JP6043469B2 - 脈管周囲の間葉系前駆細胞 - Google Patents
脈管周囲の間葉系前駆細胞 Download PDFInfo
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Description
多数の異なる成体組織(皮膚、毛包、骨髄、腸、脳、膵臓およびより最近では歯髄を含む)において同定された幹細胞の適所は、しばしば高度に脈管新生された部位である(1)。通常は休止状態の幹細胞集団の維持および調節は、宿主組織の必要に応じて局所的微小環境によって厳密に制御されている(2、3)。骨髄および歯髄の両方の支持的な結合組織は、顕著な厳格さでそのそれぞれの微小環境(骨および象牙質の周囲の石灰化した構造を含む)を再生することが可能である高い増殖能力を有する間質幹細胞集団を含む(4、5)。生後の生体組織において、骨髄間質はゆるく編まれた高度に脈管化された組織として存在し、この組織は、造血を支持および調節する(6〜8)。多くの組織がその再生能力を失うかまたは低下させた時点で、成体骨髄は、造血実質組織の継続的な更新のための能力を保持し、隣接骨表面の再構築を担う(9、10)。対照的に、歯の内部髄室は、石灰化した象牙質によって埋められた微小脈管ネットワークによって浸潤された、非造血性の緻密な線維性組織からなる(11〜13)。歯の成熟後、歯髄は比較的静的であり、う蝕または機械的外傷のような損傷によって引き起こされた象牙質基質の損傷に応答した補修能力においてのみ作用する。
組織サンプル
正常なヒト成人志願者由来の腸骨稜由来の骨髄単核細胞(BMMNC)を、Royal Adealaide Hospital Human Ethics Committeeによって示されたガイドラインの下で得た。正常なヒトの埋伏した第3大臼歯を、それぞれ、University of Adelaide Human Ethics Committeeによって示された承認されたガイドラインの下でUniversity of Adelaide Dental Clinic Researchにて若い成人から収集した。廃棄された全厚の皮膚および末梢脂肪組織を、Royal Adelaide Hospital Human Ethics Committeeによって示されたガイドラインの下で、Skin Cell Engineering Laboratoryからの慣用的な形成外科手順から得た。歯髄組織を、以前に記載されたように歯冠および歯根から分離した(4)。3mg/mlのI型コラゲナーゼ(Worthington Biochem、Freehold、NJ)および4mg/mlのディスパーゼ(Boehringer Mannheim、GMBH、Germany)の溶液中での37℃で1〜3時間の酵素消化によって、歯髄、皮膚および脂肪組織の単細胞懸濁物を調製した。70μmの濾過器(Falcon、BD Labware、Franklin Lakes、NJ)に細胞を通過させることによって単細胞懸濁物を得た。次いで、以下に記載されるように、骨髄、歯髄、皮膚および脂肪の細胞(0.01〜1×105/ウェル)調製物を、免疫選択、RNA抽出または6ウェルプレート(Costar、Cambridge、MA)における直接的培養のいずれかに使用した。
単細胞懸濁物を低いプレーティング密度(6ウェルプレート中に3連で、1ウェル当たり1,000細胞と10,000細胞との間)でプレートして、異なる免疫選択された細胞画分のコロニー形成効率を評価した。これらの細胞を、20%の胎仔ウシ血清、2mMのL-グルタミン、100μMのL-アスコルビン酸-2-リン酸、100U/mlのペニシリンおよび100μg/mlのストレプトマイシンを補充したα-改変イーグル培地中で5% CO2中37℃で培養した。14日目に培養物を4%のホルマリンで固定し、次いで0.1%のトルイジンブルーで染色した。50個以上の細胞の凝集物を、コロニー形成単位-線維芽細胞(CFU-F)と等価なクローン原性コロニーとしてスコアリングした。
この手順は、他に記載された手順の改変である(25)。簡潔に述べると、約1×108のBMMNCを、STRO-1bri上清(マウス抗ヒトBMSSC、IgM)(29)(1/2)と共に氷上で1時間インキュベートした。次いで、これらの細胞をPBS/5% FBSで洗浄し、1/50希釈のビオチン化ヤギ抗マウスIgM(μ-鎖特異的;Caltag Laboratories、Burlingame、CA)中に氷上で45分間懸濁した。洗浄後、これらの細胞をストレプトアビジンマイクロビーズ(Miltenyi Biotec、BergischGladbach、F.R.G.)と共に氷上で15分間インキュベートし、次いで製造者の推奨にしたがってMini MACS磁気カラム(Miltenyi Biotec)上で分離した。
STRO-1bri MACS単離した細胞を、ストレプトアビジン-FITCコンジュゲート(1/50;CALTAG Laboratories)と共に氷上で20分間インキュベートし、次いでPBS/5% FBSで洗浄した。単色蛍光活性化細胞分類(FACS)を、FACStarPLUSフローサイトメータ(Becton Dickinson、Sunnyvale、CA)を使用して実施した。二色-FACS分析を、MACS単離したSTRO-1bri BMMNCを、飽和(1:1)レベルのCC9抗体上清(マウス抗ヒトCD146/MUC-18/Mel-CAM、IgG2a、Stan Gronthos博士)と共に氷上で1時間インキュベートすることによって達成した。PBS/5% FBSで洗浄した後、これらの細胞を第2の標識ヤギ抗マウスIgG2a(γ-鎖特異的)フィコエリスリン(PE)コンジュゲート抗体(1/50、CALTAG Laboratories)と共に氷上で20分間インキュベートした。次いでこれらの細胞をFACStarPLUSフローサイトメータの自動細胞堆積ユニット(ACDU)を使用して分類した。限界希釈アッセイ:1ウェル当たり1、2、3、4、5および10個の細胞を播種し、24回反復し、以前に記載されたように10日間にわたって血清除去した培地中で培養した(26)。同様に、新たに調製した分画していないBMMNCを、CC9(IgG2a)抗体および3G5(IgM)抗体、またはアイソタイプが一致した陰性対照抗体と共に、氷上で1時間インキュベートした。PBS/5% FBSで洗浄した後、これらの細胞を第2の標識ヤギ抗マウスIgG2a(γ-鎖特異的)フィコエリスリン(PE)およびIgM(1/50;CALTAG Laboratories)コンジュゲート抗体と共に氷上で30分間インキュベートした。細胞をPBS/5% FBS中で洗浄し、その後FACStarPLUSフローサイトメータを使用して分析した。各抗体に対する陽性の反応性は、アイソタイプが一致した対照抗体の99%より高い蛍光レベルとして規定した。
ex vivoで増殖させた骨髄MPCの単細胞懸濁物を、トリプシン/EDTA処理によって調製し、次いでニートなSTRO-1上清または異なる細胞系統に関連するマーカーを同定する抗体(10μg/ml)と共に氷上で1時間インキュベートした。次いでこれらの細胞をPBS/5% FBS中で洗浄し、次いで、ヤギ抗マウスIgM-フィコエリスリン(1/50、SouthernBiotechnologies)、ヤギ抗マウスIgG-フィコエリスリンまたはヤギ抗ウサギIgG-フィコエリスリン(Caltag Laboratories)のいずれかと共にインキュベートした。細胞内抗原を同定する抗体について、細胞調製物の細胞膜を透過性にし、その後細胞内マーカーについて染色した。アイソタイプが一致した対照抗体を同一条件下で処理した。フローサイトメトリー分析を、COULTER EPICS装置を使用して実施した。ドットブロットは、5,000リストモード(listmode)の事象を示し、これは、アイソタイプが一致した陰性対照抗体を参照した各系統の細胞マーカーについての蛍光強度のレベルを示す。
ヒト組織切片(μm)をキシレン中で脱ワックス(de-wax)し、PBS中の勾配付エタノールによって再水和した。凍結組織切片(μm)およびサイトスピン調製物を冷アセトンで-20℃で15分間固定し、次いでPBS中で洗浄した。これらのサンプルを引き続いて1.5%の過酸化水素を含むPBSで30分間処理し、洗浄し、次いで5%の非免疫ヤギ血清を用いて室温で1時間ブロッキングした。サンプルを1次抗体と共に室温で1時間インキュベートした。使用した抗体は以下である:マウス(IgG1およびIgG2a)対照(Caltag、Burlingame、CA);ウサギ(Ig)対照、1A4(抗α平滑筋アクチン、IgG1)、2F11(抗神経フィラメント、IgG1)、F8/86(マウス抗フォンビルブランド因子、IgG1)(Dako、Carpinteria、CA);STRO-1;CC9(抗CD146);LF-151(ウサギ抗ヒト象牙質シアロタンパク質(dentinsialoprotein);L. Fisher博士、NIDCR/NIH、MD)。作業希釈:ウサギ血清(1/500)、モノクローナル上清(1/2)および精製した抗体(10μg/ml)。単一の染色を、適切な2次抗体であるビオチン化ヤギ抗マウスIgM、IgG1、IgG2aまたはビオチン化ヤギ抗ウサギ(Caltag Laboratories)と共にサンプルを室温で1時間インキュベートすることによって実施した。次いで、アビジン-ペルオキシダーゼ複合体および基質を製造業者の指示にしたがって添加した(Vectastain ABC Kit standard、Vector Laboratories)。サンプルをヘマトキシリンで対比染色し、水性媒体中に設置した。二重抗体標識を、2次抗体であるヤギ抗マウスIgM-Texas RedおよびIgG-FITC (CALTAG Laboratories)を、室温で45分間添加することによって達成した。洗浄後、これらのサンプルをVECTASHIELD蛍光マウンタント(mountant)中に設置した。
歯髄組織の単細胞懸濁物を、STRO-1(1/2)、CD146(1/2)または3G5(1/2)に対して反応性の抗体と共に氷上で1時間インキュベートした。これらの細胞をPBS/1% BSAで2回洗浄し、次いでヒツジ抗マウスIgGコンジュゲート磁気Dynabeadsまたはラット抗マウスIgMコンジュゲート磁気Dynabeads(1細胞当たり4個のビーズ;Dynal、Oslo、Norway)のいずれかと共に、4℃でロータリーミキサーで40分間インキュベートした。ビーズに結合している細胞を、製造業者の推奨するプロトコルにしたがってMPC-1磁気粒子濃縮器(Dynal)を使用して取り出した。
ex vivoで増殖させた骨髄STRO-1brightMPCの単細胞懸濁物をトリプシン/EDTA処理によって調製し、次いで200μlのマトリゲルを含む48ウェルプレート中に配置した。このSTRO-1brightMPCを、10ng/mlの増殖因子PDGF、EGF、VEGFを補充した無血清培地(Gronthosら、2003)中に、1ウェル当たり20,000細胞でプレートした。5%のCO2中で37℃での24時間の培養後、これらのウェルを洗浄し、次いで4%のパラホルムアルデヒドで固定した。免疫組織化学研究を、上記のように、ヤギ抗マウスIgG西洋ワサビペルオキシダーゼ抗体/Vectastaining Kitを用いて同定したα-平滑筋アクチンに対して引き続いて実施した。
ex vivoで増殖させた脂肪由来のMPCの単細胞懸濁物を、以前に示されたように、10%のFCS、100μMのL-アスコルビン酸-2-リン酸、デキサメタゾン10-7Mおよび3mMの無機リン酸を補充したαMEM中で培養して、石灰化した骨マトリクスをin vitroで形成するように骨髄MPCを誘導した(Gronthosら、2003)。ミネラルの沈着を、陽性のvon Kossa染色によって同定した。脂肪生成を、以前に記載されたように(Gronthosら、2003)、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誘導した。Oil Red O染色を使用して、脂質が堆積した脂肪細胞を同定した。軟骨形成分化を、記載されたように(Pittengerら、1999)、10ng/mlのTGF-β3で処理した凝集培養物中で評価した。
以前に記載されたように(4)、約5.0×106のex vivoで増殖させた細胞(STRO-1bri/CD146+のBMSSCまたはCD146+のDPSCのいずれかに由来する)を、40mgのヒドロキシアパタイト/リン酸三カルシウム(HA/TCP)セラミック粉末(Zimmer Inc、Warsaw、IN)と混合し、次いで10週齢の免疫無防備状態のベージュマウス(NIH-bg-nu-xid、Harlan Sprague Dawley、Indianapolis、IN)の背側表面中に皮下移植した。これらの手順を、承認された動物プロトコル(NIDCR番号00-113)の仕様にしたがって実施した。
総RNAを、STRO-1BRI/CD146+で分類したBMMNCおよび対照細胞(10-7Mのデキサメタゾンの存在下で3週間培養された初代BMSSC培養物)から、RNA STAT-60(TEL-TEST Inc.Friendswood TX)を使用して調製した。第1鎖cDNA合成を、オリゴ-dTプライマーを使用して第1鎖cDNA合成キット(GIBCO BRL、Life Technologies)を用いて実施した。第1鎖cDNA(2μl)を、46μlの1×PCRマスター反応ミックス(Roche Diagnostics、Gmbh Mannheim Germany)および10pMolの各ヒト特異的プライマーセット:CBFA1(632bpおよび3つのより小さい選択的スプライス改変体)(27)センス5'-CTATGGAGAGGACGCCACGCCTGG-3'[配列番号1]、アンチセンス、5'-CATAGCCATCGTAGCCTTGTCCT-3'[配列番号2];オステオカルシン(310bp)(4)センス、5'-CATGAGAGCCCTCACA-3'[配列番号3]、アンチセンス、5'-AGAGCGACACCCTAGAC-3'[配列番号4];GAPDH(800bp)(4)センス、5'-AGCCGCATCTTCTTTTGCGTC-3'[配列番号5];アンチセンス5'-TCATATTTGGCAGGTTTTTCT-3'[配列番号6]に添加した。これらの反応を、PCR Express Hybaidサーマルサイクラー(Hybaid、Franklin、MA)中で、95℃で2分間を1サイクル、次いで94℃/(30秒間)、60℃/(30秒間)、72℃/(45秒間)を35サイクル、最後に72℃で7分間の伸長でインキュベートした。増幅後、各反応を1.5%アガロースゲル電気泳動によって分析し、エチジウムブロマイド染色によって可視化した。
BMSSCおよびDPSCは、in vivoで、脈管関連抗原STRO-1およびCD146を発現する。
本発明者らは、STRO-1抗原の高い発現に基づいて、ヒト髄の吸引物から全ての検出可能なクローン原性コロニーを単離および富化するための、磁気活性化細胞分類(MACS)の有効性を以前に実証している(25、26)。BMSSCをさらに特徴付けるために、本発明者らは、内皮細胞および平滑筋細胞上に存在する細胞表面抗原CD146(MUC-18、Mel-CAMおよびSendo-1としても知られる)を認識する別のモノクローナル抗体CC9(28)と共にSTRO-1bri MACS単離した細胞をインキュベートした。これらの研究は、CC9が、二色FACS分析によって、総STRO-1+集団由来のSTRO-1 brightを発現する画分(STRO-1BRT)に選択的に結合することを実証した(図1A)。ポワソン分布統計を使用するクローニング効率アッセイにより、BMSSCの発生率の顕著な増大(プレートした5個のSTRO-1BRT/CD146+細胞当たり1コロニー)が得られ、分画していない髄と比較してクローン原性コロニー集団の2×103倍の富化が達成された(図1B)。STRO-1BRT/CD146-細胞画分においてはコロニー形成は検出できなかった(データ示さず)。
本研究において、フローサイトメトリー分析により、細胞表面抗原3G5が、大きい割合(54%)の造血髄細胞によって高度に発現されたことが明らかとなった(図4A)。この観察により、ヒト髄の吸引物からBMSSCの直接精製された集団を単離するための候補マーカーとして3G5が排除された。さらに、3G5およびSTRO-1の発現に基づく二重FACS分析は、両方の抗体が同じアイソタイプを共有したので不可能であった。それにもかかわらず、異なる3G5/CD146 FACS分類した部分画分についてのin vitroのコロニー効率アッセイにより、小さい割合(14%)の骨髄クローン原性コロニーだけが低いレベルで3G5抗原を発現したことが実証された(図4B)。逆に、より大きい割合(63%)のクローン原性DPSC(プレートした105個の細胞当たり192個のコロニー形成細胞±18.4 SE、n=3)が、免疫磁気ビーズ選択後の3G5+細胞中に存在した(図2)。3G5は、ヒト歯髄組織の凍結切片中の周皮細胞に対する特異的な反応性を実証した(図3F)。
本研究は、その個体発生および発生能が異なる2種の間葉系幹細胞集団が共に、そのそれぞれの組織の微小脈管系に関連するという直接的な証拠を提供している。
[成人ヒト骨髄MPCは、STRO-1抗原の高い発現およびCD34発現の欠如によって、間質前駆細胞、造血幹細胞および血管芽細胞から識別される。]
生後の骨髄は、血球形成(造血幹細胞)、内皮発生(血管芽細胞)および結合組織/間質分化(間質前駆細胞/骨髄間質幹細胞/間葉系幹細胞)を担う常在の幹細胞型および前駆細胞型の中心であるようである。本発明者らのグループによる最近の研究(Gronthosら、2003;ShiおよびGronthos 2003)は、ヒト多能性骨髄間葉系前駆細胞(MPC)を、STRO-1抗原の高い発現に基づき、免疫グロブリンスーパーファミリーメンバーVCAM-1(CD106)およびMUC-18(CD146)の同時発現によって、初めて精製および特徴付けした。SimmonsおよびTorok-Storb(1991aおよびb)による初期の研究は、in vitroで接着性コロニーを形成する能力を有する骨髄由来のSTRO-1+間質前駆細胞もまた、造血幹細胞マーカーCD34を低いレベルではあるものの発現したことを示している。これらの研究は、髄吸引物中の高い割合の接着性コロニー形成細胞を排除するために、CD34抗体-補体媒介性の細胞溶解を使用した(SimmonsおよびTorok-Storb 1991b)。STRO-1抗体は、ヒトのCD34+骨髄細胞を用いたマウスの免疫後に産生されるが、これは、STRO-1抗原がCD34+/グリコホリン-A+有核赤血球およびCD34+/CD20+ Bリンパ球上でも中程度〜低いレベルで発現されるという事実に起因して生じた可能性があることに留意することが重要である。本発明者らは、洗練された蛍光活性化細胞分類技術を使用して、多能性成人ヒト骨髄MPCが高レベルのSTRO-1を発現するが、間質前駆細胞、造血幹細胞および血管芽細胞のマーカー(CD34)、白血球抗原(CD45)ならびに有核赤血球マーカー(グリコホリン-A)の発現を欠くという直接的な証拠をここに提供する(図6A〜C)。これらのデータは、成人ヒト骨髄由来のMPCが、より成熟した間質前駆細胞、造血幹細胞および血管芽細胞とは別個の新規幹細胞集団であることを実証している(図7)。
[異なるヒト組織中の多能性MPCの同定]
異なる組織中のMPCの存在および正確な位置はほぼ未知であるものの、本発明者らは、MPCがヒト骨髄組織および歯髄組織中の脈管周囲の間隙中に存在するようであることを最近実証した(ShiおよびGronthos 2003)。これらの観察は、間葉系幹細胞マーカーSTRO-1、平滑筋および周皮細胞のマーカーCD146、α平滑筋アクチン、ならびに周皮細胞特異的マーカー3G5の発現に基づいて、異なるMPC集団を同定および単離するための免疫組織化学方法および免疫選択方法の組み合わせに基づいていた。本発明者らは、心臓、肝臓、腎臓、皮膚、脾臓、膵臓、リンパ節を含む広範な種々の組織におけるSTRO-1/CD146抗原、STRO-1/α-平滑筋アクチン抗原および3G5/CD146抗原の同時局在を実証するこれらの研究をここで展開した(図8)。
[ex vivoで増殖させたヒト骨髄間葉系前駆細胞の免疫表現型分析]
本発明者らは、多能性間葉系前駆細胞(MPC)が、表現型STRO-1bright/VCAM-1(CD106)+またはSTRO-1bright/MUC-18(CD146)+に基づいて、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ら、2003;ShiおよびGronthos 2003)。このMPC集団は、既定された培養条件下でin vitroで容易に増殖させることが可能である(Gronthosら、2003)。本発明者らはここで、逆転写酵素-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分析をそれぞれ使用して、mRNAレベルおよびタンパク質レベルの両方で、異なる細胞系統と関連するマーカーに基づいてex vivoで増殖させたMPCの子孫を特徴付けるデータを提示する。
Claims (19)
- 脂肪組織由来の表面マーカー3G5及びCD146陽性である間葉系前駆細胞(MPC)を富化する工程を含む、MPCを富化する方法であって、前記MPCが、クローン原性コロニーを形成することが可能であり、2種以上の間葉系組織型へと分化することが可能である方法。
- 3G5及びCD146の存在に基づいてMPCを富化する前に、脂肪組織由来の単細胞懸濁物を調製する工程をさらに含む、請求項1に記載の方法。
- 前記MPCが造血マーカーCD45、CD34およびグリコホリン-A陰性である、請求項1に記載の方法。
- 前記MPCが哺乳動物から単離される、請求項1に記載の方法。
- 前記哺乳動物がヒトである、請求項4に記載の方法。
- 前記MPCが、少なくとも骨芽細胞、象牙芽細胞、象牙質産生、軟骨細胞、腱、靭帯、軟骨、脂肪細胞、線維芽細胞、髄間質、破骨細胞支持間質および造血支持間質、心筋、平滑筋、骨格筋、周皮細胞、脈管、上皮、神経膠、ニューロン、星状膠細胞または稀突起神経膠細胞の細胞型のうち2種または複数を含む細胞を形成するように分化するよう誘導される能力を有する、請求項1に記載の方法。
- 前記MPCを富化した集団を増殖させる工程をさらに含む、請求項1に記載の方法。
- 前記MPCを増殖させない、請求項1に記載の方法。
- 前記富化した集団が、クローン原性コロニーを形成することが可能であり、3種以上の間葉系組織型へと分化することが可能であるMPCを少なくとも0.01%含む、請求項1に記載の方法。
- 前記富化した集団が、クローン原性コロニーを形成することが可能であり、3種以上の間葉系組織型へと分化することが可能であるMPCを少なくとも0.1%含む、請求項1に記載の方法。
- 前記富化した集団が、クローン原性コロニーを形成することが可能であり、3種以上の間葉系組織型へと分化することが可能であるMPCを少なくとも1%含む、請求項1に記載の方法。
- 前記富化した集団が、少なくとも0.01%のSTRO-1briのMPCを含む、請求項10または11に記載の方法。
- 前記富化した集団が、少なくとも0.1%のSTRO-1briのMPCを含む、請求項10または11に記載の方法。
- 前記富化した集団が、少なくとも1%のSTRO-1briのMPCを含む、請求項1に記載の方法。
- 前記増殖させた集団が、マーカーSTRO-1 bri 、3G5またはMUC18/CD146のうち1種または複数を高レベルで発現する細胞を少なくとも0.1%含む、請求項7に記載の方法。
- 前記増殖させた集団が、マーカーSTRO-1bri、3G5またはMUC18/CD146のうち1種または複数を高レベルで発現する細胞を少なくとも1%含む、請求項7に記載の方法。
- 前記増殖させた集団が、マーカーSTRO-1bri、3G5またはMUC18/CD146のうち1種または複数を高レベルで発現するMPCを少なくとも2%含む、請求項7に記載の方法。
- 前記増殖させた集団が、マーカーSTRO-1bri、3G5またはMUC18/CD146のうち1種または複数を高レベルで発現する細胞を少なくとも5%含む、請求項7に記載の方法。
- 前記増殖させた集団が、マーカーSTRO-1bri、3G5またはMUC18/CD146のうち1種または複数を高レベルで発現する細胞を少なくとも10%含む、請求項7に記載の方法。
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