JP6612722B2 - バイオマトリックス足場 - Google Patents
バイオマトリックス足場 Download PDFInfo
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- JP6612722B2 JP6612722B2 JP2016237356A JP2016237356A JP6612722B2 JP 6612722 B2 JP6612722 B2 JP 6612722B2 JP 2016237356 A JP2016237356 A JP 2016237356A JP 2016237356 A JP2016237356 A JP 2016237356A JP 6612722 B2 JP6612722 B2 JP 6612722B2
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- cells
- tissue
- biomatrix scaffold
- biomatrix
- scaffold
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Description
本願は、35 U.S.C § 119(e)に基づき、2010年7月2日出願の米国仮出願出願番号61/360,939による優先権を主張するものであり、その全内容は、参照により本願に組み込まれる。
本発明の側面は、米国国立衛生研究所(National Institutes of Health)(NIH)助成金番号AA014243およびIP30-DK065933、国立糖尿病・消化器・腎疾病研究所(National Institute of Diabetes and Digestive and Kidney Diseases)(NIDDK)助成金番号DK34987、米国立癌研究所(National Cancer Institute)(NCI)助成金番号CA016086ならびに国立歯科・頭蓋顔面研究所(National Institute of Dental and Craniofacial Research)番号DE019569の下に政府の支援を受けて行われた。アメリカ合衆国政府は本発明に一定の権利を有する。
本発明は、バイオマトリックス足場、バイオマトリックス足場の製造方法および、無傷の足場としてのあるいは特定の実験および臨床用途のために切片化されるかまたは粉砕されさまざまに分散された足場としての、様々な用途におけるバイオマトリックス足場の使用に関する。
ここで、本発明を以下にさらに詳細に説明する。しかしながら、本発明は、他の形態で実施することが可能であり、本発明を本明細書に示す実施形態に限定するものと解釈してはならない。むしろ、これらの実施形態は、本開示を詳細かつ完全なものにするために、かつ本発明の範囲を当業者に十分に伝えるために提供されるものである。
a)本発明の方法によってバイオマトリックス足場を製造し;b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;c)(b)のバイオマトリックス足場に腫瘍細胞を播種し;d)(c)のバイオマトリックス足場を培養条件下に維持し;e)(d)のバイオマトリックス足場での腫瘍細胞集団を確立すること;を含み、それによって宿主動物への移植のための腫瘍移植片を製造する前記方法を提供する。いくつかの実施形態において、本方法は、宿主動物に腫瘍移植片を移植する段階をさらに含むことができる。種々の実施形態において、腫瘍移植片は宿主動物に対して同系(syngeneic)、同種(allogeneic)または異種(xenogenic)であることができる。
組織特異的バイオマトリックス足場によって、ヒト肝幹細胞の成熟運命への系統限定が効率的となる
要約。幹細胞の分化のための現行のプロトコルは、可溶性シグナルおよび/またはマトリックス因子の複数の処理を利用し、一般的には、成人組織特異的遺伝子の過小発現または過剰発現を伴う成熟細胞への部分的分化をもたらす。本発明において、目的とする成人細胞型に合わせた、無血清ホルモン添加培地(HDM)と組み合わせた、バイオマトリックス足場の基材である細胞外マトリックスの富化した組織特異的抽出物と関連する増殖因子およびサイトカインとを用いる、幹細胞の迅速かつ効率的な分化のための戦略が開発された。本明細書に記載の研究は、ヒト肝幹細胞(hHpSC)を成熟運命に分化させることおよび、成熟実質細胞を完全に機能するように長期間維持することにおける本発明のバイオマトリックス足場の有効性を明らかにしている。バイオマトリックス足場は、すべてのコラーゲンタイプを不溶性に保つように設計された条件を用いる新規4段階潅流脱細胞化プロトコルによって製造された。この足場は、天然組織構造、親血管、おおよそ1%の組織タンパク質(ただし組織のコラーゲンは95%を超える)、組織のコラーゲン結合性マトリックス成分の大部分ならびに生理的レベルのマトリックス結合性増殖因子およびサイトカインを維持していた。コラーゲンは、ほとんど検出できないレベルから足場のタンパク質の15%を超えるレベルまで増加し、残りは、組織構造と関連したパターンでラミニン、フィブロネクチン、エラスチン、ナイドジェン/エンタクチン、プロテオグリカンならびにマトリックス結合性サイトカインおよび増殖因子を含んでいた。肝臓バイオマトリックス足場に播種され、成人肝臓細胞に合わせたHDMに入れられたヒト肝幹細胞(hHpSC)は、おおよそ1週間で幹細胞マーカーを消失し、機能しうる成熟実質細胞に分化し、8週間を超えて生存し、安定な成熟細胞表現型を維持していた。従って、本発明のバイオマトリックス足場は、系統が限定された幹細胞の生物学的および医薬研究に、成熟細胞の維持に、そして操作された植込み型血管化組織または臓器に用いることができる。
(1).潅流洗浄および潅流リンス:無血清基礎培地(例えば、RPMI-1640);
(2).洗浄剤での潅流:36単位/L PLA2+1%SDC;
(3).高塩での潅流:0.1mg/ml大豆トリプシンインヒビターを含む3.4M NaCl;
(4).ヌクレアーゼでの潅流:5mg/100ml RNアーゼ、1mg/100ml DNアーゼおよび0.1mg/ml大豆トリプシンインヒビター(例えば、RPMI 1640で調製)。
1)培養選択。10cm組織培養ディッシュのKM中におおよそ3x105細胞をプレーティングした。培地を3日毎に交換した。コロニーは5〜7日以内に形成され、これを3ヶ月目まで観察した。14〜18日後に、倒立顕微鏡(1X-FLAIII;Olympus社、日本およびメルヴィル、ニューヨーク)を用いて、コロニーを手で拾った。
2)多能性肝前駆細胞サブ母集団(hHpSCおよびhHB)の磁気免疫選択は、製造業者による使用説明書50に従って、Miltenyi Biotech MACSシステム(ベルギッシュ・グラートバッハ、ドイツ)による磁性ビーズ免疫選択技術を用いて、上皮細胞接着分子(EpCAM、CD326)に陽性な細胞を選択することによって達成した。簡潔に言えば、磁気マイクロビーズに結合させたEpCAM抗体と共に解離した細胞を4℃で30分間インキュベートし、製造業者の推奨する手順に従って、Miltenyi製の磁気カラム分離システムを用いて分離した。
腫瘍細胞株培養物または腫瘍初代培養物のためのバイオマトリックス足場の使用
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕生体組織からのバイオマトリックス足場の製造方法であって、
a)第1培地で生体組織を灌流するかまたは生体組織をホモジナイズし、ここで前記第1培地の重量オスモル濃度は約250mOsm/kg〜約350mOsm/kgであり、前記第1培地は無血清かつ中性pHであり;
b)前記第1培地にリパーゼおよび/または洗浄剤を含む脱脂緩衝液で段階(a)の生体組織を灌流するかまたは段階(a)のホモジネートを抽出し;
c)中性pHかつ約2.0M NaCl〜約5.0NaClの塩濃度であって、生体組織内で同定されるコラーゲンを不溶性に保つように選択された塩濃度を含む緩衝液で段階(b)の組織を灌流するかまたは段階(b)のホモジネートを抽出し;
d)緩衝液中、RNアーゼおよびDNアーゼで段階(c)の組織を灌流するかまたは段階(c)のホモジネートを抽出し;
e)中性pHかつ無血清であり、約250mOsm/kg〜約350mOsm/kgの重量オスモル濃度を有する第2培地で段階(d)の組織またはホモジネートをリンスする段階;
を含み、それによって生体組織から、無傷のまたはホモジナイズしたバイオマトリックス足場であって、コラーゲンの少なくとも95%および生体組織のコラーゲン結合性マトリックス成分およびマトリックス結合性増殖因子、ホルモンおよびサイトカインの大部分を含む前記足場を製造する前記方法。
〔2〕第1培地が、塩、ミネラル、アミノ酸、ビタミンおよび糖を含む、前記〔1〕に記載の方法。
〔3〕第1培地が基礎培地である、前記〔1〕に記載の方法。
〔4〕基礎培地が、RPMI 1640、DME/F12、DME、F12、ウェイマウスおよびウィリアム培地からなる群から選択される、前記〔3〕に記載の方法。
〔5〕第2培地が、間質液に存在する成分の少なくとも1つを含む、前記〔1〕に記載の方法。
〔6〕段階(b)の脱脂緩衝液が、第1培地に約20単位/L〜約50単位/LのホスホリパーゼA2および約1%のデオキシコール酸ナトリウムを含む、前記〔1〕に記載の方法。
〔7〕段階(c)の緩衝液の塩濃度が、成人肝臓からの足場製造に用いる場合、約3.4M NaCl〜約3.5M NaClであり、胎児肝臓からの足場製造に用いる場合、約4.0M NaCl〜約4.5M NaClである、前記〔1〕に記載の方法。
〔8〕段階(c)の緩衝液がプロテアーゼインヒビターをさらに含む、前記〔1〕に記載の方法。
〔9〕プロテアーゼインヒビターが大豆トリプシンインヒビターである、前記〔8〕に記載の方法。
〔10〕段階(d)の緩衝液がプロテアーゼインヒビターをさらに含む、前記〔1〕に記載の方法。
〔11〕プロテアーゼインヒビターが大豆トリプシンインヒビターである、前記〔10〕に記載の方法。
〔12〕段階(a)〜(e)のすべての培地および緩衝液が、細胞外マトリックス成分を分解する酵素の検出可能な量を含まない、前記〔1〕に記載の方法。
〔13〕バイオマトリックス足場を滅菌することをさらに含む、前記〔1〕に記載の方法。
〔14〕滅菌段階がバイオマトリックス足場のγ線照射を含む、前記〔13〕に記載の方法。
〔15〕生体組織が肝臓組織、肺組織、膵臓組織、甲状腺組織、腸管組織、皮膚組織、血管組織、膀胱組織、心臓組織および腎組織からなる群から選択される、前記〔1〕に記載の方法。
〔16〕生体組織が哺乳動物由来である、前記〔1〕に記載の方法。
〔17〕前記〔1〕〜〔16〕のいずれかに記載の方法によって製造されるバイオマトリックス足場。
〔18〕コラーゲン、フィブロネクチン、ラミニン、ナイドジェン/エンタクチン、エラスチン、プロテオグリカン、グリコサミノグリカン、増殖因子、サイトカインまたはそれらの任意の組み合わせをすべてバイオマトリックス足場の一部として含むバイオマトリックス足場。
〔19〕細胞培養物の製造方法であって、
a)前記〔1〕〜〔16〕のいずれかに記載の方法によってバイオマトリックス足場を製造し;
b)段階(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)段階(b)のバイオマトリックス足場に細胞を播種すること;
を含み、それによって細胞培養物を製造する前記方法。
〔20〕細胞培養物の製造方法であって、
a)前記〔1〕〜〔16〕のいずれかに記載の方法によってバイオマトリックス足場を製造し;
b)段階(a)のバイオマトリックス足場を凍結し;
c)段階(b)のバイオマトリックス足場から細胞培養基材として凍結切片を調製し;
d)段階(c)の細胞培養基材と細胞培養培地を培養装置内で接触させ;
e)段階(d)の細胞培養基材に細胞を播種すること;
を含み、それによって細胞培養物を製造する前記方法。
〔21〕細胞培養物の製造方法であって、
a)前記〔1〕〜〔16〕のいずれかに記載の方法によってバイオマトリックス足場を製造し;
b)段階(a)のバイオマトリックス足場を粉末に粉砕し;
c)培養装置の少なくとも一部に段階(b)の粉末をコーティングして細胞培養基材を製造し;d)(c)の細胞培養基材と細胞培養培地を培養装置内で接触させ;
e)(d)の細胞培養基材に細胞を播種すること;
を含み、それによって細胞培養物を製造する前記方法。
〔22〕バイオマトリックス足場の粉砕が、フリーザーミル内で液体窒素温度またはその付近の温度で行われる、前記〔21〕に記載の方法。
〔23〕細胞培養培地が、間質液に存在する成分の少なくとも1つを含み、前記培地の重量オスモル濃度が約250mOsm/kg〜約350mOsm/kgであり、前記培地が無血清である、前記〔19〕〜〔22〕のいずれかに記載の方法。
〔24〕培地がRPMI-1640である、前記〔23〕に記載の方法。
〔25〕細胞が、バイオマトリックス足場の製造に用いられる生体組織の細胞と同じ型である、前記〔19〕〜〔24〕のいずれかに記載の方法。
〔26〕細胞が、胚性幹(ES)細胞、人工多能性幹(iPS)細胞、決定された幹細胞、周産期幹細胞、羊水由来幹細胞(AFSC)、任意の起源の間葉系幹細胞(MSC)、任意の組織型の、分化方向を決定された前駆細胞または成人細胞、成熟細胞、正常細胞、罹患細胞、腫瘍細胞およびそれらの任意の組み合わせからなる群から選択される、前記〔19〕〜〔24〕のいずれかに記載の方法。
〔27〕細胞が、肝臓細胞、実質細胞、星細胞、内皮細胞、肝細胞、胆管細胞、胆管細胞ではない胆樹細胞および膵臓細胞からなる群から選択される、前記〔19〕〜〔24〕のいずれかに記載の方法。
〔28〕胚性幹細胞または人口多能性細胞の特定の運命への分化を促進するための組織特異的バイオマトリックス足場の使用。
〔29〕羊水由来幹細胞または骨髄、脂肪組織、任意の胎児組織もしくは任意の出生後組織からの間葉系幹細胞または決定された幹細胞の特定の成人運命への分化を促進するための組織特異的バイオマトリックス足場の使用。
〔30〕前記〔19〕〜〔27〕のいずれかに記載の方法によって製造される細胞培養物。
〔31〕幹細胞および/または前駆細胞の成熟細胞への分化を増進し加速させる方法であって、前記〔19〕〜〔27〕のいずれかに記載の方法によって細胞培養物を製造することを含む前記方法において、細胞が幹細胞であり、成熟細胞のための細胞培養培地を処方し、それによって幹細胞および/または前駆細胞の成熟細胞への分化を増進し加速させる前記方法。
〔32〕細胞が、任意の型の成人細胞であるか、あるいは胚性幹細胞、人工多能性幹細胞、胚葉幹細胞、決定された幹細胞、周産期幹細胞、羊水由来幹細胞、間葉系幹細胞、一過性増殖細胞または任意の組織型の、分化方向を決定された前駆細胞からなる群から選択される幹細胞または前駆細胞である、前記〔31〕に記載の方法。
〔33〕細胞培養培地が、RPMI 1640、DME/F12、DME、F12、ウェイマウスおよびウィリアム培地からなる群から選択される、前記〔31〕に記載の方法。
〔34〕被験者に細胞を送達する方法であって、前記〔17〕または〔18〕のいずれかに記載のバイオマトリックス足場に細胞を播種し、次いで、細胞を播種されたバイオマトリックス足場を被験者に移植することを含む前記方法。
〔35〕組織型における腫瘍細胞の転移能を同定する方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に腫瘍細胞を播種し;
d)(c)のバイオマトリックス足場を培養条件下に維持し;
e)(d)のバイオマトリックス足場での腫瘍細胞の増殖をモニタリングすること;
を含む前記方法において、バイオマトリックス足場での腫瘍細胞の増殖が、バイオマトリックス足場が製造された組織型に腫瘍細胞がin vivoでコロニーを形成することができることを同定し、それによって前記組織型における腫瘍細胞の転移能を同定する前記方法。
〔36〕抗腫瘍処置に感受性のある腫瘍細胞を同定する方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に腫瘍細胞を播種し;
d)(c)のバイオマトリックス足場を培養条件下に維持し;
e)バイオマトリックス足場での腫瘍細胞に抗腫瘍処置を適用し;
f)(e)のバイオマトリックス足場での腫瘍細胞の増殖をモニタリングすること;
を含む前記方法において、(e)のバイオマトリックス足場での腫瘍細胞の増殖の欠如および/または腫瘍細胞の死が抗腫瘍処置に感受性のある腫瘍細胞を同定する前記方法。
〔37〕宿主動物への移植のための腫瘍移植片の製造方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に腫瘍細胞を播種し;
d)(c)のバイオマトリックス足場を培養条件下に維持し;
e)(d)のバイオマトリックス足場で腫瘍細胞集団を確立すること;
を含み、それによって宿主動物への移植のための腫瘍移植片を製造する前記方法。
〔38〕宿主動物に腫瘍移植片を移植する段階をさらに含む、前記〔37〕に記載の方法。
〔39〕腫瘍移植片が宿主動物に対して同系、同種または異種である、前記〔38〕に記載の方法。
〔40〕系統依存性ウイルスのウイルス粒子の製造方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に、系統依存性ウイルスに感染されることができる型および系統段階の細胞を播種し;
d)(c)の細胞を系統依存性ウイルスに感染させ;
e)バイオマトリックス足場での感染細胞を培養条件下に維持し;
f)感染細胞内で製造されるウイルス粒子を採取すること;
を含み、それによって系統依存性ウイルスのウイルス粒子を製造する前記方法。
〔41〕系統依存性ウイルスが、C型肝炎ウイルス、B型肝炎ウイルス、ノロウイルスおよびヒト乳頭腫ウイルスからなる群から選択される、前記〔40〕に記載の方法。
〔42〕バイオマトリックス足場の再細胞化によって形成されるオルガノイドの製造方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に、バイオマトリックス足場の製造に用いた生体組織と同じ組織型の細胞を播種し;
d)バイオマトリックス足場での細胞を培養条件下に維持し、それによって細胞からオルガノイドが形成されること;
を含み、それによってバイオマトリックス足場の再細胞化によって形成されるオルガノイドを製造する前記方法。
〔43〕補助デバイスとして使用するために、オルガノイドを被験者に接触させる段階をさらに含む、前記〔42〕に記載の方法。
〔44〕細胞が肝臓細胞である、前記〔42〕に記載の方法。
〔45〕バイオマトリックス足場で培養された細胞内での目的とするタンパク質の製造方法であって、
a)前記〔1〕〜〔16〕のいずれか1つに記載の方法によってバイオマトリックス足場を製造し;
b)(a)のバイオマトリックス足場と細胞培養培地を培養装置内で接触させ;
c)(b)のバイオマトリックス足場に目的とするタンパク質を製造する細胞を播種し;
d)バイオマトリックス足場での(c)の細胞を培養条件下に維持し;
e)(d)の細胞によって製造される目的とするタンパク質を採取すること;
を含み、それによってバイオマトリックス足場で培養された細胞内で目的とするタンパク質を製造する前記方法。
〔46〕段階(e)において採取した目的とするタンパク質を精製する段階をさらに含む、前記〔45〕に記載の方法。
Claims (1)
- 生体組織からのバイオマトリックス足場の製造方法であって、
a)第1培地で生体組織を灌流するかまたは生体組織をホモジナイズし、ここで前記第1培地の重量オスモル濃度は250mOsm/kg〜350mOsm/kgであり、前記第1培地は無血清かつ中性pHであり;
b)前記第1培地中に、リゾレシチンを生成することができるリパーゼおよび洗浄剤を含む脱脂緩衝液で段階(a)の生体組織を灌流するかまたは段階(a)のホモジネートを抽出し、ここで前記洗浄剤は、デオキシコール酸の塩、1-ヘプタンスルホン酸の塩、N-ラウリルサルコシンの塩、ラウリル硫酸の塩、1-オクタンスルホン酸の塩、タウロコール酸の塩、塩化ベンザルコニウム、セチルピリジニウム、塩化メチルベンゼトニウム、臭化デカメトニウム、アルキルベタイン、アルキルアミドアルキルベタイン、N-ドデシル-N,N-ジメチル-3-アンモニオ-1-プロパンスルホナート、ホスファチジルコリン、n-デシルα-D-グルコピラノシド、n-デシルβ-D-マルトピラノシド、n-ドデシルβ-D-マルトシド、n-オクチルβ-D-グルコピラノシド、ソルビタンエステル、n-テトラデシルβ-D-マルトシド、Nonidet-P-40、ポロキサマー188、及び、ツイーングループの洗浄剤のいずれかからなる群より選ばれる;
c)中性pHかつ2.0M NaCl〜5.0NaClの塩濃度であって、生体組織内で同定されるコラーゲンを不溶性に保つように選択された塩濃度を含む緩衝液で段階(b)の組織を灌流するかまたは段階(b)のホモジネートを抽出し;
d)緩衝液中、RNアーゼおよびDNアーゼで段階(c)の組織を灌流するかまたは段階(c)のホモジネートを抽出し;
e)中性pHかつ無血清であり、250mOsm/kg〜350mOsm/kgの重量オスモル濃度を有する第2培地で段階(d)の組織またはホモジネートをリンスする段階;
を含み、それによって生体組織から、無傷のまたはホモジナイズしたバイオマトリックス足場であって、コラーゲンの少なくとも95%および生体組織のコラーゲン結合性マトリックス成分およびマトリックス結合性増殖因子、ホルモンおよびサイトカインの大部分を含む前記足場を製造する前記方法。
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