JP2013526297A - 実質組織からの細胞の移植方法 - Google Patents
実質組織からの細胞の移植方法 Download PDFInfo
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- JP2013526297A JP2013526297A JP2013509287A JP2013509287A JP2013526297A JP 2013526297 A JP2013526297 A JP 2013526297A JP 2013509287 A JP2013509287 A JP 2013509287A JP 2013509287 A JP2013509287 A JP 2013509287A JP 2013526297 A JP2013526297 A JP 2013526297A
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Abstract
【選択図】図1
Description
[関連特許出願の相互参照]
本出願は、2010年5月7日出願の米国仮特許出願番号61/332,441の権利を主張するものであって、前記出願の全体が本明細書に参照として組み込まれる。
[技術分野]
本発明によれば、好ましい細胞集団は、「正常で」「健全な」組織及び/又は細胞を有するドナーから入手してよい 誘導されてよく、ここで、前記組織及び/又は細胞は、罹患していない又は機能障害に冒されていない組織及び/又は細胞を指す。当然、このような細胞集団は、罹患した又は機能不全の臓器に苦しんでいる人から入手してもよいが、このような状態ではない臓器の一部から入手してもよい。細胞は、年齢にかかわらず、胎児、新生児、小児及び成人の組織を含むあらゆる適切な哺乳動物の組織から入手可能である。病状の実験モデルを構築しようとする場合、罹患した細胞を、好適な実験宿主へ移植するための移植片に利用してもよい。
本発明のゲル形成生体材料を使用すると、細胞支持体用の足場、並びに移植工程及び再生工程の成功に役立つシグナルが付与される。生物内の実質臓器の組織が一定の再構築を経ると、解離細胞が、その自然構造を好適な環境条件下で再生成する傾向がある。細胞は、培養液(例えば、RPM1640)、シグナリング分子(例えば、インシュリン、トランスフェリン、VEGF)及び1種以上の細胞外基質成分(例えば、ヒアルロン酸、コラーゲン、ナイドジェン、プロテオグリカン)のうちの1つ以上と混合してもよい。
組織型に応じて、適切な移植方法を選択してよい。移植片と罹患組織又は欠損組織(例えば、骨)とを置換する組織の場合、植え込み型移植片が好適である。次に、選択された方法に応じて、適切な生体材料を選択することで方法を褒めてよい(compliment)。様々な方法が必要となるであろう。例えば、骨の例では、固体基質は、細胞を、必要な増殖因子と共に当該基質に播種し、培養した後、患者に移植することができる。図1。
本発明のもう一つの実施態様では、HAゲルを従来の凍結保存法と併用することで、優れた保存性と解凍時の生存率が得られる可能性がある。本方法の概略を図6に示す。理論にとらわれたり束縛されるものではないが、HAの混入は、細胞の培養及び解凍後の機能保全を促す接着機序(例えば、β1−インテグリンの発現)を刺激することによって保存性を向上させるものと考えられる。好ましくは、HA濃度は0.01〜1重量%程度、より好ましくは0.5〜0.10%程度である。
マウス肝前駆細胞は、宿主であるC57/BL6マウス(4〜5週齢)から、報告されたプロトコルに従って単離した。「移植」実験において、GFPレポーターを肝前駆細胞に導入した。次に、前記細胞を、ヒアルロン酸(HA)ヒドロゲルと混合し、このHAをポリ(エチレングリコール)ジアクリレート(PEG−DA)で架橋してから対象マウスに導入した。導入/移植のために、マウスをケタミン(90〜120mg/kg)及びキシラジン(10mg/kg)で麻酔して開腹した。その後、前記細胞を、HAと共に又はHAを用いずに、前側肝葉に徐々に注入した。切開部を閉じ、そして動物に、ブプレノルフィン0.1mg/kgを12時間毎に48時間与えた。48時間後、動物を安楽死させ、組織を取り出して固定して、組織学的検査用の薄片を作製した。
24時間後では、HAを用いずに移植片を注入した「対照」細胞は、肝臓と肺の両方で見つかった。しかし、72時間後では、前記「対照」細胞はほとんど存在しておらず、膵臓内には、識別可能な「対照」細胞がほんの少量残存していた。これとは対照的に、本発明に従って移植された細胞では、肝臓に上手く融合した細胞群が24時間後及び72時間後にいずれも認められ、2週間後もまだ残存していた。また、この幹細胞ニッチ移植によって移植された細胞は、ランダム化組織試料アッセイでの分析によれば、ほとんど肝臓組織にだけ位置していることが分かり、しかも他の組織では見つからなかった(図7)。
ヒト肝前駆細胞は、胎児肝臓組織(16〜20週齢)から、報告されたプロトコルに従って単離した。肝前駆細胞にルシフェラーゼ発現アデノウィルスベクターを導入した。次いで、前記細胞を、チオール修飾カルボキシメチルHA(CMHA−S)と、架橋剤であるポリ(エチレングリコール)ジアクリレート(PEG−DA)の存在下で混合してから、対照マウスに導入した。より具体的には、ヒドロゲルは、HA乾燥試薬をKMに溶解して2.0(重量/容量)%溶液とすることで構築し、また、架橋剤は、KMに溶解して4.0重量/容量%溶液とした。その後、試料を37℃の水浴内でインキュベートして完全に溶解させた。III型コラーゲン及びラミニンは、1.0mg/mlの濃度に調整して、架橋剤/ヒドロゲルと1:4の割合で混合した。
7日目に、血液試料を採取し、また、組織を摘出して固定して組織学的検査を行った。健全なモデルと対比して障害モデルでは、血清アルブミンに僅かな増加が認められ、また、HA移植法により、HAを含まない細胞懸濁液からの結果と比較して増殖していることが分かった(図8)。
ヒト膵臓前駆細胞を膵臓から単離する。前記前駆細胞に、ルシフェラーゼ発現アデノウィルスベクターを導入する。次いで、前記細胞を、実施例2の記載と同様にして、チオール修飾されたカルボキシメチルHA(CMHA−S)と、架橋剤であるポリ(エチレングリコール)ジアクリレート(PEG−DA)の存在下で混合する。
24時間後では、HA移植を用いずに移植片を注入した「対照」細胞は、幾つかある臓器の中でも特に膵臓で見つかる。しかし、72時間後では、前記「対照」細胞はほとんど存在しておらず、膵臓内には、識別可能な「対照」細胞がほんの少量残存している。これとは対照的に、本発明によって移植された細胞は、膵臓に上手く融合した細胞群として24時間及び72時間の両者で認められ、そして2週間後でもまだ残存している。
ヒドロゲルに播種した肝幹細胞の生存率及び機能を評価するために実験を行った。生存率は、モレキュラー・プローブズ・カルセインAM(Molecular Probes Calcein AM)生細胞生存率測定キット(オレゴン州ユージーンのモレキュラー・プローブズ(Molecular Probes))を用いて評価した。膜浸透性カルセインAM(Calcein AM)が生細胞内のエステラーゼによって割裂されると、細胞質の緑色蛍光が生じた。分泌されたアルブミン、トランスフェリン及び尿素の培地中での濃度レベルを培養後1週間測定した。簡単に言えば、培地の上澄部を回収して、分析するまで−20℃で冷凍保存した。アルブミンの産生は、ELISAによって、ヒトアルブミンELISA定量セットを用いて測定した。尿素の産生は、血中尿素窒素比色試薬を用いて分析した。分析結果はいずれも、細胞蛍光分析器スペクトラマックス250(Spectramax 250)多穴プレートリーダーで別個に求めた。
結果を図9及び10に記載する。3週間培養後に、細胞の遺伝子発現を調べた。mRNA発現量は、GAPDHを基準とした。測定結果はいずれも、ヒアルロン酸ヒドロゲルでの三次元培養前の初期の肝幹細胞コロニーと比較した倍率変化として表している。どちらのヒアルロン酸培養実験条件(HA、及びHA+III型コラーゲン+ラミニン)でも、初期コロニー発現に比べてEpCAM(7.72±1.42、9.04±1.82)及びアルブミン(5.57±0.73、4.84±0.84)が著しく増加している。また、両方の条件では、肝芽細胞分化マーカーであるAFPも著しく低下した(0.55±0.11、0.17±0.03)。さらに、HA+III型コラーゲン+ラミニン(HA+CIII+Lam)条件では、基準のHA培養に比べてAFP発現が著しく低下することも分かった。
無血清培地で培養した植え込み型hHpSCsに対する、様々な濃度のHA及びPEGDAを有するHAヒドロゲルの機械的性質の影響を調べた。使用した製剤を以下の表3にまとめる。
KM−HAヒドロゲルの剛性、粘弾性及び粘度は、CMHA−S含有量及びPEGDA含有量によって決まる。KM−HAヒドロゲルは、強制周波数が増加するにつれてその粘度が低下したため、広範な強制周波数域にわたって一定の剛性を維持すると同時に完全な弾性的挙動を示し、そしてずり減粘を示した。CMHA−S含有量及びPEGDA含有量が、KM−HAヒドロゲルの機械的性質を支配していた(図11a)。一方で、KM−HAヒドロゲルの拡散特性は、クボタ培地単独の拡散特性と同程度であるため、最適である(図11b)。
細胞の培養を促しかつ解凍後の機能保全を高める可能性がある、HAの接着機序の保全増強効果を評価した。新たに単離されたhHpSCs及び肝芽細胞は、胎児の肝臓から単離して、ヒアルロン酸(HA)を0.5%又は0.10%補充した或いはヒアルロン酸を補充していない多数の様々な凍結保存緩衝液のうちの1種で凍結保存した。より具体的には、試料を、10%DMSO又はクライオストア(Cryotor)TM−CS10(バイオライフ・ソリューションズ(Biolife Solutions))と0重量%、0.05重量%又は0.10重量%のHAとを補充した培地を含む凍結保存溶液中に細胞数2×106個/mlで凍結させた。前記細胞は、凍結保存溶液中に4℃で10分間平衡させてから、非架橋のHA中に、図13に示す制御された方法で凍結させた。
試験した緩衝液ではいずれも、解凍時の生存率は高かった(80〜90%)。また一方、HAを補充することで、保存された細胞の、組織培養表面へ付着して培養される能力がかなり向上することが分かった。最良の測定結果は、少量のヒアルロン酸(0.05%又は0.10%)を補充したCS10等張培地で凍結保存された細胞であった。これらの発見は、新たに単離されたヒト肝前駆細胞を無血清条件下で凍結保存する際の改良方法を示しており、研究用途及び潜在的な治療用途の両方において幹細胞をより効率良く保存する方法を提供するものである。
Claims (40)
- 罹患状態又は機能不全状態の内臓を持つ対象における内臓細胞の移植方法であって、
(a)ドナーの内臓から正常細胞を得る工程と、
(b)前記細胞を、1種以上のゲル形成生体材料と混合して混合物を生成する工程と、
(c)場合により、前記混合物を、培養液、シグナリング分子、細胞外基質タンパク質又はこれらの組み合わせと混合する工程と、
(d)工程(b)の前記混合物を前記対象に導入する工程と
を含み、前記工程(d)において導入された前記細胞の実質部分は、生体内で前記内臓の少なくとも一部の中で又はその上に定着する方法。 - 前記正常細胞が、幹細胞、関連前駆細胞、又は成熟細胞である、請求項1に記載の方法。
- 前記内臓が、肝臓、肺、消化管、腸、心臓、腎臓、胆管、甲状腺、胸腺、甲状腺、脳又は膵臓である、請求項1に記載の方法。
- 前記内臓が肝臓である、請求項3に記載の方法。
- 前記細胞懸濁液が、肝幹細胞、肝芽細胞、胆管上皮若しくは肝細胞の関連前駆細胞、又は成熟した肝細胞若しくは胆管細胞によるものである、請求項3に記載の方法。
- 前記ドナーが、罹患状態又は機能不全状態の内臓を有する前記対象であり、そして前記正常細胞が、罹患していない又は機能不全状態にない内臓の一部から得られる、請求項1に記載の方法。
- 前記ドナーが、非自己移植ドナーである、請求項1に記載の方法。
- 前記ドナーが、胎児、新生児、小児又は成人である、請求項1に記載の方法。
- 前記追加の細胞が、血管芽細胞、内皮細胞、星細胞の前駆細胞、星細胞、間質細胞、上皮幹細胞、成熟実質細胞又はこれらの組み合わせを含む、請求項1に記載の方法。
- 前記1種以上の生体材料が、コラーゲン、ラミニン、接着分子、プロテオグリカン、ヒアルロン酸、グリコサミノグリカン鎖、キトサン、アルギン酸塩、並びに合成、生分解性及び生体適合性のポリマー、又はこれらの組み合わせを含む、請求項1に記載の方法。
- 前記シグナリング分子が、線維芽細胞増殖因子、肝細胞増殖因子、上皮細胞増殖因子、血管内皮細胞増殖因子(VEGF)、インスリン様増殖因子I、インスリン様増殖因子II(IGF−II)、オンコスタチンM、白血病抑制因子(LIF)、インターロイキン、トランスフォーミング増殖因子β(TGF−β)、HGF、トランスフェリン、インスリン、トランスフェリン/fe、トリヨードチロニン、T3、グルカゴン、グルココルチコイド、成長ホルモン、エストロゲン、アンドロゲン、甲状腺ホルモン及びこれらの組み合わせを含む、請求項1に記載の方法。
- 前記インターロイキンが、IL−6、IL−11、IL−13又はこれらの組み合わせである、請求項11に記載の方法。
- 前記細胞が、無血清培地で培養される、請求項11に記載の方法。
- 前記培地が、インスリン、トランスフェリン、脂質、カルシウム、亜鉛及びセレンを含む、請求項13に記載の方法。
- 前記内臓の前記細胞懸濁液が、前記細胞を前記対象に導入する前に細胞外で生体材料内で凝固される、請求項1に記載の方法。
- 前記細胞懸濁液が、前記罹患組織又は機能障害性組織に又はそれと近接して導入される、請求項1に記載の方法。
- 前記細胞懸濁液が直接組織に導入される、請求項16に記載の方法。
- 前記組織が、網又は肝臓である、請求項17に記載の方法。
- 前記細胞懸濁液が、注入、生分解性被膜又はスポンジを介して導入される、請求項1に記載の方法。
- 対象における内臓の組織の修復方法であって、前記内臓が罹患状態又は機能不全の状態にあるものであり、
(a)ドナーから内臓の正常細胞懸濁液を得る工程と、
(b)前記細胞懸濁液を、1種以上の生体材料と混合する工程と、
(c)場合により、前記細胞懸濁液を、増殖因子、サイトカイン、追加細胞又はこれらの組み合わせと混合する工程と、
(d)工程(b)又は(c)の前記懸濁液を前記対象に導入する工程と
を含み、前記工程(d)において導入された前記細胞の実質部分は、生体内で前記内臓の少なくとも一部の中で又はその上に定着する方法。 - (a)移植しようとする細胞を得る工程と、
(b)前記細胞を、ゲル形成生体材料と混合して混合物を形成する工程と、
(c)場合により、1種以上の等張性培養液、シグナリング分子及び細胞外基質成分と混合する工程と、
(d)前記混合物を凍結させる工程と
を含む細胞の凍結保存方法。 - 前記1種以上の生体材料が、コラーゲン、ラミニン、接着分子、プロテオグリカン、ヒアルロン酸、グリコサミノグリカン鎖、キトサン、アルギン酸塩、並びに合成、生分解性及び生体適合性のポリマー、又はこれらの組み合わせを含む、請求項1に記載の方法。
- 前記生体材料がヒアルロン酸を含む、請求項22に記載の方法。
- 前記細胞懸濁液が、ジメチルスルホキシド(DMSO)、グリセロール、エチレングリコール、エタエジオール(ethaediol)、1,2−プロパエンジオール(1,2-propaendiol)、2,−3ブテンジオール、ホルムアミド、N−メチルホルムアミド、3−メトキシ−1,2−プロパンジオールの単体及びこれらの組み合わせからなる群から選択される凍結保護剤と更に混合される、請求項21に記載の方法。
- 前記細胞懸濁液が、糖、グリシン、アラニン、ポリビニルピロリドン、ピルビン酸塩、アポトーシス阻害剤、カルシウム、ラクトビオン酸塩、ラフィノース、デキサメタゾン、還元ナトリウムイオン、コリン、抗酸化物質、ホルモン類又はこれらの組み合わせと更に混合される、請求項21に記載の方法。
- 前記糖が、トレハロース、フルクトース、グルコース又はこれらの組み合わせである、請求項25に記載の方法。
- 前記抗酸化物質が、ビタミンE、ビタミンA、βカロチン又はこれらの組み合わせである、請求項25に記載の方法。
- 1種以上の生体材料と混合されて移植片を形成する細胞を含む組織移植片であって、前記移植片の前記要素の剛性率が25〜520Pa程度である組織移植片。
- 内臓細胞を、標的とする内臓の表面に、その内部に又はそれらの両方に局在化させる方法であって、前記内臓細胞と1種以上のヒドロゲル形成前駆物質の溶液とを含む調合液を有効量の架橋剤の存在下で、生体内で前記標的とする内臓の表面に、その内部に又はそれらの両方に導入する工程を含み、前記調合液は、前記標的とする内臓の表面に、その内部に又はそれらの両方に、前記内臓細胞を含むヒドロゲルを形成する方法。
- 前記内臓細胞が、前記標的とする内臓の表面に、その内部に又はその両方に少なくとも12時間、少なくとも24時間若しくは少なくとも約48時間又は少なくとも72時間局在化される、請求項29に記載の方法。
- 前記内臓細胞が、腫瘍細胞でもなく、癌細胞でもなく、又は異常細胞でもない、請求項29に記載の方法。
- 前記内臓細胞が、正常細胞、腫瘍細胞若しくは癌細胞、又はウィルス、細菌、マラリアからなる群から選択される病原体に感染した細胞である、請求項29に記載の方法。
- 前記1種以上のヒドロゲル形成前駆物質が、グリコサミノグリカン類、ヒアルロン酸類、プロテオグリカンド(proteoglycand)、ゼラチン類、コラーゲン類、ラミニン類、他の付着タンパク質、植物由来基質成分、これらの変性型、又はこれらの組み合わせを含む、請求項29に記載の方法。
- 前記1種以上のヒドロゲル形成前駆物質が、チオール修飾ヒアルロン酸ナトリウム及びチオール修飾ゼラチンを含む、請求項29に記載の方法。
- 前記架橋剤が、ポリエチレングリコールジアクリレート又はそのジスルフィド含有誘導体を含む、請求項29に記載の方法。
- 前記ヒドロゲルの粘度が約0.1〜約100kPa程度、好ましくは約1〜約10kPa程度、より好ましくは約2〜約4kPa程度である、請求項29に記載の方法。
- 前記調合液が、有効量の前記架橋剤の存在下で、前記標的とする内臓の表面に形成されたポケットに導入される、請求項29に記載の方法。
- 前記ポケットが、網、スパイダーシルク及び/又は天然絹糸から製造される、請求項37に記載の方法。
- 前記標的とする内臓が、肝臓、膵臓、胆管、甲状腺、腸、肺、前立腺、乳房、脳、子宮、骨又は腎臓からなる群から選択される、請求項29に記載の方法。
- 前記ヒドロゲルが現場で形成される、請求項29に記載の方法。
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