JP6190536B2 - 幹細胞由来のエキソソームを有効成分に含む脳室内出血治療用薬学的組成物 - Google Patents
幹細胞由来のエキソソームを有効成分に含む脳室内出血治療用薬学的組成物 Download PDFInfo
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Description
幹細胞由来のエキソソームを分離するために、超遠心分離機(Ultracentrifuge)を利用した。より具体的に、間葉系幹細胞を1×105細胞/mlの濃度となるように希釈した後、60mm培養皿に3mlずつ分注して1週間の間培養した。培養皿に細胞がいっぱいに増殖したことを確認した後、50U/ml濃度のトロンビン(thrombin)が希釈されている培養培地に取り替え、さらに24時間の間培養した。その後、培養液を2ml遠心分離チューブに分けて入れて、4℃、10000gで30分間遠心分離し、上澄み液を新しいチューブに移して細胞破片(debris)を除去した。前記上澄み液を再び4℃、100,000gで2時間の間超遠心分離し、上澄み液を除去してエキソソームを分離した。
前記実施例1で収得した幹細胞由来のエキソソームの神経細胞保護効果をin vitroで検証するために、下記のような実験を遂行した。
妊娠週齢18.5日となった白ネズミから胎児を取り出して大脳皮質を分離した後、神経細胞を7日間培養した。培養された神経細胞にトロンビン処理濃度(10〜80U/ml)および時間(8または16時間)を異ならせて細胞死滅を誘導した。Cell count kit(Dojindo、Kumamoto、Japan)を利用して細胞生存能を測定した。その結果を図4に示した。
前記実施例2−1と同じ方法でトロンビンを処理して細胞死滅が誘導された神経細胞に前記実施例1で収得した幹細胞由来のエキソソームを15μg/mlの濃度で1mlを処理した後、cell count kitを利用して細胞生存能を測定した。その結果を図5および図6に示した。
前記実施例1で収得した幹細胞由来のエキソソームの脳血管疾患治療効果をin vivoで検証するために、下記のような実験を遂行した。
実験動物としては、雄SD白ネズミ(Sprague−Dawley rats、Orient Co、Seoul、Korea)を利用し、実験は出生4日目(P4)から32日(P32)まで進行された。脳室内出血(IVH)を誘導するために、P4の白ネズミを1.5%〜2%イソフルラン(isoflurane)を利用して麻酔させた後、白ネズミの母親の微静脈から採取した200μLの血液をstereotaxic guidance (Digital Stereotaxic Instrument with Fine Drive、MyNeurolab、St.Louis、MO;coordinates:x=±0.5、y=+1.0、z=+2.5mm relative to bregma)を利用してゆっくり両側の脳室内に投与した(右側、左側脳室にそれぞれ100μlずつ投与)。対照群(NC)の場合、血液を投与することなく同じ手術だけを遂行した。IVH誘導1日後である、出生5日目(P5)白ネズミの脳を7−teslar MRIを利用して撮影し、脳室内出血が正常に誘導されたかを確認した。IVH誘導2日後である、出生6日目(P6)の白ネズミを1.5%〜2%イソフルラン(isoflurane)を利用して麻酔させた後、食塩水(saline)(IC)、20μg間葉系幹細胞由来のエキソソーム(IM exo)、または20μg繊維芽細胞(fibroblast)由来のエキソソーム(IF exo)を各白ネズミの右側脳室内にゆっくり投与した。IVH誘導7および28日後(P11およびP32)に白ネズミの脳MRIイメージを収得し、IVH誘導28日後に白ネズミを殺して脳組織を分析した。以上の具体的な実験デザインを図7に示した。
IVH誘導1、7および28日後に収得した白ネズミの脳MRIイメージを分析した。Image Jプログラムを利用して脳室の拡張程度を分析し、全体脳室のvolume/全体脳のvolumeを求めた。その結果を図8および図9に示した。
陰性走地性(Negative geotaxis)評価は従来の公知の方法にしたがって傾斜板の上に白ネズミの頭が下方を向くようにしておき、前記頭が傾斜面の上側を向くのに要される時間を記録することによって分析し、評価はP11、P18、P25、およびP32にそれぞれ遂行した。また、長期的な運動機能に及ぼす影響を分析するためのロータロッド(rotatod)評価は従来の公知の方法にしたがってP30からP32まで連続して遂行した。その結果をそれぞれ図10および図11に示した。
実験終了後、脳を分離してパラフィンに包埋させた後、4μm厚さのパラフィンを除去した脳組織切片を製造した。脳室周囲の白色物質(periventricular white matter)での細胞死滅を分析するために、TUNEL(terminal deoxynycleotidyltransferase−mediated deoxyuridine triphosphate nick−end labeling) technique(kit S7110 ApopTag、Chemicon、Temecula、CA)を利用した免疫蛍光分析を遂行した。この時、脳ブレグマ(Bregma)で+0.95mm〜−0.11mm位置(coronal section)で三つのセクションを無作為で選定し、このうち顕微鏡で無作為部位をそれぞれ3回検査して、これらの平均値で統計的分析を施行した。その結果を図12に示した。
反応性神経膠症(reactive gliosis)の程度を分析するために、前記実施例3−4と同じ方法で収得した脳組織切片で従来の公知の方法にしたがってGFAP(neuronal specific glial fibrillary acidic protein)抗体(rabbit polyclonal、Dako、Glostrup、Denmark;1:1000dilution)を利用して免疫組織化学分析を遂行した。その結果を図13に示した
脳炎症反応で特徴的に観察できる活性化された小膠細胞(activated microglia)を分析するために、前記実施例3−4と同じ方法で収得した脳組織切片でED−1抗体(mouse monoclonal、Millipore、Concord Road、MA、USA;1:100dilution)を利用して免疫組織化学分析を遂行した。その結果を図14に示した
髄鞘化(myelination)の程度を分析するために、前記実施例3−4と同じ方法で収得した脳組織切片でMBP(myelin basic protein)抗体(rabbit polyclonal、Abcam、Cambridge、MA、USA;1:1000dilution)を利用して免疫組織化学分析を遂行した。その結果を図15に示した
脳組織の均質懸濁液でMilliplex MAP ELISA Kit(Millipore、Billerica、MA)を利用して炎症性サイトカインであるIL(Interleukin)−1α、IL−1β、IL−6およびTNF(tumor necrosis factor)−αの濃度を測定した。その結果を図16に示した
Claims (4)
- 幹細胞由来のエキソソーム(exosome)を有効成分として含む、脳室内出血(IVH、intraventricular hemorrhage)治療用薬学的組成物。
- 前記幹細胞は胚性幹細胞または成体幹細胞であることを特徴とする、請求項1に記載の脳室内出血(IVH)治療用薬学的組成物。
- 前記成体幹細胞は間葉系幹細胞、ヒト組織由来の間葉系基質細胞、ヒト組織由来の間葉系幹細胞、多分化能幹細胞および羊膜上皮細胞で構成された群から選択される1種以上の成体幹細胞であることを特徴とする、請求項2に記載の脳室内出血(IVH)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、羊膜および胎盤で構成された群から選択される1種以上の組織から由来した間葉系幹細胞であることを特徴とする、請求項3に記載の脳室内出血(IVH)治療用薬学的組成物。
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KR20130154891 | 2013-12-12 | ||
KR10-2013-0154891 | 2013-12-12 | ||
PCT/KR2014/012289 WO2015088286A1 (ko) | 2013-12-12 | 2014-12-12 | 줄기세포 유래 엑소좀을 유효성분으로 포함하는 뇌혈관 질환 치료용 약학적 조성물 |
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JP2016539061A Active JP6343671B2 (ja) | 2013-12-12 | 2014-12-12 | トロンビンを利用した幹細胞由来のエキソソームの生成促進方法 |
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EP (2) | EP3081223B1 (ja) |
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KR101661847B1 (ko) * | 2014-03-18 | 2016-09-30 | 사회복지법인 삼성생명공익재단 | 줄기세포 유래 엑소좀을 유효성분으로 포함하는 뇌 염증성 질환의 치료용 조성물 |
EP4218780A1 (en) * | 2015-06-12 | 2023-08-02 | Hudson Institute of Medical Research | Allogeneic mammalian amniotic exosomes for treating diseases |
WO2017123022A1 (ko) * | 2016-01-12 | 2017-07-20 | 주식회사 강스템바이오텍 | 고함량의 성장인자를 함유한 줄기세포 유래 엑소좀 |
KR101843634B1 (ko) | 2016-04-15 | 2018-03-30 | 사회복지법인 삼성생명공익재단 | 트롬빈 처리 줄기세포에서 유래된 엑소좀을 포함하는 만성폐질환 치료용 조성물 |
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