JP6796143B2 - トロンビン処理幹細胞に由来するエキソソームを含む慢性肺疾患治療用組成物 - Google Patents
トロンビン処理幹細胞に由来するエキソソームを含む慢性肺疾患治療用組成物 Download PDFInfo
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Description
第二に、幹細胞自体の大きいサイズに起因して血管閉塞(vascular obstruction)や心筋梗塞を誘発することがある(Circ Heart Fail.2010;3:e5−e6参照)。
第三に、臍帯血のような同種細胞を使用して移植(同種移植)する場合、細胞表面抗原(surface antigen)による拒絶反応の問題がある。
第四に、一般的に、細胞治療剤は、製造工程が複雑であり、保管運送に制約が多いため、生産費用が高いという限界がある。
1−1.トロンビンによるエキソソーム分泌誘導
ヒト臍帯血由来間葉系幹細胞(3×105個)を60mmの培養皿(orange scientific、cat# 4450200)に分注した後、1週間培養した。培養皿に細胞が飽和増殖したことを確認した後、50unit/mlのトロンビン(REYON Pharmaceutical.Co.,LTD)が希釈されている血清フリー培養培地(MEM alpha media)に交替し、さらに6時間培養した。
前記実施例1−1で収得したエキソソームがトロンビン処理により成長因子やIL−6のような抗炎症サイトカインなどの発現が増加したかを確認した。
2−1.肺細胞死滅抑制効果
ラット肺上皮細胞株(rat pulmonary epithelial cells、韓国細胞株バンク)L2 cell lineにH2O2を1時間処理して、酸化的損傷(oxidative injury)を誘導することにより、高濃度酸素誘導肺疾患(hyperoxic lung disease)のin vitroモデルを製作した。
前記実施例2−1の高濃度酸素誘導肺疾患(hyperoxic lung disease)のin vitroモデルを利用して、エキソソームの肺細胞死滅抑制効果が濃度依存的に発揮されるかを確認した。
3−1.気管支肺異形成症動物モデル製作
すべての動物実験は、三星生命科学研究所の実験動物委員会(Research Animal Laboratory Committee of Samsung Biomedical Research Institute、韓国)により承認を受け、機関のガイドラインに従った。
前記実施例1の方法で収得したエキソソーム、すなわちトロンビン処理により効能増強されたエキソソーム20ugをFBSフリー−MEMに懸濁させ、0.05mlの懸濁液を26ゲージ針を利用して、前記実施例3−1で高濃度酸素に露出させた出生5日目のラットの気道内に投与した。
4%ホルムアルデヒドで24時間固定させた前記肺組織の断片をパラフィンに包埋させた後、4μmの厚さでカットして、ヘマトキシリン/エオシン組織染色して、光学顕微鏡で組織観察することにより、高濃度酸素で損傷誘導された肺組織に対して幹細胞と幹細胞由来エキソソームの治療的効果を比較評価した。
TUNELアッセイ(Terminal deoxynucleotidyl−mediated dUTP nick−end labeling assay)は、細胞死滅程度を測定する染色方法であると広く知られている。死滅する細胞のDNAは、正常細胞とは異なって、3’−OH DNA末端を露出させた切断されたDNA断片を有するので、TdT(Terminal Deoxynucleotidyl Transferase)という酵素を利用して3’−OH DNA末端に フルオレセイン−12−dUTP(nucleotide)で標識させて、死滅する細胞を正常細胞と区別して測定することができるようにする方法であって、TUNEL陽性染色細胞数が多いほど死滅した細胞が多いことを意味する。
本発明のトロンビン誘導された幹細胞由来エキソソームが血管新生を誘導して気管支肺異形成症の治療効果を発揮するかを確認するために、間葉系細胞が血管内皮細胞に分化するとき、合成分泌するフォン・ヴィレブランド因子(von Willebrand factor;vWf)の活性を観察することにより、血管新生(angiogenesis)程度を分析した。
Claims (13)
- 幹細胞に由来するエキソソーム(exosome)を有効成分として含む、慢性肺疾患(Chronic Pulmonary Disease)の予防または治療用薬学的組成物であって、前記慢性肺疾患は気管支肺異形成症であり、前記幹細胞は間葉系幹細胞であり、前記幹細胞はトロンビンで処理されたものである、予防または治療用薬学的組成物。
- 前記間葉系幹細胞は、臍帯、臍帯血、骨髄、脂肪、筋肉、神経、皮膚、羊膜、または胎盤に由来する、請求項1に記載の薬学的組成物。
- 前記薬学的組成物は、個体の気道または血管内に投与される、請求項1に記載の薬学的組成物。
- 前記薬学的組成物は、培養培地、サイトカイン、成長因子、および遺伝子よりなる群から選択される補助成分をさらに含む、請求項1に記載の薬学的組成物。
- 前記エキソソームは、成長因子、免疫調節因子、抗酸化因子、または再生因子の発現が、トロンビンで処理されていない幹細胞に由来するエキソソームと比ベて増加している、請求項1に記載の薬学的組成物。
- 前記成長因子は、BDNF(brain−derived neurotropic factor)、FGF(fibroblast growth factor)、HGF(hepatocyte growth factor)、NGF(nerve growth factor)、またはVEGF(vascular endothelial growth factor)である、請求項5に記載の薬学的組成物。
- 請求項1に記載の組成物を含有する、慢性肺疾患(Chronic Pulmonary Disease)の予防または治療用薬学製剤であって、前記慢性肺疾患が気管支肺異形成症である、予防または治療用薬学製剤。
- 前記製剤は、注射剤形、注入剤形、または噴霧剤形である、請求項7に記載の薬学製剤。
- 前記製剤は、薬学的に許容可能な担体をさらに含む、請求項7に記載の薬学製剤。
- 下記の段階を含む、請求項1に記載の薬学的組成物の製造方法:
(a)トロンビンを含む培養液中で幹細胞を培養する段階;
(b)前記段階(a)の前記培養液からエキソソームを分離する段階;および
(c)前記段階(b)で分離したエキソソームを有効成分として含有する組成物を製造する段階。 - 前記段階(a)のトロンビンは、培地内に1〜1000unit/mlの濃度で含まれる、請求項10に記載の製造方法。
- 前記段階(c)のエキソソームは、遠心分離される、請求項10に記載の製造方法。
- 前記遠心分離は、5,000〜500,000gで10分間〜5時間行われる、請求項12に記載の製造方法。
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