JP2008520185A - 分化多能性増殖間葉系前駆細胞子孫(memp)およびその使用 - Google Patents
分化多能性増殖間葉系前駆細胞子孫(memp)およびその使用 Download PDFInfo
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Abstract
Description
本発明は、分化多能性増殖(expanded)間葉系前駆細胞子孫(MEMP)に関する。本発明はまた、MEMPの生成方法および治療用途のためのMEMPの使用にも関する。
体内に存在し、単離した場合に分化多能性細胞を生じさせる非造血性前駆細胞は、間葉系前駆細胞(MPC)と呼ばれる。より詳細には、精製したMPCは非常に数多くの分化多能性細胞コロニーを形成する能力を有する。
1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1α)からなる群から選択される1つもしくは複数の刺激因子の存在下で、MPCまたはその子孫とTSCCとを含む細胞集団を培養すること、ならびに
その培養した集団を、MPCまたはTSCCの分化を特定組織種に偏らせる条件に供すること、
を含む方法も提供する。
図1。培養したMPCに由来するSTRO-1briまたはSTRO-1dim発現細胞の遺伝子発現プロフィール。ex vivoで増殖させた骨髄MPCの単細胞懸濁液をトリプシン/EDTA処理によって調製した。STRO-1抗体を用いて細胞を染色し、次いでこれをヤギ-抗ネズミIgM-フルオレセインイソチオシアネートと共にインキュベーションすることによって示した。全細胞RNAは、蛍光活性化細胞分取の後のSTRO-1dimまたはSTRO-1bri発現細胞の精製集団から調製した(A)。RNAzolB抽出方法、および標準の手順を用いて、全RNAを各部分集団から単離し、cDNA合成の鋳型として用いた。様々な転写物の発現は、以前に記載されている標準プロトコルを用いて、PCR増幅によって評価した(Gronthos他、Journal of Cell Science 116: 1827-1835, 2003)。この研究で用いたプライマーセットを表2に示す。増幅後、各反応混合物を1.5%アガロースゲル電気泳動によって解析し、臭化エチジウム染色によって可視化した(B)。ハウスキーピング遺伝子であるGAPDHの発現を基準として、ImageQantソフトウェアを用いて、それぞれの細胞マーカーについて相対遺伝子発現を評価した(C)。
本発明者らは今回、ex vivoで増殖させたMPCが、分化多能性を保持する細胞部分集団を含むという驚くべき発見を行った。より詳細には、本発明者らは、収集したMPC細胞由来の増殖集団を、STRO-1抗体によって認識される抗原の発現レベルに基づいてSTRO-1briおよびSTRO-1dimの少なくとも2つの集団へと分離できることを発見した。本明細書中に提示する機能的データにより、増殖させたSTRO-1bri細胞は分化決定性がより低く、脂肪の発達、軟骨の発達および骨の発達を支援する誘導因子に応答する能力がより高いことが示されている。対照的に、STRO-1dim細胞はより分化した集団を表し、組織特異的分化決定済細胞(Tissue Specific Committed Cell; TSCC)種を含む。増殖させた子孫内のStro-1bri細胞を、本明細書中では分化多能性増殖MPC子孫(MEMP)と呼ぶ。
1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1αからなる群から選択される1つもしくは複数の刺激因子の存在下で、MPCまたはその子孫とTSCCとを含む細胞集団を培養すること、ならびに
その培養した集団を、MPCまたはTSCCの分化を特定組織種に偏らせる条件に供すること、
を含む方法も提供する。
一実施形態では、本発明は、表現型STRO-1bri、ALP-を有する、単離され、遺伝的に改変された間葉系前駆細胞(MPC)子孫を提供する。好ましくは、異種タンパク質を生成するようにMEMPを遺伝的に改変する。典型的には、異種タンパク質が細胞から分泌されるように細胞を遺伝的に改変する。
本発明の方法は、MEMPをin situで濃縮するために、1つまたは複数の刺激因子を被験体に投与することを含み得る。
MEMPおよび/またはTSCCを含む本発明の細胞性組成物は、骨、軟骨、腱、靱帯、筋肉、皮膚、および他の結合組織、ならびに神経、心臓、肝臓、肺、腎臓、膵臓、脳、および他の器官の組織を含めた様々な種類の組織の再生に有用であり得る。
事前に形成したウェル中でMEMPを培養または共培養をすることにより、事前に決定した厚さおよび体積の組織パッチの製造が可能となる。その結果生じる組織パッチの体積は、ウェルの体積およびウェル中のMEMP数に依存する。事前に決定した最適な体積の組織は、前述のパラメータの一方または双方を変更することによって、日常的な実験によって調製し得る。
本発明の細胞性組成物またはその共培養物を三次元足場(scaffold)上もしくはその中に播種してin vivoに埋め込んでもよく、播種した細胞はここでフレームワーク上で増殖して、患者の細胞と協力して骨組織などの置換組織をin vivoで形成する。
本発明の細胞、またはそれから生成される生組織の埋込みに代わる方法として、組織の修復、置換、または補強を必要としている被験体は、細胞外基質(ECM)もしくはこれらの細胞によって生成される細胞溶解液などの、MEMPの成分または産物(特にこれらが遺伝的に改変されている場合)を投与することによって利益を受けうる。
被験体、細胞培養物および抗体
BM吸引液を、インフォームドコンセントののち、Royal Adelaide Hospital、南オーストラリア州の倫理委員会によって認可された手順に従って正常な成人ボランティア(20〜35歳)の後部腸骨稜から得た。骨髄単核細胞(BMMNC)を、1.077g/mlのフィコール(Lymphoprep、Nycomed、Oslo、ノルウェー)上、400gで30分間遠心分離することによって取得し、その後、1%のウシ血清アルブミンおよび10mMのHEPESを含むハンクス緩衝生理食塩水pH 7.35(HBSS)で洗浄してそれに再懸濁させた。BMSSC初代培養は、コロニー効率アッセイ、RT-PCR、免疫組織化学および発生学的研究について以前に記載されているように(GronthosおよびSimmons, Blood 85(4):929-940, 1995)、20%のウシ胎児血清および100MのL-アスコルビン酸-2-リン酸を添加した-MEM中で確立した。BMSSCクローン細胞系は、増殖、RT-PCR、免疫組織化学、および発生学的研究のための血清充満(replete)培地中での継代培養ののち、以下に記載のようにSTRO-1bri/VCAM-1+で分別した細胞に由来する14日目のコロニーからの限界希釈によって作製した。
これは、以前に記載されているようにして行った(Gronthos他、Isolation, Purification and In Vitro Manipulation of Human Bone Marrow Stromal Precursor Cells. In Marrow Stromal Cell Culture. Owen M.およびBeresford J.N.編 Cambridge University Press UK, 第3章, ページ26-42, 1998; GronthosおよびSimmons, Blood 85(4): 929-940, 1995)。約1×108個のBMMNCを、STRO-1上清と共に、10μg/mlの最終濃度で、60分間、氷上でインキュベーションを行った。STRO-1で標識された細胞をHBSSで洗浄し、1/50希釈したビオチン標識ヤギ抗マウスIgM(μ鎖特異的; Southern Biotechnology Associates、アラバマ州Birmingham)またはビオチン標識ヤギ抗マウスIgG(γ鎖特異的; Southern Biotechnology Associates、アラバマ州Birmingham)を含む1mlのHBSSにそれぞれ45分間、氷上で再懸濁させた。その後、細胞をMACS緩衝液(1%のBSA、5mMのEDTAおよび0.01%のアジ化ナトリウムを添加したシングル強度(single strength)のCa2+およびMn2+を含まないPBS)で2回洗浄し、100μlのストレプトアビジンマイクロビーズ(Miltenyi Biotec、Bergisch Gladbach、ドイツ連邦共和国)を加えた900μlのMACS緩衝液に再懸濁させた。細胞をさらに15分間、氷上でインキュベーションを行い、その後、ストレプトアビジン-フルオレセインイソチオシアネート(FITC)コンジュゲート(1/50;Caltag Laboratories、カリフォルニア州San Francisco)を懸濁液に直接加えてさらに5分間置いた。細胞をMini MACS磁性カラム(カラム容量107個の細胞、Miltenyi Biotec)上で、製造業者の説明書に従って分離した。
STRO-1+MACS単離細胞をストレプトアビジンコンジュゲート化FITCで標識し、その後、精製した抗CD106(VCAM-1)抗体6G10もしくは抗CD146(MUC-18)抗体またはアイソタイプ対照1B5(10μg/ml)のいずれかと共に、30分間、氷上でインキュベーションを行い、洗浄し、フィコエリスリン(PE)コンジュゲート化ヤギ抗マウスIgG抗体(1/50; Southern Biotechnology Associates、アラバマ州Birmingham)と共にさらに20分間、氷上でインキュベーションを行った。FACStarPLUSフローサイトメーター(Becton Dickinson、カリフォルニア州Sunnyvale)を用いて細胞を分別した。STRO-1bri/CD106+またはSTRO-1bri/CD146+細胞を20%のウシ胎児血清、2mMのL-グルタミン、アスコルビン酸-2-リン酸(100μM)を添加したα-改変イーグル培地中で培養して、5%のCO2中、37℃の加湿雰囲気中で初代培養を開始した。
この手順は以前に報告されている(Gronthos他、Isolation, Purification and In vitro Manipulation of Human Bone Marrow Stromal Precursor Cells. In Marrow Stromal Cell Culture. Owen M.およびBeresford J.N.編 Cambridge University Press UK, 第3章, ページ26-42, 1998)。手短に述べると、MPCの初代培養物またはMPCに由来する細胞をトリプシン/EDTA消化によって遊離させ、その後、30分間、氷上でインキュベーションを行った。約2×105個の細胞を洗浄し、その後、200μlの一次抗体カクテル中に1時間、氷上で再懸濁させた。一次抗体カクテルは、飽和濃度のマウスIgMモノクローナル抗体STRO-1および/またはヒトアルカリホスファターゼに対するマウスIgGモノクローナル抗体(ALP、B4-78)からなっていた。細胞内抗原と反応性を有する抗体を用いた染色のため、細胞をまずPBSで洗浄し、その後、氷上で10分間、70%のエタノールで処理することによって透過処理し、その後、染色前に洗浄した。マウスアイソタイプIgMおよびIgG陰性対照Mabを同一条件下で処理した。一次抗体とのインキュベーションののち、細胞を洗浄し、飽和レベルのヤギ抗マウスIgMμ鎖特異的-FITC(1/50希釈)とヤギ抗マウスIgGγ特異的-PE(1/50希釈)または抗ウサギIg特異的-PE(1/50希釈)(Southern Biotechnology Associates)のどちらかとに対し最終体積100μlで曝した。45分間、氷上で細胞のインキュベーションを行い、2回洗浄し、その後、FAX FIX(1%(v/v)、2%(w/v)D-グルコース、0.01%のアジ化ナトリウムを添加したPBS)中で固定した。その後、細胞をEpics(登録商標)-XL-MCLフローサイトメーター(Beckman Coulter、フロリダ州Hialeah)で解析した。
細胞透過性フルオレセイン系色素CFSEを用いて、MPCに由来する細胞の発生の際の分裂に関連する表現型変化および機能変化を研究した。CFSEは細胞の細胞質成分に共有結合して均一な明るい蛍光をもたらし、これは、細胞分裂時に娘細胞に等しく分配される。この技術により、最大8サイクルまでの細胞分裂をフローサイトメトリーにより分離することが可能となる。ex vivoで増殖させたMPCに由来する細胞の単細胞懸濁液を1回洗浄し、1mlのPBS/0.1%のBSAに再懸濁させ、2μlの5mMのCFSE(最終10μM)を加えたのち、37℃で10分間、インキュベーションを行った。染色は、5倍体積の氷冷培地α-MEM-10を加えることにより消光し、さらに氷上で5分間インキュベーションした。細胞を培地中で3回洗浄し、その後、1×105の低密度で培養フラスコ(T-25)にプレーティングした。様々な時点で、トリプシン-EDTAによって細胞を剥離し、フローサイトメトリー解析によって解析した。
初代MPC由来培養物をトリプシン/EDTA処理によって遊離させ、その後、上述のようにSTRO-1上清で染色した。洗浄後、細胞をフィコエリスリン(PE)コンジュゲート化ヤギ抗マウスIgM抗体(1/50; Southern Biotechnology Associates、アラバマ州Birmingham)と共にさらに20分間、氷上でインキュベーションを行った。FACStarPLUSフローサイトメーター(Becton Dickinson、カリフォルニア州Sunnyvale)を用いて細胞を分別した。RNAzolB抽出方法(Biotecx Lab. Inc.、テキサス州Houston)を用いて、製造業者の説明書に従い、全細胞RNAを、2×106個のSTRO-1briまたはSTRO-1dimのどちらかで分別した初代細胞、軟骨細胞ペレットおよび他の誘導培養物から調製し、溶解した。その後、各部分集団から単離したRNAを、First-strand cDNA合成キット(Pharmacia Biotech、スウェーデンUppsala)を用いて調製したcDNA合成の鋳型として用いた。様々な転写物の発現は、以前に記載されている標準プロトコル(Gronthos他、J. Bone and Min. Res. 14:48-57, 1999)を用いて、PCR増幅によって評価した。この試験で用いたプライマーセットを表2に示す。増幅後、各反応混合物を1.5%アガロースゲル電気泳動によって解析し、臭化エチジウム染色によって可視化した。RNAの完全性はGAPDHの発現によって評価した。
本発明者らは、10%のFCS、100μMのL-アスコルビン酸-2-リン酸、10-7Mのデキサメタゾンおよび3mMの無機リン酸塩を添加したαMEM中で培養したヒトBM間質細胞がin vitroで石灰化骨基質の生成を誘導する条件を以前に報告している(Gronthos他、Blood. 84: 4164-4173, 1994)。ミネラル沈降物は陽性フォンコッサ染色によって同定した。脂肪生成は、0.5mMのメチルイソブチルメチルキサンチン、0.5μMのヒドロコルチゾン、および60μMのインドメタシンの存在下で、以前に記載のように誘導した(Gimble, J. M. Marrow stromal adipocytes. Marrow stromal cell culture. Owen M.およびBeresford J.N.編 Cambridge: Cambridge University Press UK. 第5章, ページ67-87, 1998)。オイルレッドO染色を用いて脂質を含有する脂肪細胞を同定した。軟骨形成の分化は、記載のように10ng/mlのTGF-β3で処理した凝集培養物において評価した(Pittenger他、Science, 284:143-147, 1999)。
2〜3継代目のSTRO-1bri/VCAM-1+細胞に由来する接着細胞をトリプシン処理し、40mgのヒドロキシアパタイト/リン酸三カルシウムセラミック粒子(Zimmer Corporation、インディアナ州Warsaw)と混合し、その後、以前に記載のようにして2カ月齢のSCIDマウスの背側表面の皮下ポケット内に移植した(Gronthos他、Proceedings of the National Academy of Sciences (USA), 97 (25): 13625-13630, 2000)。これらの手順は、認可された動物プロトコルの規定に従って行った(Adelaide University AEC# M/079/94)。6〜8週間後に埋込物を回収し、4%のパラホルムアルデヒドで2日間固定し、その後、さらに10日間、10%のEDTA中で脱灰化したのち、パラフィンに包埋した。組織学的解析には、埋込物の5μm切片を調製し、ヘマトキシリンおよびエオシンで染色した(Gronthos他、Proceedings of the National Academy of Sciences (USA), 97 (25): 13625-13630, 2000)。
本発明者らは、表現型STRO-1bri/VCAM-1(CD106)+またはSTRO-1bri/MUC-18(CD146)+に基づいて分化多能性の間葉系前駆細胞(MPC)を成人ヒト骨髄単核細胞から精製できることを、以前に報告している(Gronthos他J. Cell Sci 116:1827-1835, 2003; ShiおよびGronthos JBMR 18(4): 696-704, 2003; PCT AU2004/000416号)。MPC集団は、in vitroの定義された培養条件下で容易に増殖させることができる(Gronthos他J. Cell Sci 116:1827-1835, 2003)。本発明者らは今回、mRNAレベルおよびタンパク質レベルの両方において、それぞれ逆転写-ポリメラーゼ連鎖反応(RT-PCR)およびフローサイトメトリー解析を用いて、ex vivoで増殖させたMPC子孫を様々な細胞系統に関連したマーカーに基づいて特徴付けるデータを提示する。すべての新たに単離した骨髄MPCはSTRO-1を高レベルで発現するが(Stro-1bri)、細胞の大多数はex vivoでの増殖後にSTRO-1の発現をダウンレギュレーションする(Stro-1dim)(Gronthos他J. Cell Sci 116:1827-1835, 2003)。最初の一連の実験では、半定量的RT-PCR解析を用いて、STRO-1dimまたはSTRO-1bri集団によって発現され、蛍光活性化細胞分取によって単離した様々な系統に関連する遺伝子の遺伝子発現プロフィールを検査した(図1A)。ハウスキーピング遺伝子であるGAPDHの発現を基準として、ImageQantソフトウェアを用いて、それぞれの細胞マーカーの相対的な遺伝子発現を評価した(図1B、C)。さらに、2色フローサイトメトリー解析を用いて、STRO-1抗体と組み合わせたより広範囲の細胞系統関連マーカーのその発現に基づいて、ex vivoで増殖させたMPCのタンパク質発現プロフィールを検査した(図2)。STRO-1dimおよびSTRO-1bri培養細胞の遺伝子ならびにタンパク質発現に基づいた一般的な表現型の要約を表3に示す。データは、ex vivoで増殖させたSTRO-1briMPCが、アンジオポエチン-1、VCAM-1、SDF-1、IL-1β、TNFα、およびRANKLを含めた血管周囲細胞に関連したマーカーが示差的により高い発現を示すことを示唆している。逆に、STRO-1dimでex vivoにて増殖させた細胞は、ネスチン、GFAP、オステリックス、オステオカルシン、SOX9、GATA-4、レプチン、および平滑筋ミオシン重鎖をより高いレベルで発現した。したがって、ex vivoで増殖させたSTRO-1briMPCは、軟骨芽細胞、骨芽細胞、脂肪芽細胞、上皮細胞、神経前駆細胞および心筋芽細胞を含むより強く分化決定された前駆細胞種に特徴的な表現型を示すSTRO-1dim細胞と比較して、より未熟かつ血管周囲様の表現型を示すようである。STRO-1dim培養細胞とSTRO-1bri培養細胞とのタンパク質および遺伝子発現プロフィールの比較を表3、4ならびに5にまとめる。新たに単離したMPCと、MPCのSTRO-1bri培養子孫(MEMP)とのマーカー発現の比較を表6に示す。
本発明者らは次に、STRO-1dim培養細胞とSTRO-1bri培養細胞との遺伝子およびタンパク質発現プロフィールで観察された差異が、複数の細胞系統へと分化するその能力におけるいずれかの機能的差異を反映しているかどうかを検査した。ex vivoで増殖させたSTRO-1bri/CD146+由来細胞の培養物は、上述のようにそのSTRO-1抗原の発現に基づいたFACSによって単離した。次いで、FACSで単離したSTRO-1dimおよびSTRO-1bri培養細胞を、脂肪(図3)、骨(図4)および軟骨(図5)形成の誘導条件下で平板培養した。すべての場合で、STRO-1bri培養細胞は、STRO-1dim培養細胞と比較した場合に、特定した条件下で脂肪、骨および軟骨を形成する能力がより高いことが示された。これらの実験からのデータは、上記より得た遺伝子およびタンパク質の発現結果を裏付けており、このことは、STRO-1bri培養細胞が、適切な培養条件下では任意の特定された細胞系統に向かって分化するように促進され、またMPCと呼ばれうる、分化決定がより弱い前駆細胞を、高い割合で含む原始集団であること(図3、4、5)を実証している。逆に、STRO-1dim培養細胞は様々な系統を示す分化決定済細胞を高い割合で含み、TSCCと呼ばれ得る。Stro-1dim集団は、一連の様々な組織種に個別に分化決定された細胞を含む異質性のものであることが提案されている。
異なる発生学的段階を示す2つの異なるex vivoで増殖させたMPC由来細胞集団の同定は、臨床治療のためのStro-lbri細胞に由来する全培養調製物の使用において顕著な意味をもつ。最初の研究は、原始的で分化決定がより弱いSTRO-1bri培養MPCが、より成熟し分化決定されたSTRO-1dim培養TSCCの増殖に与える影響を、検査するように設計した。実験は、漸増パーセンテージのFACS単離したSTRO-1bri培養MPCを、事前に蛍光タグCFSEで標識したFACS単離したSTRO-1dim培養TSCCと共に加えるように設計した。図6は、標識されたSTRO-1dim細胞の増殖が非標識STRO-1bri細胞の存在によって影響を受けることを示している。CFSEで標識した細胞が分裂する際、2つの娘細胞は親細胞の蛍光の半分を含む。したがって、娘細胞の異なる世代は比例的に漸減する蛍光強度を有する蛍光分布として表され、ここで、ヒストグラムの一番右の曲線(垂直線が交わっている)は最初のSTRO-1dim集団の点を表す(図6)。このデータにより、より高い割合のSTRO-1dim細胞が刺激されてその増殖速度を増加させることが実証され、その場合、5%を超えるSTRO-1bri細胞を加えた後により多くの細胞が少なくとも3〜4回分裂することが示された。したがって、未分画MPCに由来する細胞の持続可能かつ効率的なex vivo増殖を得るためには、培養物は5%を超えるSTRO-1bri細胞が集団内に存在することを必要とするということになる。
STRO-1bri培養MEMPがより多くのTSCCの増殖を増大させる能力を実証したのち、本発明者ら次に、様々な成長因子についてのex vivoで増殖させたSTRO-1briMPCの割合を増加させる効果について検査した(図9)。STRO-1bri/CD146+単離骨髄細胞に由来する確立された培養物を、10%のFCS(A)、または、1×10-8Mの1α,25-ジヒドロキシビタミンD3(1,25D)(B)10ng/mlの血小板由来成長因子(PDGF)(C)、10ng/mlの腫瘍壊死因子-α(TNF-α)(D);10ng/mlのインターロイキン-1β(IL-1β)(E)および30ng/mlの間質由来因子1-α(SDF-1α)(F)を含めた様々な因子、を添加した基本培地中で5日間増殖させ、STRO-1 mAbで染色した。(図9)。これらの因子はSTRO-1briMPC数の数値をin vitroで大きく増強させることが見出された。
様々な因子の存在下でSTRO-1bri培養MEMPの割合を増強させる能力は、Stro-1dim細胞数の増加とも相関していた。たとえば、STRO-1bri/Alk Phos+細胞(図10B)は骨芽前細胞に一致する表現型を示す(Gronthos他、J Bone Miner Res. 14: 47-56, 1999; Pan他、Bone 34(1):112-23, 2004)。したがって、本発明者らは、この表現型の変化がさらに、誘導されたSTRO-1briMPCが骨形成細胞である骨芽細胞へと分化する能力の増大と相関していたかどうかを検査した。図11は、IL-1βはSTRO-1陽性MPCの増殖を刺激しただけでなく、骨誘導剤であるデキサメタゾンの存在下でその骨形成能も増強したことを示している。0.01ng/mlの濃度のIL-1βは、MPC数を、未処理の対照培養物の136.6±1.2%まで有意に増加させた(図11A)。0.1ng/mlを超える濃度でプラトー効果が得られた。方法に記載したように、ex vivoで増殖させたMPCの子孫を骨誘導条件の存在下で24ウェルプレートに播種した。細胞を10ng/mlの濃度のIL-1βでも処理し、培養物にIL-1βを含む新鮮な培地を週1回「給餌した」。絶対細胞外基質カルシウム濃度を方法に従って決定した。結果により、未処理の細胞と比較して(図11B)IL-1βで処理した細胞においてミネラル沈降が増加していたことが示された(図11C)。4週間目および6週間目のどちらにおいても、IL-1βで処理した細胞中のカルシウムレベルは未処理の細胞のそれよりも有意に高かった。
方法に記載したようにヒトBMの吸引液を調製し、mAb STRO-1を用いたMACS選択によってMPCを回収した。間接免疫蛍光法およびフローサイトメトリーを用いて、MACS陽性画分(初期培養物すなわちP0培養物を確立するために用いる細胞)を、STRO-1抗原を高レベルで発現する細胞(STRO-1bright)の割合について評価したところ、これは全集団の22.4%であることが判明した(データ示さず)。その後、これらの細胞を1×104個の細胞/cm2でプレーティングし、以前に記載のように80〜90%のコンフルエンスに達するまで血清充満培地中で培養した(Gronthos他、Journal of Cell Science 116: 1827-1835, 2003)。各継代において、方法に記載のように細胞を剥離して1×104個の細胞/cm2で再播種した。各継代からの細胞試料を、そのSTRO-1およびTSCCマーカーであるアルカリホスファターゼ(ALP)の発現について染色した。図14に示すように、4継代後、STRO-1を高レベルで発現する(かつTSSCマーカーであるALPを感知可能なレベルで欠いている)細胞の割合は12.7%まで下がったが、これらの培養物はなお、相当数のSTRO-1briALP- MEMPを含んでいた。
Claims (55)
- 全細胞集団の少なくとも10%が、表現型STRO-1bri、ALP-を有する分化多能性増殖間葉系前駆細胞子孫(MEMP)である濃縮細胞集団。
- 全細胞集団の少なくとも20%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項1に記載の濃縮細胞集団。
- 全細胞集団の少なくとも40%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項1に記載の濃縮細胞集団。
- 全細胞集団の少なくとも50%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項1に記載の濃縮細胞集団。
- 全細胞集団の少なくとも70%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項1に記載の濃縮細胞集団。
- 全細胞集団の少なくとも90%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項1に記載の濃縮細胞集団。
- 前記MEMPがマーカーKi67、CD44および/もしくはCD49c/CD29、VLA-3、α3β1のうちの1つまたは複数に対しても陽性である、請求項1〜6のいずれか一項に記載の濃縮集団。
- 前記MEMPがTERT活性を示さない、かつ/または前記マーカーCD18に対して陰性である、請求項1〜7のいずれか一項に記載の濃縮集団。
- 全細胞集団が組織特異的分化決定済細胞(TSCC)をさらに含む、請求項1〜8のいずれか一項に記載の濃縮集団。
- 前記TSCCが、骨、神経組織、脂肪、軟骨、骨格筋、心筋、上皮組織、骨芽細胞、腱、靱帯、象牙芽細胞、周皮細胞、平滑筋、神経膠組織、血管組織、内皮組織、造血組織、肝臓組織および腎臓組織からなる群から選択される組織または細胞種の系統へと分化決定されている、請求項9に記載の濃縮細胞集団。
- 培養したおよび/または増殖させた細胞集団を含む組成物であって、該全細胞集団の少なくとも1%が、表現型STRO-1bri、ALP-を有するMEMPであり、かつ該組成物が主に1つの組織種のTSCCをさらに含む、前記組成物。
- 全細胞集団の少なくとも5%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項11に記載の組成物。
- 全細胞集団の少なくとも10%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項11に記載の組成物。
- 全細胞集団の少なくとも20%が、表現型STRO-1bri、ALP-を有するMEMPである、請求項11に記載の組成物。
- 前記TSCCが、骨、神経組織、脂肪、軟骨、骨格筋、心筋、上皮組織、骨芽細胞、腱、靱帯、象牙芽細胞、周皮細胞、平滑筋、神経膠組織、血管組織、内皮組織、造血組織、肝臓組織および腎臓組織からなる群から選択される組織または細胞種の系統へと分化決定されている、請求項11〜14のいずれか一項に記載の組成物。
- 前記TSCCが造血細胞である、請求項11〜14のいずれか一項に記載の組成物。
- 前記MEMPおよびTSCCがどちらも自己起源由来である、請求項11〜16のいずれか一項に記載の組成物。
- 前記MEMPおよびTSCCがどちらも同種起源由来である、請求項11〜16のいずれか一項に記載の組成物。
- 前記MEMPおよびTSCCが、一方が自己起源であり他方が同種起源である異なる起源由来である、請求項11〜16のいずれか一項に記載の組成物。
- 前記集団が少なくとも5×106個の細胞を含む、請求項11〜19のいずれか一項に記載の組成物。
- 前記集団が少なくとも107個の細胞を含む、請求項11〜19のいずれか一項に記載の組成物。
- 前記集団が少なくとも109個の細胞を含む、請求項11〜19のいずれか一項に記載の組成物。
- TSCCを表現型STRO-1bri、ALP-を有するMEMPと共培養することによって、またはTSCCを表現型STRO-1bri、ALP-を有するMEMP由来の培養上清、細胞溶解液もしくは画分と接触させることによって、TSCCの増殖を刺激する方法。
- 前記MEMPが、TSCCとの共培養条件において1%を超えるレベルで存在する、請求項23に記載の方法。
- 前記MEMPが、TSCCとの共培養条件において5%を超えるレベルで存在する、請求項23に記載の方法。
- 前記MEMPが、TSCCとの共培養条件において10%を超えるレベルで存在する、請求項23に記載の方法。
- 前記MEMPが、TSCCとの共培養条件において20%を超えるレベルで存在する、請求項23に記載の方法。
- 前記MEMPが、TSCCとの共培養条件において約40%を超えるレベルで存在する、請求項23に記載の方法。
- TSCCをin vitroで培養する、請求項23〜28のいずれか一項に記載の方法。
- 前記MEMPとの、または前記MEMP由来の培養上清、細胞溶解液もしくは画分とのTSCCの共培養が、レシピエントの外部で行われ、その共培養したTSCCがin vivoで前記レシピエントの組織部位に送達される、請求項23〜28のいずれか一項に記載の方法。
- TSCCがレシピエントにとって内在性であり、かつ組織部位にin situで局在し、さらに、TSCCの前記共培養が、MEMPまたはMEMP由来の培養上清、細胞溶解液もしくは画分の前記組織部位への送達の後にin vivoで行われる、請求項23〜28のいずれか一項に記載の方法。
- TSCCが、骨、神経組織、脂肪、軟骨、骨格筋、心筋、上皮組織、骨芽細胞、腱、靱帯、象牙芽細胞、周皮細胞、平滑筋、神経膠組織、血管組織、内皮組織、造血組織、肝臓組織および腎臓組織からなる群から選択される組織種へと分化決定されている、請求項23〜31のいずれか一項に記載の方法。
- TSCCが造血細胞である、請求項23〜31のいずれか一項に記載の方法。
- MPCまたはその子孫を、1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1α)からなる群から選択される1つまたは複数の刺激因子の存在下で培養することを含む、表現型STRO-1bri、ALP-を有するMEMPを濃縮する方法。
- 前記MPCまたはその子孫を2つまたはそれ以上の刺激因子の存在下で培養する、請求項34に記載の方法。
- 前記MPCまたはその子孫がex vivoで増殖させたものである、請求項34または請求項35のいずれか一項に記載の方法。
- 前記MPCが、単離したMPCの未増殖集団である、請求項34〜35のいずれか一項に記載の方法。
- 前記刺激が、非刺激の対照と比較して10%を超えて表現型STRO-1bri、ALP-を有するMPC子孫の増加をもたらす、請求項34〜37のいずれか一項に記載の方法。
- 前記刺激が、非刺激の対照と比較して50%を超えて表現型STRO-1bri、ALP-を有するMPC子孫の増加をもたらす、請求項34〜37に記載の方法。
- 前記MPCが、骨髄、歯髄細胞、脂肪組織および皮膚を含む群からなる任意の1つもしくは複数の組織由来、またはおそらくより広範には脂肪組織、歯、歯髄、皮膚、肝臓、腎臓、心臓、網膜、脳、毛嚢、腸、肺、脾臓、リンパ節、胸腺、膵臓、骨、靱帯、骨髄、腱および骨格筋由来である、請求項34〜39のいずれか一項に記載の方法。
- 前記MPCまたはその子孫を、1つまたは複数の刺激因子の存在下、in vivoで培養する、請求項34〜40のいずれか一項に記載の方法。
- 前記刺激因子を、MPCまたはその子孫を含む細胞集団と組み合わせて組織部位に投与する、請求項41に記載の方法。
- 外来TSCCを投与することをさらに含む、請求項42に記載の方法。
- 組織特異的分化決定済細胞集団の生成方法であって、
1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1α)からなる群から選択される1つまたは複数の刺激因子の存在下で、MPCまたはその子孫とTSCCとを含む細胞集団を培養すること、ならびに
その培養した集団を、MPCまたはTSCCの分化を特定組織種に偏らせる条件に供すること、
を含む方法。 - 前記組織種が心筋、平滑筋、血管組織、骨組織、軟骨組織、神経組織、脂肪組織、上皮組織および内皮組織からなる群から選択される、請求項44に記載の方法。
- MPCまたはその子孫と、1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1α)からなる群から選択される刺激因子とを含む組成物。
- TSCCをさらに含む請求項46に記載の組成物。
- TSCCもしくはMPCまたはその両方の分化を1つの特定組織種に偏らせる因子をさらに含む、請求項46または請求項47に記載の組成物。
- 前記組織種が心筋、平滑筋、血管組織、骨組織、軟骨組織、神経組織、脂肪組織、上皮組織および内皮組織からなる群から選択される、請求項48に記載の組成物。
- 被験体に請求項1〜10のいずれか一項に記載の濃縮集団を投与することを含む、被験体において組織を生成または修復する方法。
- 被験体に請求項11〜22のいずれか一項に記載の組成物を投与することを含む、被験体において組織を生成または修復する方法。
- 前記組織が心筋、平滑筋、血管組織、骨組織、軟骨組織、神経組織、脂肪組織、上皮組織および内皮組織からなる群から選択される、請求項50または請求項51に記載の方法。
- 表現型STRO-1bri、ALP-を有する、単離され遺伝的に改変されたMEMP。
- 異種タンパク質を発現するよう遺伝的に改変されている、請求項53に記載の単離され遺伝的に改変されたMEMP。
- 前記異種タンパク質が1α,25-ジヒドロキシビタミンD3(1,25D)、血小板由来成長因子(PDGF)、腫瘍壊死因子α(TNF-α)、インターロイキン-1β(IL-1β)および間質由来因子1α(SDF-1α)、デキサメタゾンなどの合成糖質コルチコイド、またはBMP-2、BMP-3、BMP-4、BMP-6もしくはBMP-7などの骨形態形成タンパク質からなる群から選択される、請求項54に記載の単離され遺伝的に改変されたMEMP。
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CN101506355A (zh) | 2009-08-12 |
TR201900968T4 (tr) | 2019-02-21 |
US20080260694A1 (en) | 2008-10-23 |
CA2580975A1 (en) | 2006-03-30 |
US20240101961A1 (en) | 2024-03-28 |
CN102391981A (zh) | 2012-03-28 |
CN101506355B (zh) | 2012-06-27 |
EP2348105A1 (en) | 2011-07-27 |
KR20140032507A (ko) | 2014-03-14 |
KR101536613B1 (ko) | 2015-07-14 |
EP2348105B1 (en) | 2018-10-24 |
US20140178991A1 (en) | 2014-06-26 |
JP5927080B2 (ja) | 2016-05-25 |
US20210355447A1 (en) | 2021-11-18 |
JP5265190B2 (ja) | 2013-08-14 |
US20190177685A1 (en) | 2019-06-13 |
KR20070085289A (ko) | 2007-08-27 |
US20180237746A1 (en) | 2018-08-23 |
CN102391981B (zh) | 2014-08-20 |
CA2866468A1 (en) | 2006-03-30 |
JP2013027394A (ja) | 2013-02-07 |
CA2866468C (en) | 2019-09-03 |
EP1807510A1 (en) | 2007-07-18 |
KR101441026B1 (ko) | 2014-10-01 |
WO2006032092A1 (en) | 2006-03-30 |
ES2710099T3 (es) | 2019-04-23 |
EP1807510A4 (en) | 2008-01-23 |
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