JP2023501795A - 内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物 - Google Patents
内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物 Download PDFInfo
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Abstract
Description
本発明は、血管分化誘導因子が導入されたアニオン性ヒアルロン酸を含む第1溶液と、
カチオン性物質を含む第2溶液とから構成され、
前記第1溶液及び第2溶液のうちいずれか1つ以上の溶液に幹細胞捕捉因子がさらに含まれ、
前記第1溶液及び第2溶液が混合されると、静電気的な引力によりヒドロゲルが形成されることを特徴とする、内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物を提供する。
血管分化誘導因子が導入されたアニオン性ヒアルロン酸を含む第1溶液と、
カチオン性物質を含む第2溶液とから構成され、
前記第1溶液及び第2溶液のうちいずれか1つ以上の溶液に幹細胞捕捉因子がさらに含まれ、
前記第1溶液及び第2溶液が混合されると、静電気的な引力によりヒドロゲルが形成されることを特徴とする、内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物に関する。
[実施例1]
血管内皮細胞成長因子模倣ペプチドが導入されたヒアルロン酸の製造
本発明では、内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物を製造するために、まず、血管内皮細胞成長因子模倣ペプチドが導入されたヒアルロン酸を製造した。
(キトサン及びHA-VPの比率によるゼータ電位及び流動学的特性の測定)
本発明では、前記実施例1で製造したHA-VP及びキトサンが静電気的な引力を通じてヒドロゲルを形成するかを確認するために、キトサン及びHA-VPの比率によるゼータ電位(Zeta potential)及び流動学的特性を測定した。
(静電気的な引力を通じたヒドロゲルの製造)
(3-1:カチオン性物質及びアニオン性物質の種類によるヒドロゲル製造)
本発明では、カチオン性ポリマーであるキトサン(CH)、カチオン性デキストラン(cationic dextran;CD)、ポリエチレンイミン(Polyethyleneimine;PEI)、ポリリシン(polylysine;PL)、ポリヒスチジン(poly histidine;PH)と、アニオン性であるHA又は血管内皮細胞成長因子模倣ペプチドが導入されたヒアルロン酸(HA-VP)をそれぞれ混合して、静電気的な引力を通じてヒドロゲルを製造した。
実施例3-1で製造したCH溶液とHA溶液又はCH溶液とHA-VP溶液を同じ体積で混合してCHHAヒドロゲル又はCHHA-VPヒドロゲルを製造した。また、同じ濃度のCH、HA、HA-VP溶液それぞれにSP、WKYMVM、SDF1α、G-SCF、MCP-1(Genscript、米国)のうちの1つをそれぞれ1μg/mlの濃度で溶かした溶液を製造して、上記でヒドロゲルを形成したことと同じ方式で行った。
(ヒドロゲルの流動学的特性の評価)
前記実施例3で製造したCHHA及びCHHA-VPヒドロゲルの流動学的特性を評価するために、粘弾性測定装置(modular compact rheometer;MCR 102,Anton Paar、オーストリア)を用いて弾性率及び粘度を測定した。ここで、使用した平行板(parallel plate)が直径25mmであり、底面との間隔が0.3mmであり、25℃で歪み(strain)2%、1Hzである。
(生体外(In vitro)における幹細胞捕捉因子及びVPの放出挙動の確認)
本発明では、静電気的な引力により製造したヒドロゲルで幹細胞捕捉因子及びVPの放出の度合いを確認しようとした。
(ヒドロゲルの毒性評価)
本発明で製造したヒドロゲルの毒性有無を評価した。
(SPの幹細胞捕捉能力の確認)
本発明では、SPの幹細胞捕捉能力を確認した。
(生体外で本発明のヒドロゲルによる血管形成効果の確認)
(8-1:免疫蛍光分析を通した血管形成の確認)
本発明の注入型ヒドロゲルの血管形成誘導効果を確認するために、前記実施例6と同じ方法でヒト由来間葉系幹細胞が含まれたCHHA、CHHA+VP及びCHHA-VPヒドロゲルをそれぞれ製造し、3日ごとに培地を交換しつつ、4週間培養した。
前記実施例8-1のヒドロゲルからmRNAを抽出した後、抽出したmRNAを用いてcDNAを合成し、qRT-PCR(quantitative real time polymerase chain reaction)を通じて血管細胞で発現するフォン・ヴィレブランド因子(vWF)遺伝子及びCD31遺伝子の発現変化を確認した。
(生体内でヒドロゲルによる幹細胞捕捉能力の確認)
本発明のヒドロゲルにより生体内で実際に幹細胞が捕捉されるかを確認した。
(生体内でヒドロゲルによる血管形成誘導能の確認)
(10-1:ヒドロゲルの製造及び注入)
本発明のヒドロゲルにより生体内で実際に血管形成が誘導されるかを確認した。
前記実施例10-1で摘出したヒドロゲルに捕捉されたhMSC及び血管形成程度を確認するために、BrdU及びCD31に対する免疫蛍光分析を行った。観察結果は、図13a及び図13bに示し、BrdUは赤色、CD31は緑色で染色した。
前記実施例10-1で摘出したヒドロゲルからmRNAを抽出し、前記実施例8-2と同じ方法でqRT-PCRを行った。
配列番号2は、幹細胞捕捉因子であるサブスタンスP(SP)ペプチドのアミノ酸配列を示す。
配列番号3は、幹細胞捕捉因子であるWKYMVMペプチドのアミノ酸配列を示す。
配列番号4は、vWFの正方向プライマーの塩基配列を示す。
配列番号5は、vWFの逆方向プライマーの塩基配列を示す。
配列番号6は、CD31の正方向プライマーの塩基配列を示す。
配列番号7は、CD31の逆方向プライマーの塩基配列を示す。
配列番号8は、GAPDHの正方向プライマーの塩基配列を示す。
配列番号9は、GAPDHの逆方向プライマーの塩基配列を示す。
Claims (10)
- 血管分化誘導因子が導入されたアニオン性ヒアルロン酸を含む第1溶液と、
カチオン性物質を含む第2溶液とから構成され、
前記第1溶液及び第2溶液のうちいずれか1つ以上の溶液に幹細胞捕捉因子がさらに含まれ、
前記第1溶液及び第2溶液が混合されると、静電気的な引力によりヒドロゲルが形成されることを特徴とする、内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。 - 前記血管分化誘導因子が、血管内皮細胞成長因子模倣ペプチドであることを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記血管内皮細胞成長因子模倣ペプチドが、配列番号1で表されるアミノ酸配列を含むことを特徴とする、請求項2に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記血管分化誘導因子が導入されたアニオン性ヒアルロン酸が、血管分化誘導因子とカルボン酸官能基が活性化したアニオン性ヒアルロン酸を反応させて製造することを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記カチオン性物質が、キトサン、カチオン性デキストラン(cationic dextran)、ポリエチレンイミン(Polyethyleneimine)、ポリリシン(polylysine)及びポリヒスチジン(poly histidine)からなる群から選ばれた1種以上であることを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記幹細胞捕捉因子が、サブスタンスP(substance P)、WKYMVM、SDF1α、G-SCF及びMCP-1からなる群から選ばれた1つ以上であることを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記第1溶液の血管分化誘導因子が導入されたアニオン性ヒアルロン酸及び第2溶液のカチオン性物質の比率が、3:1~1:3であることを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 前記第1溶液及び第2溶液の混合によって形成されたヒドロゲルの貯蔵弾性率が、10~100Paであることを特徴とする、請求項1に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物。
- 請求項1~8のいずれか一項に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物を含む、組織再生用注射剤。
- 請求項1~8のいずれか一項に記載の内在性前駆細胞又は幹細胞捕捉能及び捕捉された細胞の血管分化誘導能を有する注入型ヒドロゲル組成物を含む、フィラー用注射剤。
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