゼラチンビーズ(Cultispher SおよびCultispher GL)をそれぞれ、Sigma−Aldrich(St.Louis、MO)およびFisher Scientific(Pittsburgh、PA)から購入した。架橋HAおよびHA/ゼラチン(Glycosan BioSystems、Salt Lake City、UTからのHyStem(登録商標)およびExtracel(登録商標))粒子を、メーカーのインストラクションに従って作成した凍結乾燥スポンジから形成した。ゼラチン(Sigma)粒子を架橋、凍結乾燥スポンジから形成した。
配を800xgで20分間、室温で遠心分離した(ブレーキ無し)。対象のバンドをピペットで取り出し、無菌の燐酸塩緩衝食塩水(PBS)で2回洗浄した。
生体材料の腎実質中への注射に対する哺乳類腎臓組織の応答:健康なラット腎臓への直接注射により、生体材料の腎臓細胞/生体材料複合体としての使用の可能性を分析した(表15.3)。組織応答を、注射後1および4週目の病理組織学パラメーター(炎症、線維形成、壊死、石灰化/鉱質化)および生体適合性パラメーター(生体材料分解、新血管新生、および新組織形成)の程度を測定することにより評価した。
慢性腎疾患(CKD)モデルの立証された治療機能を有する腎臓上皮細胞選択集団(B2)の単離および機能における酸素圧力の役割を調査した。この調査では、処理中の低酸素暴露が選択されたヒトの選択腎臓細胞(SRC)または生理活性腎臓細胞(BRC)の組成および機能を変えるのか否かを調べた。2%酸素への暴露に際し、以下が観察された:密度勾配全体にわたる細胞の分布の変化(Presnell et al.国際公開第10/056328号を参照;この特許は参照によりその全体が本明細書に組み込まれる)、全体の勾配後収率の改善、酸素により調節される遺伝子発現(Kelley et al.前出、(2010)、で以前に報告)の調節、エリスロポエチン、VEGF、HIF1アルファ、およびKDR(VEGFR2)の発現増加。処理中の低酸素への暴露は、選択生理活性腎臓細胞の傷害性尿細管を修復/再生する能力を高める。
尿中に排出された腎臓由来微小胞の内腔含有物内に含まれるmiRNAおよびタンパク質の分析を行い、再生結果を評価するためのバイオマーカーとして使用可能かどうかを判定した。過剰微小胞が細胞外の空隙に排出されるに従い、一部は隣接細胞と融合し、他のものは、尿中に分泌される(Zhou et al.2008.Kidney Int.74(5):613−621)。これらの尿中の微小胞は、今度は、処置結果のより良い理解に向けたアッセイ開発のための優れたバイオマーカーになる。
1:ZSF1動物−PBS溶媒注射;注射後197日に尿採取
2:ZSF1動物−PBS溶媒注射;注射後253日に尿採取
3:ZSF1動物−B2+B4画分注射;注射後197日に尿採取
4:ZSF1動物−B2+B4画分注射;注射後253日に尿採取
5.ZSF1動物−注射なし;調査の197日目に尿採取
6.ZSF1動物−注射なし;調査の253日目に尿採取
7.健康動物−注射なし;調査の197日目に尿採取
8.健康動物−注射なし;調査の253日目に尿採取
処置後197日目および約253日目に試験動物から尿を採取した。当技術分野で既知の標準的な方法により尿から微小胞を回収した(例えば、Zhou et al.Kidney Int.2008 September;74(5):613−621、を参照)。図35の標準的ウェスタンブロッティングで示されるように、処置動物の尿から回収された微小胞(レーン3〜4)は、溶媒処置(レーン1〜2)または未処置対照(レーン5〜8)に比較して、前駆細胞関連タンパク質(CD133およびWNT7A)の増加を示した。実際、微小胞は、微小胞特異的タンパク質CD63の発現(図35)により示されるように、病気の動物の尿(レーン1〜6)のみから回収され、健康な対照(レーン7〜8)からは回収されなかった。CD133含有微小胞は、腎臓細胞から排出されたプロミノソーム(prominosome)であるように見える。CD133およびWNT7Aの両方は、再生および幹細胞分裂に関連するとされてきた(Romagnani P and Kalluri R.2009.Fibrogenesis Tissue Repair.2(1):3;Lie et al.2005.Nature.437(7063):1370−5;Willert et al.2003.Nature.423(6938):448−52;Li et al.2009.Am J Physiol Renal Physiol.297(6):F1526−33)。まとめると、このことは、再生をモニターするように設計されたアッセイ開発のために、微小胞中でバイオマーカーとして発現したタンパク質を標的とすることを支持する。
Claims (9)
- 富化腎臓細胞集団により産生されるヒト分泌小胞を含む組成物であって、該小胞がパラクリン因子を含むエキソソームを含み、該パラクリン因子は、プラスミノーゲン活性化因子阻害剤−1(PAI−1)シグナル伝達および/または形質転換増殖因子β(TGFβ)シグナル伝達を減弱する、ヒト被検体での腎疾患の治療において該組成物の該被検体へのインビボ投与により腎臓線維形成を低減させる方法における使用のための組成物。
- 小胞が微小胞をさらに含む、請求項1に記載の使用のための組成物。
- 小胞がエキソソームである、請求項1に記載の使用のための組成物。
- 腎臓線維形成が上皮間葉転換(EMT)の阻害により減少させられる、請求項1から3のいずれか1項に記載の使用のための組成物。
- 小胞が、TGF−β1を阻害するmiRNAを含む、請求項1から4のいずれか1項に記載の使用のための組成物。
- 小胞が、PAI−1を阻害するmiRNAを含む、請求項1から4のいずれか1項に記載の使用のための組成物。
- 集団が:
(a)尿細管細胞の富化集団を含む第1細胞集団、B2;または
(b)第1細胞集団、B2を含むヒト腎臓細胞、および第2細胞集団の混合物
を含み、B2が尿細管細胞の富化集団を含み、第2細胞集団が1つまたは複数の糸球体細胞および血管細胞を含む、請求項1から6のいずれか1項に記載の使用のための組成物。 - 富化腎臓細胞集団がネイティブ腎臓に対し非自己である、請求項1から7のいずれか1項に記載の使用のための組成物。
- 富化腎臓細胞集団がネイティブ腎臓に対し自己である、請求項1から7のいずれか1項に記載の使用のための組成物。
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