JP5656183B2 - 滑膜由来間葉幹細胞(MSCs)の軟骨・半月板再生への応用 - Google Patents
滑膜由来間葉幹細胞(MSCs)の軟骨・半月板再生への応用 Download PDFInfo
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- JP5656183B2 JP5656183B2 JP2009525260A JP2009525260A JP5656183B2 JP 5656183 B2 JP5656183 B2 JP 5656183B2 JP 2009525260 A JP2009525260 A JP 2009525260A JP 2009525260 A JP2009525260 A JP 2009525260A JP 5656183 B2 JP5656183 B2 JP 5656183B2
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Description
自家滑膜由来間葉幹細胞をex vivoで培養すること;
間葉幹細胞を移植して軟骨欠損部及び半月板欠損部を間葉幹細胞により被覆すること;そして
間葉幹細胞を軟骨細胞に分化させることにより、in situで軟骨欠損部または半月板欠損部で軟骨組織を再生すること;
から構成される。
[0033] 本研究において、本発明者らは滑膜から間葉幹細胞を分離した。ex vivoで増殖した後、過塩素酸1,1’-ジオクタデシル-3,3,3’,3’-テトラメチルインドカルボシアニン(DiI)で標識した間葉系幹細胞を全層関節軟骨欠損部に移植した。詳細な組織学的解析により、移植した間葉幹細胞は時間経過とともに局所微小環境に応じて変化することが示された。局所微小環境は、骨領域、軟骨と骨との境界、軟骨中心部、表面領域、そしてもとの軟骨に隣接する領域に分類された。分化培地により事前に誘導させなくても、間葉幹細胞のin situ軟骨形成により、関節軟骨欠損は修復された。このシステムは間葉幹細胞を軟骨に移植した後の細胞動態を詳細に解析することを可能にし、軟骨損傷に対する、間葉幹細胞の治療への応用を発展させた。
自家滑膜由来間葉幹細胞(MSC)をex vivoで培養する工程;
軟骨欠損部または半月板欠損部を間葉幹細胞により覆うように、間葉幹細胞を移植する工程;そして
間葉幹細胞を軟骨細胞に分化させることによって、軟骨欠損部または半月板欠損部でin situで軟骨組織を再生させる工程;
を含む。本発明において移植された間葉幹細胞は、局所微小環境に従って軟骨細胞に分化する。間葉幹細胞のin situ軟骨形成の結果、軟骨欠損部または半月板欠損部で軟骨組織が再生されて、欠損部が修復され、そして軟骨欠損の場合には骨領域、軟骨と骨との境界、軟骨中心部、表面領域、そしてもとの軟骨に隣接する領域をもとの軟骨が天然軟骨組織として形成され、または半月板欠損の場合には半月板軟骨が形成される。
軟骨損傷部を上方に向けるように体位を保持すること;
間葉幹細胞の細胞シート、間葉幹細胞の懸濁液、または間葉幹細胞を含むゲル状物質を関節軟骨欠損部の表面に静置すること;そして
特定の時間体位を保持して、それにより間葉幹細胞を軟骨欠損部の表面に接着させること;
を含む。
半月板欠損部が下向きになるように体位を保持すること;
間葉幹細胞の懸濁液を膝関節内に注射すること;そして
特定の時間体位を保持して、間葉幹細胞を半月板欠損部に接着させること;
を含む。
[0056] 本実施例は、ウサギから滑膜由来間葉幹細胞を採取するための方法を示すものである。
[0061] 本実施例において、本発明者らはヒトの滑膜由来間葉幹細胞と骨髄由来間葉幹細胞を分離し、その特徴を明らかにした。
[0062] 本研究は東京医科歯科大学の学内倫理委員会により承認され、全ての被験者の同意を得て行われた。ヒト滑膜と骨髄は8人の患者(27±5歳)から膝前十字靭帯(ACL)再建術の際に採取された。
[0070] 間葉幹細胞は、間葉系組織由来の細胞として、そしてコロニー形成単位-線維芽細胞アッセイ(Friedenstein, A.J., 1976, Int Rev Cytol. 47:327-59)により一般的に特定される自己再生能と、多数の分化した子孫を生み出す多分化能(McKay, R., 1997, Science. 276:66-71;Prockop, D.J., 1997, Science. 276:71-4)を有するものと定義される。
実施例3 滑膜由来間葉幹細胞の軟骨形成能
[0076] 本実施例は、ウサギ滑膜由来間葉幹細胞の体外での軟骨形成能を示すものである。
[0081] DiIで標識しない細胞(図4D)、DiIで標識した細胞(図4E、図4F)の蛍光顕微鏡による観察像を示す。核をDAPIで対比染色した(図4F)。DiIの蛍光は細胞外基質に漏出することなく、少なくても21日間高度に保たれた(図4E、図4F)。
実施例4 軟骨欠損を治療するための新たな低侵襲性手技の開発
[0085] 本実施例においては、軟骨欠損を治療するための新たな低侵襲性手技を提示する。
[0087] 間葉幹細胞は軟骨欠損部に対する接着能力が高い。間葉幹細胞を軟骨欠損部に留めておくために、軟骨欠損部を真上に向けるように体位を保持し、そして次いで、間葉幹細胞を上方に向いた軟骨欠損部に設置することができる。
実施例5 in vivoへの移植と組織学的解析
[0090] 本実施例において、本発明者らは滑膜由来間葉幹細胞の移植後に、軟骨欠損の肉眼的観察を行なった。
[0100] 本実施例において、本発明者は組織学的検討と蛍光顕微鏡による観察を行なった。
(i) 移植後1日の組織学的解析
[0104] 移植後1日の組織学的解析を図7に示す。軟骨欠損の矢状切片を、「欠損群」(図7A上)、「ゲル群」(図7A下)、および「FBS群」(図7B上)において、トルイジンブルーで染色した。蛍光顕微鏡での「FBS群」の連続切片を図7B下に示す。
[0107] 移植後4週の「欠損群」(図8A上)、「ゲル群」(図8A下)の、トルイジンブルー染色した軟骨欠損部の矢状断像を示す。移植後4週には「欠損群」では、線維組織が部分的に欠損を充填した(図8A上)。「ゲル群」では骨膜がまだ残存し(図8A下)、少数の細胞を伴うコラーゲンゲルが認められる(データは未掲載)。軟骨細胞様細胞が欠損の周縁領域で部分的に認められるが(データは未掲載)、軟骨基質の産生量は乏しいように見えた。
[0110] 移植後24週の、トルイジンブルー染色による軟骨欠損部の矢状断像を示す。「欠損群」(図10A上)、「ゲル群」(図10A下)、「FBS群」(図10B上)。「FBS群」の連続切片を蛍光顕微鏡下で観察した(図10B下)。図10B上の四角で囲った領域の強拡像を図10Cに示し、そこでトルイジンブルー染色した切片を図10C左に示し、そしてその蛍光顕微鏡下で観察された切片を図10C右に示す。図10C右において、核はDAPIで対比染色されている。大腿骨遠位部は右に位置する。バーは1 mm(図10Aおよび図10B);50μm(図10C)を示す。
[0012] 本実施例では、発明者らは軟骨再生の組織学的スコアを調べた。
[0113] 以前に記載された軟骨欠損の組織学的評価尺度(Wakitani et al., 1994, J Bone Joint Surg Am. 76:579-92)を用いて、盲検組織学的観察を、定量化した(表1)。
実施例8 ヒトの軟骨再生に向けた滑膜間葉幹細胞を用いた新しい移植方法
[0116] 新規の薬剤や医療技術の開発にあたり、たとえ動物実験がよいデータを示したとしても、臨床研究がしばしば期待に沿わない結果や予期しない副作用を生じる。このことは、動物実験の結果が必ずしも臨床研究の結果と対応していないことを意味する。これは、細胞や組織の機能がヒトと他の動物との間で異なることによるものである。それゆえ、動物実験においてある仮説が真実だとしても、臨床応用のためにヒトにおいて、必ず確認する必要がある。
[0120] このようにして得られた滑膜(0.2 g)は、ハンクス平衡塩類溶液(HBSS; Invitrogen, Carlsbad, CA)中3 mg/mlのコラゲナーゼを含有する溶液中で37℃にて酵素処理した。3時間後に、酵素処理細胞を70μmのナイロンフィルター(Beckton Dickinson)に通した。有核細胞(1300万個)は150 cm2のディッシュ25枚に播種し、そして完全培地〔α-改変イーグル培地(α-MEM;Invitrogen)、100 units/mlペニシリン、100μg/mlストレプトマイシン、250 ng/mlアンホテリシンB(Invitrogen)に10%自己ヒト血清を添加したもの〕中で14日間培養した。TrypLE(Invitrogen)を37℃にて15分間使用して細胞を回収し、血球計算板を使用して計数して、初代の細胞数を調べた。
[0123] 4日時のMRI検査によると、大腿骨内顆の軟骨欠損が示され、一方2ヶ月時のMRI検査によると、軟骨欠損が軟骨様組織で充填されていた(図12)。
[0124] 本実施例において、本発明者らは、滑膜間葉幹細胞を移植することによる半月板再生を検討した。すべての研究は東京医科歯科大学の動物実験委員会の承認後に行なわれた。
[0129] 注射したルシフェラーゼ/lacZダブルポジティブの滑膜間葉幹細胞を、In Vitro Imaging System(IVIS)とX-gal染色により検出した。再生半月板は肉眼的に評価された。
Claims (10)
- 関節軟骨欠損部または半月板欠損部に注入し、欠損部を覆うように用いられ、欠損部の表面に静置するようにして少なくとも10分間保持し、欠損部の表面に接着させて欠損部の軟骨組織を再生させることにより、関節軟骨欠損または半月板欠損に関連する疾患を治療するための、自己血清を含有する培地中で培養された自家滑膜由来間葉幹細胞を含む、懸濁液の形態の医薬組成物。
- 上方に保持された関節軟骨欠損部に、ex vivoで培養した自家滑膜由来間葉幹細胞を含む懸濁液の形態の移植材料を注入し、その欠損部表面を移植材料で覆い、少なくとも10分間、滑膜由来間葉幹細胞を含む移植材料を軟骨欠損部の表面に接着させて、滑膜由来間葉幹細胞が関節軟骨欠損部に集簇するように用いられることを特徴とする、請求項1に記載の医薬組成物。
- 下方(下向き)に保持された半月板欠損部に、ex vivoで培養した自家滑膜由来間葉幹細胞を含む懸濁液の形態の移植材料を注入し、その欠損部を移植材料で覆い、少なくとも10分間、滑膜由来間葉幹細胞を含む移植材料を半月板欠損部に接着させて、滑膜由来間葉幹細胞が半月板欠損部に集簇するように用いられることを特徴とする、請求項1に記載の医薬組成物。
- 滑膜由来間葉幹細胞が未分化細胞である、請求項1〜3のいずれか1つに記載の医薬組成物。
- 滑膜由来間葉幹細胞が初代培養細胞または第一継代細胞である、請求項1から4のいずれか1つに記載の医薬組成物。
- 再生される軟骨組織が硝子軟骨または繊維軟骨である、請求項1から5のいずれか1つに記載の医薬組成物。
- 再生される軟骨組織が肥大軟骨細胞も骨細胞も含有しないものである、請求項1から6のいずれか1つに記載の医薬組成物。
- 自己血清を含有する培地が分化培地ではない、請求項1〜7のいずれか1つに記載の医薬組成物。
- 自己血清を含有する培地が骨形成因子(BMP)、デキサメタゾンあるいはトランスフォーミング増殖因子β(TGF-β)のいずれをも含有しない培地である、請求項8に記載の医薬組成物。
- 関節軟骨欠損又は半月板欠損に関連する疾患が、外傷性軟骨損傷、離弾性骨軟骨症、無腐性骨壊死、変形性膝関節症、および半月板損傷からなる群より選択されるものである、請求項1から9のいずれか1つに記載の医薬組成物。
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US20100178274A1 (en) | 2010-07-15 |
JP2010501547A (ja) | 2010-01-21 |
JP5928961B2 (ja) | 2016-06-01 |
JP2014196354A (ja) | 2014-10-16 |
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