JP2016504017A - 腎細胞集団及びその使用 - Google Patents
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Abstract
Description
本出願は、2012年10月24日に出願された「単離された再生腎細胞及びその使用」と題する米国特許仮出願番号61/718,150及び2013年9月11日に出願された「腎細胞集団及びその使用」と題する同61/876,616の優先権を主張する。
赤血球を作るように骨髄を刺激するエリスロポイエチン又はEPOと、
血圧を調節するレニンと、
生体における骨及び正常な化学均衡のためにカルシウムを維持するのを助けるビタミンDの活性型であるカルシトリオールと
を放出する。
哺乳類の腎臓試料から細胞を単離する工程と、
前記単離された細胞を1以上の標識された検出部分に暴露する工程と、
生体マーカーのそれぞれを発現する細胞の比率を決定する工程とを含み、
各標識された検出部分は異なる前記生体マーカーに向けられ、異なる標識で標識される。
特に定義されない限り、本明細書で使用される専門用語及び科学用語は、本発明が属する技術の当業者によって一般に理解されるものと同じ意味を有する。Principles of Tissue Engineering,第3版(Edited by R Lanza, R Langer, & J Vacanti),2007は当業者に本出願で使用される用語の多数に対する一般的な指針を提供する。当業者は、本発明の実践で使用されればよい、本明細書で記載されるものに類似する又は同等である多数の方法及び材料を認識するであろう。
本開示の製剤は、腎疾患の治療にて使用するための、特定の生物活性のある成分又は細胞型について濃縮され、及び/又は特定の不活性の又は望ましくない成分又は細胞型を枯渇させた、単離された不均質な腎細胞の集団及びその混加物を含有し得る、すなわち、腎機能の安定化及び/又は改善及び/又は再生を提供することは、その内容全体が参照によって本明細書に組み入れられるPresnellらのU.S.2011−0117162及びIlaganらのPCT/US2011/036347にて以前記載された。製剤は、健常個体に比べて細胞成分を欠くが、治療特性を保持する単離された腎細胞の分画を含有し得る、すなわち、腎機能の安定化及び/又は改善及び/又は再生を提供し得る。本明細書で記載される細胞の細胞集団、細胞分画及び/又は混加物は、健常個体、腎疾患の個体、又は本明細書で記載されるような対象に由来し得る。
本開示は、必要とする対象における標的の臓器又は組織に投与されるべきである生物活性のある細胞集団に好適である治療用製剤を企図する。生物活性のある細胞集団は一般に対象への投与の際、潜在的に治療特性を有する細胞集団を指す。たとえば、必要とする対象への投与の際、生物活性のある腎細胞集団は対象における腎機能の安定化及び/又は改善及び/又は再生を提供することができる。治療特性には再生効果が含まれ得る。
他の態様の1つでは、本開示の製剤は細胞の凝集体又はスフェロイドを含有する。一実施形態では、細胞凝集体は本明細書で記載される生物活性のある細胞集団を含む。別の実施形態では、細胞凝集体は、たとえば、腎細胞の混加物、濃縮された腎細胞集団及び腎細胞分画の組み合わせのような生物活性のある腎細胞を含む。
本明細書で記載されるように、生物活性のある成分について濃縮され、活性のない又は望ましくない成分を枯渇させた腎細胞の不均質な集団の特定の亜分画は、出発集団よりも優れた治療成果及び再生成果を提供する。好まれる実施形態では、本開示によって提供される製剤は、B1及び/又はB5細胞集団を枯渇させている細胞集団を含有する。たとえば、以下:B2、B3及びB4(又はB4’)の2以上の混加物;B2、B3及びB4(又はB4’)の濃縮された細胞集団はB1及び/又はB5を枯渇させてもよい。
態様の1つでは、本開示の製剤は、腎臓組織から単離され、及び/又は培養されている細胞集団を含有する。腎疾患、貧血、EPO欠乏症、尿細管輸送欠損症、及び糸球体濾過欠損症の治療を含む治療用途のために製剤にて使用されるであろう腎細胞成分、たとえば、濃縮された細胞集団を分離し、単離するために方法が本明細書で提供される。一実施形態では、細胞集団は、新しく消化された、すなわち、機械的に若しくは酵素的に消化された腎臓組織から、又は哺乳類の腎細胞の不均質な試験管内の培養から単離される。
種々の生体材料を活性剤と組み合わせて本開示の治療用製剤を提供し得る。生体材料は任意の好適な形状(たとえば、ビーズ)又は形態(たとえば、液体、ゲル等)であってもよい。Bertramらの米国の公開された出願20070276507(その全体が参照によって本明細書に組み入れられる)に記載されたように、高分子のマトリクス又は足場はいくつもの望ましい構成に成形されて全体的な系、構造又は空間のいくつもの制約を満たし得る。一実施形態では、本開示のマトリクス又は足場は三次元であってもよく、臓器又は組織の構造の寸法及び形状に適合するように成形され得る。たとえば、腎疾患、貧血、EPO欠乏症、尿細管輸送欠損症又は糸球体濾過欠損症を治療するための高分子足場の使用では、三次元(3−D)マトリクスが使用され得る。種々の異なって成形された3−Dの足場が使用され得る。当然、高分子マトリクスは様々なサイズ及び形状に成形されて様々な大きさの患者に適合し得る。高分子マトリクスは他の方法でも成形されて患者の特定のニーズを受け入れ得る。別の実施形態では、高分子のマトリクス又は足場は生体適合性で多孔性の高分子足場であり得る。足場は、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、セルロース性エステル、フッ素化ポリエチレン、石炭酸、ポリ−4−メチルペンタン、ポリアクリロニトリル、ポリアミド、ポリアミドイミド、ポリアクリレート、ポリベンゾオキサゾール、ポリカーボネート、ポリシアノアリールエーテル、ポリエステル、ポリエステルカーボネート、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、ゼラチン、アルギン酸塩、ラミニン、フィブロネクチン、絹、エラスチン、アルギン酸塩、ヒアルロン酸、アガロース、又はそれらのコポリマー又は物理的な混合物を含むが、これらに限定されない種々の合成の又は天然存在する材料から形成され得る。足場の構成は、液体の懸濁液から、軟性の多孔性足場に、剛性の形状保持型の多孔性足場に及ぶ。一実施形態では、構成はヒドロゲルになることが可能である溶液の液体形態である。
態様の1つでは、本開示は、必要とする対象にて腎疾患、貧血又はEPO欠乏症を治療するための本明細書で記載される1以上の細胞集団を有する埋め込み可能な構築物を含有する製剤を提供する。一実施形態では、構築物は、生体適合性材料又は生体材料、1以上の合成の又は天然に存在する生体適合性材料で構成される足場又はマトリクス、及び付着及び/又は捕捉によって足場の表面に堆積された又は埋め込まれた本明細書で記載される細胞の1以上の細胞集団又は混加物で作られる。特定の実施形態では、構築物は、生体材料と、生体材料成分で被覆された、その上に堆積した、その中に堆積した、それに付着した、それに捕捉された、それに埋め込まれた、それに播かれた又はそれに混ぜ合わせられた本明細書で記載される細胞の1以上の細胞集団又は混加物とから作られる。濃縮された細胞集団又はその混加物を含む、本明細書で記載される細胞集団のいずれかをマトリクスと組み合わせて用いて構築物を形成し得る。
工程の任意の段階で単離された細胞はその表現型によって特徴付けられ得る。一実施形態では、細胞は濃縮されている不均質な腎細胞集団である。さらなる実施形態では、濃縮された不均質な腎細胞集団は低酸素条件下で少なくとも24時間培養されている。さらにさらなる実施形態では、濃縮された不均質な腎細胞集団は密度勾配に供されている。
別の態様では、本開示の製剤は疾患の治療のために投与され得る。たとえば、本明細書で記載される製剤の一部として生物活性のある細胞が生来の臓器に投与され得る。一実施形態では、生物活性のある細胞は、投与の対象である生来の臓器を供給源としてもよく、又は標的の生来の臓器ではない供給源に由来してもよい。
別の態様では、本開示は、本明細書で記載される細胞集団、混和物又は構築物を含有する製剤の対象への投与又は埋め込みに続く生来の腎臓の再生をモニターする予後診断法を提供する。一実施形態では、方法は、対象から得た試験試料及び対照試料におけるマーカー発現のレベルを検出する工程を含み、その際、対照試料に比べて試験試料におけるマーカーの発現の高いレベルは対象における生来の腎臓の再生の予測である。別の実施形態では、方法は試料における1以上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;及びそれらの任意の組み合わせから選択され得る(IlaganらのPCT/US2011/036347の実施例11を参照)。検出工程は、幹細胞マーカーの発現が対照試料に比べて試験試料で上方調節される又は高いことを判定することを含んでもよく、その際、発現の高いレベルは対象の生来の腎臓の再生の予測である。他の一実施形態では、幹細胞マーカーのmRNAの発現が検出される。他の実施形態では、mRNA発現の検出はPCRに基づく方法、たとえば、qRT−PCRを介し得る。In situハイブリッド形成をmRNA発現の検出に用い得る。別の実施形態では、抗幹細胞マーカー剤を用いて幹細胞マーカーのポリペプチド発現も検出され得る。他の一実施形態では、剤はマーカーに対する抗体である。別の実施形態では、幹細胞マーカーのポリペプチド発現は免疫組織化学法又はウエスタンブロットを用いて検出される。当業者は、マーカーのmRNA発現及び/又はポリペプチド発現を検出するための他の方法を十分に理解するであろう。
本明細書で記載される製剤は、対象に投与される生物活性のある腎細胞のような活性剤のための有利な環境を創る特性を有する生体材料を組み入れる。一実施形態では、製剤は、活性剤が生体材料と共に製剤化される時点から対象への投与の時点まで有利な環境を提供する第1の生体材料を含有する。他の一実施形態では、有利な環境は、対象に投与するのに先立って流体における細胞(本明細書で記載されるような)に対して実質的に固体状態に浮遊させた生物活性のある細胞を有する利点に関係する。別の実施形態では、第1の生体材料は温度感受性の生体材料である。温度感受性の生体材料は、(i)約8℃以下で実質的に固体状態を有し、且つ(ii)常温以上で実質的に液体状態を有する。一実施形態では、常温はほぼ室温である。
態様の1つでは、本開示の製剤は放出制御製剤として提供される。一般に、制御放出は、投与の際、第1の活性剤の最初の放出に第2の活性剤の少なくとも1回の追加のその後の放出が続くことを特徴とする。第1と第2の活性剤は同一であってもよいし、異なっていてもよい。一実施形態では、製剤は同一製剤における複数の成分を介して制御放出を提供する。別の実施形態では、制御放出製剤は、製剤の容量全体にわたって活性剤が自由に移動するのを可能にし、それによって投与の際、標的部位での即時放出を可能にする第1の成分の一部としての活性剤を含有する。第1の成分は実質的に液相と実質的に固相を有する温度感受性の生体材料であってもよく、その際、第1の成分は投与の時点で実質的に液相である。一実施形態では、製剤の容量全体にわたって実質的に自由に移動し、それによって投与の際、標的部位にて即時放出されるような実質的に液相にある活性剤。
本開示の生物活性のある細胞製剤は単独で、又は他の生物活性のある成分と組み合わせて投与することができる。製剤は固形臓器の内部に組み込んだ組織工学要素を注入し、又は埋め込んで組織を再生するのに好適である。加えて、製剤は中空臓器の壁に組織工学要素を注入し、又は埋め込んで組織を再生するのに使用される。
本開示はさらに、本明細書で記載されるような高分子のマトリクス及び足場及び関連する物質、及び/又は細胞培養培地及び使用の指示書を含むキットを含む。使用の指示書は、たとえば、細胞の培養又は細胞及び/又は細胞生成物の投与のための指示書を含有し得る。一実施形態では、本開示は本明細書で記載されるような足場及び指示書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の検出のための剤、その剤の使用のための試薬、及び使用の指示書を含む。このキットは、本明細書で記載される細胞集団、混加物又は構築物の埋め込み又は投与に続く対象における生来の腎臓の再生予後診断を判定する目的で使用され得る。キットはまた、本明細書で記載される細胞集団、混加物又は構築物の生物治療有効性を判定するのにも使用され得る。
本開示の方法は、商業目的で実践される場合、一般に再生予後診断の報告又は要約を作出する。本開示の方法は、本明細書で記載される細胞集団、混加物又は構築物を含有する製剤の投与又は埋め込みの前及び後での再生の考えられる経過又は成果の予測を含む報告を作出するであろう。報告には予後診断に関する指標の情報が含まれ得る。本開示の方法及び報告はさらに、報告をデータベースに保存することを含むことができる。或いは、方法はさらに対象に関するデータベースにて報告を創り、報告にデータを追加することができる。一実施形態では、報告は紙の報告であり、別の実施形態では、報告は聴覚報告であり、別の実施形態では、報告は電子報告である。報告は医師及び/又は患者に提供されることが企図される。報告を受け取ることにはさらに、データ及び報告を含むサーバーコンピュータへのネットワーク接続を確立することと、サーバーコンピュータからのデータ及び報告を要求することが含まれ得る。本明細書で提供される方法は全体として又は部分的に自動化もされ得る。
この実施例は、ヒトからの未分画(UNFX)で不均質の腎細胞集団の単離を説明する。最初の組織解離を行ってヒト腎臓組織に由来する不均質な細胞浮遊液を生成した。
腎細胞の増殖は、受け取った組織の量及び受入組織からの腎細胞の単離の成功に左右される。単離された細胞は必要に応じて凍結保存することができる(以下を参照)。腎細胞の増殖動態は、個々の患者から単離される細胞の固有の生存性のために試料ごとに異なり得る。
増やした腎細胞を日常的に凍結保存して個々の患者に由来する細胞増殖の固有の生存率を調整し、所定の臨床スケジュールで製品を送達した(図2B)。凍結保存した細胞は別のNKA必要とする(たとえば、患者の病気、予期しない過程事象による遅延)事象における細胞のバックアップ供給源も提供する。細胞を凍結保存し、融解の際生きて機能的な細胞を回収する条件を確立した。
凍結保存した細胞から増殖させる最終培養容器から又はスケジュール、図2Bに応じて増やした培養物から直接、選択された腎細胞(SRC)を調製することができる。
本試験の目的は、高含量解析(HCA)を介してヒトNKA細胞の機能的な特徴づけを決定することだった。高含量画像化(HCI)は、多数の試料にわたって2以上の蛍光プローブ(多重化)用いて複数の細胞内事象の同時画像化を提供する。高含量解析(HCA)は、高含量画像化にて捕捉された複数の細胞パラメータの同時定量測定を提供する。手短には、標準の生検手順を用いて5人の進行性慢性腎疾患(CKD)ヒトの腎臓及び3つの非CKDのヒト腎臓から採取したコア生検から未分画の(UNFX)の培養物を生成し(Aboushwareb et al., World J Urol 26, 295, 2008))、独立して維持した。UNFXの生体外での2回の継代の後、細胞を回収し、密度勾配法(BasuらのWO2012/064369の実施例2に記載された)に供して、亜分画B2、B3及び/又はB4を含む亜分画を生成した。
表現型B2及びB4の分布及び組成の対する酸素条件の効果を明らかにするために、様々な種に由来するネオ腎細胞集団を勾配工程に先立って様々な酸素条件に暴露した。Kelleyら、2010、上記にて記載されたように、ラットの細胞単離及び培養開始のための標準の手順を用いて齧歯類のネオ腎臓増強(NKA)細胞の調製物(RK069)を確立した。フラスコはすべて21%の酸素(大気)条件で2〜3日培養した。培地を交換し、フラスコの半分を2%酸素に設定した酸素制御インキュベータに移動させた一方で、残りのフラスコを21%酸素条件でさらに24時間保持した。次いで上記で記載された標準の酵素による回収手順を用いて各設定の条件から細胞を回収した。標準の手順に従って勾配工程を準備し、「正常酸素」(21%酸素)及び「低酸素」(2%酸素)の培養物を別々に回収し、隣り合って同一に勾配工程に適用した。双方の条件で4つのバンドとペレットが生成され、勾配全体にわたる細胞の分布は21%と2%の酸素条件バッチで異なった(表7.1)。具体的には、B2の収率が低酸素で上昇し、付随してB3は減少した。さらに、B4に特異的な遺伝子(たとえば、エリスロポイエチン)の発現は、低酸素で培養された細胞から生成された結果として生じる勾配で上昇した(PresnellらのWO/2010/056328の図73)。
自己免疫性糸球体腎炎患者の試料から腎細胞の未分画混合物を上述のように単離した。腎臓組織から単離し、増やした腎細胞の特定の亜集団の先入観のない遺伝子型組成を明らかにするために、定量的リアルタイムPCR(qRTPCT)解析(Brunskill et al., Dev. Cell. 2008 November; 15(5):781-791)を採用して細胞の亜分画間で差次的な細胞型特異的な及び経路特異的な遺伝子発現パターンを特定した。IlaganらのPCT/US2011/036347の表6.1に示されたように、HK20は自己免疫性糸球体腎炎患者の試料である。IlaganらのPCT/US2011/036347の表6.2に示されたように、HK20から生成された細胞はqRTPCRによって判定すると糸球体細胞を欠いている。
腎臓組織から単離し、増やした腎細胞の特定の亜集団の先入観のない遺伝子型組成を明らかにするために、定量的リアルタイムPCR(qRTPCR)解析(Brunskill et al., 上記、2008)を採用して細胞の亜分画間で差次的な細胞型特異的な及び経路特異的な遺伝子発現パターンを特定した。糸球体の大部分が破壊されている巣状分節状糸球体硬化症(FSGS)の症例に由来するヒト調製物HK023を回収時でのB4分画における糸球体細胞の存在について評価した。手短には、標準の生検手順を用いて腎臓から採取された4種のコア生検のそれぞれから未分画(UNFX)の培養物を生成し(Aboushwareb et al., World J Urol 26, 295, 2008)、独立して維持した。UNFXの生体外での2回の継代の後、細胞を回収し、BasuらのWO2012/064369の実施例6に従って密度勾配法に供し、齧歯類、イヌ、及び他のヒト検体で実施された研究に基づいて内分泌細胞、血管細胞及び糸球体細胞について濃縮されることが知られる亜分画B4を含む亜分画を生成した。
蛍光活性化細胞分類法(FACS)を用いて、単離された一次腎臓組織から1以上の単離された腎細胞を濃縮してもよく、及び/又は1以上の特定の腎細胞型を枯渇させてもよい。
単離された一次腎臓組織から1以上の単離された腎細胞を濃縮してもよく、及び/又は1以上の特定の腎細胞型を枯渇させてもよい。
以下の実施例は実施例5の選択された不均質なヒト腎細胞を特徴づけるフローサイトメトリーの使用を詳述する。不均質な腎細胞集団は、その再生潜在力で周知である腎上皮細胞から主として構成された。他の実質(血管)及び間質(集合管)の細胞は自己細胞集団にてまばらに存在し得る。
タンパク質の産生についても調べたアクアポリン2、E−カドヘリン、キュビリン、VEGF及びCD31を含む、ヒト腎臓培養物から単離されたSRCの定量的リアルタイムポリメラーゼ鎖反応(qRTPCR)による遺伝子発現のプロファイル。表12.5における遺伝子型マーカーは腎細胞培養物で見いだされることが予想され得る細胞集団を代表する。NCAD、キュビリン及びCYP2R1は尿細管上皮細胞のマーカーであり、AQP2及びECADは集合管及び遠位尿細管のマーカーである。ポドシン及びネフリンは有足細胞のマーカーである。VEGF及びCD31は内皮マーカーである。VEGF及びEPOは種々の異なる組織及び細胞型に存在する関連するmRNAを伴った酸素応答性遺伝子である。
SRCの酵素活性
画像ライブラリにおける画像との培養所見の比較によって細胞を増やしている間、細胞の形態をモニターした。各細胞継代にて細胞増殖の動態をモニターした。細胞増殖は患者ごとに変動すると予想される。トリパンブルー色素排除及び/又はPrestoBlueの代謝によってSRCの数及び生存率をモニターした。SRCはCK18、GGT1の表現型発現を特徴とする。加えて、AQP2の発現をモニターし得る。PrestoBlueの代謝並びにVEGF及びKIM−1の産生を生存可能で機能的なSRCの存在のマーカーとして使用する。LAP及びGGTによる遺伝子発現プロファイリング及び酵素活性の測定によってSRCの機能をさらに解明することができる。
NKA(ゼラチン溶液)で使用した生体材料は2つのカギとなるパラメータを特徴とする:
濃度−ゼラチン溶液の濃度は分光光度計用いて280nmでの吸光度によって測定する。ゼラチンの濃度は濃度に対する吸光度の較正曲線から決定される。
NKAで使用した生体材料をさらにレオロジー特性及び粘度について特徴づけることができる。レオロジー及び粘度の試験は検証目的のみのために行われ、他の業者から入手される生体材料の拡大された特徴づけに使用されるように意図される。
トリパンブルー色素排除を用いて実施例5に由来する洗浄したSRCを数えた。ゼラチン溶液を冷却保存から取り出し、26〜30℃に温めることによって液化した。必要とされる数の細胞を含有するSRC浮遊液の容量を遠心し、最終洗浄工程のために液体ゼラチン溶液に再浮遊させた。この浮遊液を遠心し、SRCペレットを十分なゼラチン溶液に再浮遊させて製剤化されたNKAにて100×106個/mlの結果的なSRC濃度を達成した(図2D)。
NKA製品は、組織処理及び細胞培養の操作のためのBSCにおけるNKA包装にて注射器に無菌的に充填した(図2D)。生存可能及び非生存可能な試料採取を含む動的空気試料採取を充填工程の間に行った。
NKAは、NKAシッパーへの適当な文書と共に包装された。シッパーは臨床現場への輸送の間、2〜8℃の温度範囲を維持するように意図される。冷却して(ゲル化して)製剤化された製品は3日間の保存可能期間を有する。
この実施例は選択された不均質なヒト腎細胞の再生特性を明らかにする。
NKAの送達系
埋め込みの準備では、腎臓への注入の直前にNKAを室温に温めて製品を液化した。
Claims (19)
- 生体マーカーGGT−1及びサイトケラチンを発現する濃縮された不均質な哺乳類腎細胞集団。
- 前記生体マーカーがモノクローナル抗体又はポリクローナル抗体によって検出される請求項1に記載の細胞集団。
- 18%を超える前記細胞がGGT−1を発現する請求項1に記載の細胞集団。
- 前記サイトケラチンがCK8、CK18、CK19及びそれらの組み合わせから選択される請求項1に記載の細胞集団。
- 前記サイトケラチンの発現のレベルが80%を超える請求項4に記載の細胞集団。
- 前記サイトケラチンがポリクローナル抗体によって検出される請求項1に記載の細胞集団。
- 前記細胞集団がAQPを発現する請求項1に記載の細胞集団。
- 前記細胞の40%未満がAQP2を発現する請求項1に記載の細胞集団。
- 前記AQP2がモノクローナル抗体によって検出される請求項7に記載の細胞集団。
- 前記哺乳類がヒトである請求項1に記載の細胞集団。
- 埋め込み及び/又は再生応答を引き出すことに好適な不均質な腎細胞集団を特定する方法であって、前記方法が、哺乳類の腎臓試料から細胞を単離する工程と、前記単離された細胞を1以上の標識された検出部分に暴露する工程と、異なる生体マーカーのそれぞれを発現する細胞の比率を決定する工程とを含み、各標識された検出部分が前記異なる生体マーカーに向けられ、異なる標識で標識される前記方法。
- 生体マーカーが、AQP1、AQP2、AQP4、カルビンジン、カルポニン、CD117、CD133、CD146、CD24、CD31(PECAM−1)、CD54(ICAM−1)、CD73、CK18、CK19、CK40〜67、CK7、CK8、CK18、CK19、CK8/CK18/CK19の組み合わせ、コネキシン43、キュビリン、CXCR4(フシン)、DBA、E−カドヘリン(CD324)、EPO(エリスロポイエチン)、GGT1、GLEPP1(糸球体上皮タンパク質1)、ヘプトグロビン、Itgb1(インテグリンβ1)、KIM−1/TIM−1(腎臓損傷分子−1/T−細胞免疫グロブリン及びムチン含有分子)、MAP−2(微小管結合タンパク質2)、メガリン、N−カドヘリン、ネフリン、NKCC(Na−K−Cl−共輸送体)、OAT−1(有機アニオン輸送体1)、オステオポンチン、Pan−カドヘリン、PCLP1(ポドカリキシン−様1分子)、ポドシン、SMA(平滑筋α−アクチン)、シナプトポジン、THP(タム・ホースフォールタンパク質)、ビメンチン、及びαGST−1(αグルタチオンS−トランスフェラーゼ)、及びそれらの組み合わせから選択される請求項11に記載の方法。
- 前記標識された検出部分が抗体である請求項11に記載の方法。
- 不均質な腎細胞集団を患者に投与することを含む、哺乳類における腎疾患を治療する方法であって、前記細胞集団が、GGT−1、AQP2及びサイトケラチンから成る群から選択される2以上の生体マーカーを発現する前記方法。
- 不均質な腎細胞集団を患者に投与することを含む、哺乳類における腎疾患を治療する方法であって、前記細胞集団内の細胞がそれぞれ18%及び80%を超えるGGT−1及びCK18の発現のレベルを有する前記方法。
- 不均質な腎細胞集団を患者に投与することを含む、哺乳類における腎疾患を治療する方法であって、前記細胞集団内の細胞が表12.4における発現のレベルでGGT−1、AQP2及びCK18を発現する前記方法。
- 前記細胞集団がマトリクス上で培養される請求項15又は16に記載の方法。
- 前記細胞集団をゼラチン系の生体材料に浮遊させる請求項15又は16に記載の方法。
- 前記哺乳類がヒトである請求項15又は16に記載の方法。
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