JP6486948B2 - 純粋栄養膜層から由来した幹細胞及びそれを含む細胞治療剤 - Google Patents
純粋栄養膜層から由来した幹細胞及びそれを含む細胞治療剤 Download PDFInfo
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Description
(b)前記分離された純粋栄養膜層組織にトリプシン(Trypsin)、コラゲナーゼ(collagenase)、ディスパーゼ(dispase)、DNase、RNase、プロテアーゼ(protease)、リパーゼ(lipase)、ヒアルロニダーゼ(hyaluronidase)及びエラスターゼ(elastase)からなる群から選択された1種以上の酵素を処理し、純粋栄養膜層由来の細胞を収得するステップ;及び
(c)前記収得した純粋栄養膜層由来の細胞から幹細胞を選別するステップ。
(b)25〜30以上の継代数に達するように長期間の間増殖できる能力;
(c)脂肪細胞、軟骨細胞または骨細胞に分化できる能力;
(d)集落形成能;
(e)CD44、CD73、CD90及びCD105に対して陽性の免疫学的特性;及び、
(f)CD31、CD34、CD45及びHLA−DRに対して陰性の免疫学的特性;
本発明に係る純粋栄養膜層から由来した幹細胞は、下記方法によって互いに異なる種類の細胞に分化でき、例えば、脂肪細胞、軟骨細胞、骨細胞、神経細胞、靭帯細胞または腱細胞(tenocyte)等、様々な種類の細胞に分化でき、これに制限されない。
胎盤は、サムスンソウル病院臨床試験倫理委員会指針書によってサムスンソウル病院で帝王切開した正常分娩で寄贈に同意した産婦から収集した。胎盤組織は、滅菌された容器に入れて移した。移した胎盤組織から羊膜を剥離した後、絨毛膜(CM)と脱落膜(DC)との間に位置した栄養膜層を分離し、前記栄養膜層中、絨毛膜絨毛を除いた純粋栄養膜層(chorionic trophoblast layer without villi、CT−V)を滅菌されたフォーセップス(forceps)とメスを利用して注意深く分離した。胎盤の断面図を図1に示した。
全体胎盤組織を細切し、PBSで洗浄して胎盤組織から血液及び血球細胞を除去した。前記洗浄された胎盤組織に0.2%コラゲナーゼを添加したDMEM培地を加え、37℃で撹拌機を利用して反応させ、胎盤細胞を収得した。前記収得した胎盤細胞を70μmメッシュにろ過して分解されない組織を除去し、ウシ胎児血清及び抗生剤が添加されたDMEM培地を加えた後、25℃、1000rpmで4分間遠心分離した。上清液を除去して残った沈殿した細胞に成長因子を含まず、ウシ胎児血清及び抗生剤が添加されたDMEM培地を加え、37℃、5%CO2の条件下で培養した。前記培養物から培養容器の底に付着した細胞を選別し、胎盤全体(Whole placenta、Pla)由来幹細胞を収得した。
前記実施例1で収得した胎盤の細部組織である純粋栄養膜層から由来した幹細胞をPBSで洗浄した後、成長因子を含まず、ウシ胎児血清及び抗生剤が添加されたDMEM培地を2〜3日毎に取り替えながら培養した。前記幹細胞が80%以上成長した時点でトリプル(TryPLE)を処理して幹細胞を培養容器から分離し、分離された幹細胞を1/4の割合で希釈した後、他の培養容器で培養する方法で継代培養を行った。前記のような継代培養を繰り返して行いながら、それ以上継代培養されない継代数(passage number)を測定し、継代培養する前(P0)と長期間の間継代培養した後の細胞形態を顕微鏡で観察した。また、前記比較例1で収得した胎盤全体(Whole placenta、Pla)由来幹細胞を利用して、同様の方法で継代培養を行った後、継代培養する前(P0)と長期間の間継代培養した後の細胞形態を顕微鏡で観察した。これをそれぞれ図2及び図3に示した。
前記実施例1で収得した胎盤の細部組織である純粋栄養膜層から由来した幹細胞の集落形成能を確認した。より具体的には、前記実施例1で収得した純粋栄養膜層から由来した幹細胞を前記実施例2の方法で第一の継代培養を行い、前記継代培養が終了する時点で100mmの皿に5×103個ずつ接種(seeding)した後、10日間成長因子を含まず、ウシ胎児血清及び抗生剤が添加されたDMEM培地で培養した。前記培養された幹細胞を対象にギムザ染色法(Giemsa stain)を実施して幹細胞でいくつの集落が形成されるかを計数し、これらの平均値を算出した。また、前記比較例1で収得した胎盤全体由来幹細胞を利用して、同様の方法で集落形成能を測定し、その結果値を100%として換算した。その結果を図4に示した。
前記実施例1で収得した胎盤の細部組織である純粋栄養膜層から由来した幹細胞の集団倍加時間を測定した。より具体的には、前記実施例1で収得した純粋栄養膜層から由来した幹細胞を前記実施例2の方法で第一の継代培養を行い、2〜3日間隔で細胞を収得及び継代培養を繰り返した。細胞の収得時は、増加した細胞の数を確認し、継代時は、3×105個の細胞を100mmの皿に培養をした。継代過程中にそれ以上細胞の数が増加しない時点を最終的に増加されない時点に定めた。倍加時間は、P2からP6まで継代培養された細胞数で測定し、下記のように計算した。また、前記比較例1で収得した胎盤全体由来幹細胞を利用して、同様の方法で集団倍加時間を計算した。その結果を図5に示した。
倍加=log(N初期細胞数/N増加した細胞数)/log2
図5に示したように、本発明に係る純粋栄養膜層(CT−V)由来幹細胞は、胎盤全体由来幹細胞より集団倍加時間(population doubling time)が短く、細胞増殖が速いことを確認した。
前記実施例1で収得した胎盤の細部組織である純粋栄養膜層から由来した幹細胞の免疫学的特性を確認するために、下記のような実験を行った。先ず、純粋栄養膜層から由来した幹細胞をPBSで洗浄し、トリプル処理した後、幹細胞を回収して1000rpmで4分間遠心分離した。上清液を除去した後、非特異的結合を抑制するために、2%FBS及びPBSの混合液を入れて幹細胞を洗浄した後、1000rpmで5分間遠心分離した。上清液を除去した後、幹細胞をPBSに浮遊させ、1×105cellずつフローサイトメーター専用の丸底フラスコに分注した。ここに抗体(PE−conjugated mouse anti−human monoclonal antibody)を入れて、氷で30分間インキュベーションした後、1000rpmで5分間遠心分離した。再び上清液を除去した後、PBSで洗浄し、1000rpmで5分間遠心分離した。前記過程を2回繰り返した。最後に、上清液を除去した後、幹細胞をシングル化し、フローサイトメーター(FACS)を利用して免疫学的特性を分析した。また、同様の方法で前記比較例1で収得した胎盤全体由来幹細胞の免疫学的特性を分析した。その結果を表1及び図6に示した。
前記実施例1で収得した胎盤の細部組織である純粋栄養膜層から由来した幹細胞の軟骨細胞への分化能を確認するために、幹細胞を公知になった軟骨細胞分化誘導培地(0.1μMデキサメタゾン、50μg/mlアスコルビン酸、40μg/ml L−プロリン、10ng/ml TGF−β3、500ng/ml BMP−6、50mg/ml ITS premixが含まれたDMEM培地)で3週間培養し、軟骨細胞への分化を誘導した。前記幹細胞の軟骨細胞への分化程度を測定するために、従来、公知になった方法によってSafranin−O染色及びType II collagenを用いた免疫化学染色法を行った。また、同様の方法で前記比較例1で収得した胎盤全体由来幹細胞の軟骨細胞への分化能を測定した。その結果を図7乃至図9に示した。
Claims (12)
- 胎盤の細部組織である純粋栄養膜層(chorionic trophoblast layer without villi、CT−V)から由来した幹細胞。
- 前記幹細胞は、CD44、CD73、CD90及びCD105に対して陽性の表面因子発現特性を有することを特徴とする、請求項1に記載の幹細胞。
- 前記幹細胞は、CD31、CD34、CD45及びHLA−DRに対して陰性の表面因子発現特性を有することを特徴とする、請求項1に記載の幹細胞。
- 前記純粋栄養膜層から由来した幹細胞は、絨毛膜と脱落膜との間に位置した栄養膜層中、絨毛膜絨毛を除いた組織から由来したことを特徴とする、請求項1乃至3のいずれか一項に記載の幹細胞。
- 胎盤の細部組織である純粋栄養膜層(chorionic trophoblast layer without villi、CT−V)から由来した幹細胞を有効成分として含む細胞治療剤。
- 前記幹細胞は、軟骨細胞、脂肪細胞、骨細胞、神経細胞、靭帯細胞及び腱細胞からなる群から選択された1種以上に分化されることを特徴とする、請求項5に記載の細胞治療剤。
- 前記細胞治療剤は、軟骨損傷、軟骨欠陥、骨欠損、腱・靭帯欠損、または脂肪組織欠損の治療用であることを特徴とする、請求項5または6に記載の細胞治療剤。
- 前記軟骨欠陥は、軟骨外傷、軟骨破裂、軟骨軟化、軟骨壊死、骨軟骨炎、軟骨欠損及び骨関節炎からなる群から選択された1種以上であることを特徴とする、請求項7に記載の細胞治療剤。
- 胎盤の細部組織である純粋栄養膜層(chorionic trophoblast layer without villi、CT−V)から由来した幹細胞を有効成分として含む組織再生用組成物。
- 前記組織は、軟骨、脂肪、骨、神経、靭帯及び腱からなる群から選択された1種以上であることを特徴とする、請求項9に記載の組成物。
- 前記軟骨は、硝子軟骨(hyaline cartilage)、繊維軟骨(fibrocartilage)または弾性軟骨(elastic cartilage)であることを特徴とする、請求項10に記載の組成物。
- 前記軟骨は、関節軟骨(articular Cartilage)、耳軟骨、鼻軟骨、肘軟骨、半月状軟骨(meniscus)、膝軟骨、肋軟骨、足首軟骨、器官軟骨、喉頭軟骨及び脊椎軟骨で構成された群から選択された1種以上であることを特徴とする、請求項10に記載の組成物。
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KR20130013435A (ko) * | 2011-07-28 | 2013-02-06 | 차의과학대학교 산학협력단 | 태반-유래 줄기세포의 증식방법 |
KR101669038B1 (ko) | 2014-01-08 | 2016-10-26 | 사회복지법인 삼성생명공익재단 | 영양막 기저층으로부터 유래된 줄기세포 및 이를 포함하는 세포치료제 |
JP6486948B2 (ja) | 2014-01-08 | 2019-03-20 | サムスン ライフ パブリック ウェルフェア ファウンデーション | 純粋栄養膜層から由来した幹細胞及びそれを含む細胞治療剤 |
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EP3093339A1 (en) | 2016-11-16 |
ES2870567T3 (es) | 2021-10-27 |
US10669526B2 (en) | 2020-06-02 |
JP2017503508A (ja) | 2017-02-02 |
KR20150083440A (ko) | 2015-07-17 |
CN106459908A (zh) | 2017-02-22 |
EP3093339B1 (en) | 2021-02-24 |
US20190177684A1 (en) | 2019-06-13 |
WO2015105356A1 (ko) | 2015-07-16 |
EP3093339A4 (en) | 2017-07-19 |
CN106459908B (zh) | 2019-12-13 |
US20160326487A1 (en) | 2016-11-10 |
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