JP4790592B2 - ヒト臍帯のウォートンジェリーからの前駆細胞 - Google Patents
ヒト臍帯のウォートンジェリーからの前駆細胞 Download PDFInfo
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- 210000001325 yolk sac Anatomy 0.000 description 1
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Description
下記の引用文献は引用することにより本明細書に編入される。
ヒトウォートンジェリーから前駆細胞の採取
UCは、Sunnybrook & Women’s College Hospital,Toronto,Canadaで出産直後の期間満了帝王切開幼児から採取された。UCは媒体(75%α−MEM、15%ウシ胎児血清(FBS)、10%抗生物質)を含む滅菌容器内に外科医により移され、そして直ちにInstitute of Biomaterials & Biomedical Engineering,University of Torontoにある我々の実験室に輸送された。
ウォートンジェリー前駆細胞培養の開始
18〜24時間後に、それらに付属する懸垂クランプまたは縫合糸およびピペットを用いて「ループ」を除き、そして残った懸濁液をT−75cm2 組織培養ポリスチレン皿上に直接置き、そして細胞をポリスチレン表面に付着させるように72時間そのままにした。次いで媒体を2日毎に交換した。
2.滅菌した37℃のリン酸緩衝食塩水(PBS)で二回UCを洗浄し、
3.鋭い鋏を用いてUCを約1〜2インチの断片に切断し、
4.滅菌37℃PBS中で二回、各UC断片を洗浄して残留臍帯血(UCB)をできるだけ除去し、
5.乾燥した滅菌皿上にUC断片の一つを単離し、
6.鉗子2組を用いて、外皮を約2mm離れて掴み、そして互いに引き離して外皮を引裂き、
7.UC断片の長さに沿って外皮を掴み、外皮の引き裂きを続け、その下のWJを暴露し、
8.工程6と同様に、外皮の約半分が取り去られるまで「ストリップ」状に外皮を引裂き、
9.WJを通じて臍血管が明瞭に見え、そしてUC断片の切断端に末端が遊離し、
10.鉗子一組を用いて外皮の残った部分を掴み、そして他の鉗子で血管の端を掴み、血管を本体WJから周囲のPVWJと一緒に血管を「引き取る」ことができ、
11.下にあるWJマトリックスから3本ともに離れるまでこの手順を各血管に反復し、
12.離れると各血管を37℃PBS中に配置し、
13.すべての血管が滅菌37℃PBS充填ビーカー内に単離されるまでUCの各断片を用いて工程5〜12を反復し、
14.次いで、清浄で滅菌した表面上に各血管を個別に置き、ダブルノットを用いる縫合を用いて「ループ」状に末端を一緒に括ることができ、
15.すべての血管をループ状に括ると、ループを50ml試験管の中の1mg/mlコラゲナーゼ溶液内に入れ、
16.50ml試験管を37℃、5%CO2 インキュベーター内で回転皿上に一晩置き、
17.次の日に、1mlウシ胎児血清(FBS)1mlを用いてコラゲナーゼを不活性化し、そしてループを懸濁液から取り出し
18.残った懸濁液をPBSで希釈し、1150rpmで5分間遠心分離し、そして上清を取り除き、
19.ペレット内に残った細胞を補足媒体(SM)(75%α−MEM、15%FBS、20%抗生物質)中に再懸濁し、そしてアリコートを血球計で計数し、
20.次いで細胞懸濁液をT−25組織培養ポリスチレンフラスコ内にプレートしそして増殖させ、
21.細胞がサブ集密となるまで2日毎にSMを交換し(1〜2週間)、その時点でそれらをサブ培養(継代)する。
前駆体アッセイ
細胞増殖アッセイ
週毎の継代手順(6日毎に実施)の間に、2x105 細胞のアリコートを20個のT−25cm2 組織培養ポリスチレンフラスコ内にプレートした。培養の2、4、6、10および12日目に、T−25フラスコ4個を継代し、そして細胞を計数した。それらの細胞の指数関数的増殖をプロットし、それらの培養物中の細胞について平均倍増時間を算出した。結果を図16に示す。PVWJ細胞培養物の倍増時間は全培養期間を通じて約24時間であることが認められる。対数相の間に、倍増時間は注目に値する16時間である。これは、骨髄間葉細胞の約33時間(Conget P.JJ Minguell,1999,Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells:Journal of Cell Physiology,V.181,p.67−73)および脂肪組織から誘導された間葉幹細胞の約3.2日(Sen A.,J.Cell Biochem.,v.81,p.312−319)の文献報告の倍増時間と比較される。
CFU−Oアッセイ
週毎の継代手順の間に、試験細胞集団のアリコートを、75%α−MEM、。15%FBS(StemCell,バッチ番号#:S13E40)、10%抗生物質溶液(ペニシリンG(167単位/ml)、ゲンタマイシン(50μg/ml)およびアンフォテリシンB(0.3μg/ml)含有)、およびDex(10−8M)、βグリセロリン酸(5mM)およびL−アスコルビン酸(50μg/ml)を含む骨形成媒体中、1x104 細胞/cm2 の細胞接種密度で、組織培養ポリスチレン上に直接プレートした。培養物を12日間、二日目毎に再栄養供給した。骨小結節として検出される無機化小結節形成領域が観察されるまで(通常3日)培養物を維持し、その時点で培養物に最終培養再栄養供給において媒体を含むテトラサイクリンを再供給し、次いでKarnovskyの固定液中に固定して分析に備えた。Leitz Aristoplan顕微鏡(Esselte Leitz GmbH & Co.KG,Stuttgart,Germany)を位相コントラストならびにUV蛍光下でテトラサイクリン標識培養物を可視化するために使用し、そして加速電圧15kVのHitachi S−2000走査電子顕微鏡を形態的に同定できる骨マトリックスの存在を証明するための画像を得るために使用した。
データ解析
テトラサイクリン染色
テトラサイクリン(9μg/ml)を終結の前に培養物に加えた。終結の際に、細胞をKarnovskyの固定液中で一晩固定し次いで小結節領域の無機成分のテトラサイクリン標識のUV励起蛍光画像により観察した。
走査電子顕微鏡(SEM)
CFU−O培養物の代表試料を最初に70%。80%。90%および95%エタノール中に1時間、次いで100%エタノールに3時間浸漬してSEMのために準備した。次いでそれらを臨界点乾燥した。約3nm層の金層をPolaron SC515 SEM Coating Systemを用いて試料上にスパッタリング被覆し、ついでこれを加速電圧15kVのHitachi S−2000走査電子顕微鏡で種々の倍率で検査した。得られた画像を形態的に同定できる骨マトリックスの存在を証明するために使用した。
HLA−分類のためのフローサイトメトリー
1x105 細胞を越える試験細胞集団を2%FBS(StemCellバッチ番号#S13E40)を含むPBS中で洗浄しそしてPBS+2%FBS中に下記の複合(conjugated)マウスIgG1 HLA−A,B,C−PEおよびHLA−DR,DP,DQ−FITCの飽和濃度(1:100希釈)で、30分間、4℃で再懸濁した。細胞懸濁液をPBS+2%FBSで2回洗浄し、1μg/ml 7−AAD(BD Biosciences)で染色しそしてExpoADCXL4ソフトウエア(Beckman−Coulter)を用いるフローサイトメトリー(XL,Beckman−Coulter,Miami,FL)の分析のためにPBS+2%FBS中に再懸濁した。陽性の染色は、マッチしたアイソタイプ抗体(FITC−およびPE−複合マウスIgG1、κモノクローナルアイソタイプ標準、BD Biosciences)を用いて染色した対照集団からの細胞の99%以上により得られたレベルを越える蛍光シグナルの発光として定義された。各試料に対して、少なくとも10,000リストモード(list mode)イベントが集められた。すべてのプロットはEXPO 32 ADC分析ソフトウエアで得られた。
結果
骨小結節コロニーの光学顕微鏡画像
図3、4および5は、3日目および5日目において培養物内に存在したCFU−Oを示す。それらは、骨−マトリックスを産生する多角形細胞の「凝集」により表される小結節領域を取り巻く「繊維芽細胞様」細胞の集密層を示す。これらのCFU−Oは、Dex(+)およびDex(−)培養物の双方で観察され、そして継続する継代でも同様の形態を示した。
CFU−O培養物のテトラサイクリン標識
培養物のテトラサイクリン標識は、骨の生物学的無機相と関連する新規形成リン酸カルシウムを標識するために使用された。培養物のテトラサイクリン標識は、無機化小結節領域と一致し、それは培養物のUV光への暴露により可視化された。図6および7は、WJ前駆細胞の培養3日目および5日目のテトラサイクリン標識CFU−O培養物を示す。それらの画像は、UV励起蛍光イメージングで発生し撮影された。
走査顕微鏡測定
CFU−Oは、SEM下で、成熟CFU−O内の高密度無機化マトリックスへのコラーゲン形成の初期段階からのCFU−Oの形成を証明する無機化コラーゲンマトリックスの形成について観察された。図8、9、10、11、12および14は、CFUOの走査顕微鏡画像を示す。
フローサイトメトリーおよびHLA分類
両方の主要組織適合複合体(MHC)を表す細胞表面抗原を同定するフローサイトメトリーは、MHC−/− のような単離細胞の集団の77.4%を示した。図13は、陰性対照に関連するフローサイトメトリー結果を示す。図17は、前駆細胞集団内のMHC−/−細胞の頻度に対する冷凍−解凍のインパクトを示す。冷凍−解凍の効果は、以下のように研究された。
サブ集団および細胞接種
付着した細胞は、7日後に0.1%トリプシン溶液を用いてサブ培養(継代)され、その時点で光学顕微鏡で観察して80〜90%の集密を示した。継代すると、PVWJ(脈管周囲ゾーンウォートンジェリー)細胞がMHC−A,B,C、MHC−DR,DP,DQおよびCD45の発現に関するフローサイトメトリーにより観察された。次いで、それらをSM中4x103 細胞/cm2 でT−75組織培養ポリスチレンフラスコ中にプレートし、そして10−8M Dex、5mMβ−GPおよび50μg/mlアスコルビン酸で処理してそれらの細胞の骨原性能力を試験した。それらのフラスコを培養の2、3、4、5および6日目にCFU−Oまたは骨小結節、形成について観察した。継代手順からのあらゆる残留細胞は将来の使用のために冷凍保存した。
細胞の冷凍保存
1x106 PVWJ細胞のアリコートを、90%FBS、10%ジメチルスルホキシド(DMSO)(Sigma D−2650,Lot#11K2320)を含み全体積1mlに調製し、そして1mlポリプロピレン冷凍バイアル中にピペットで移した。該バイアルを−70℃冷凍庫中に一晩置き、そして次の日に−150℃冷凍庫に長期保存のために移した。冷凍保存1週間後、PVWJ細胞を解凍しそしてMHC−A,B,C,MHC−DR,DP,DQおよびCD45の発現に関するフローサイトメトリーにより観察した。第二のアリコートは、PVWJ細胞を冷凍保存1週間後に解凍し、1週間再培養し、サブ培養し次いでMHC−A,B,C,MHC−DR,DP,DQおよびCD45の発現に関するフローサイトメトリーによる再分析に使用した。
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Claims (21)
- ヒト前駆細胞を得る方法であって、ヒト臍帯の脈管周囲ゾーンから該細胞を抽出する工程を含んで成る、上記方法。
- 抽出工程が、臍帯から切除された1以上の血管で行われる、請求項1記載の方法。
- 適切な細胞抽出媒体内で酵素消化されることにより、細胞が脈管周囲ゾーンからのウォートンジェリーから抽出される、請求項1又は2に記載の方法。
- 酵素消化が、ウォートンジェリーのコラーゲンマトリックスからの細胞の開放をもたらす、請求項3記載の方法。
- ヒト前駆細胞を含んでなる細胞集団の生産方法であって、請求項1〜4のいずれかに記載の方法によって得られた細胞を培養する工程を含んでなる、上記方法。
- 骨前駆細胞を富化するように該集団を処理する更なる工程を含んでなる、請求項1〜5のいずれかに記載の方法。
- MHCダブルネガティブ表現型を有する前駆細胞を富化するように該集団を処理する更なる工程を含んでなる、請求項1〜5のいずれかに記載の方法。
- MHCダブルネガティブ表現型を有する前駆細胞を富化するために、該集団が冷凍/解凍工程を受ける、請求項7記載の方法。
- 細胞集団が(1)ヒト臍帯の脈管周囲ゾーンのウォートンジェリーから抽出可能であり(2)脈管周囲ゾーンの外側のウォートンジェリーから抽出された他の前駆細胞集団よりも迅速に増殖し(3)骨前駆細胞を含んでなり(4)MHCダブルネガティブ表現型を有する前駆細胞を含んでなる、ヒト前駆細胞を含んでなる単離された細胞集団。
- 冷凍保存状態にある、請求項9記載の細胞集団。
- 請求項9記載の細胞集団を骨細胞への分化を誘導する条件下で成長させる工程を含んでなる、骨細胞の生産方法。
- 該細胞が骨形成性の補足物の不存在下で培養される、請求項11記載の方法。
- 請求項9記載の細胞集団を脂肪細胞への分化を誘導する条件下で成長させる工程を含んでなる、脂肪細胞の生産方法。
- 請求項9記載の細胞集団を筋芽細胞への分化を誘導する条件下で成長させる工程を含んでなる、筋芽細胞の生産方法。
- 医学的病状、疾患および障害の処置のための薬剤の製造における請求項9及び10のいずれかに記載の細胞集団の使用。
- ヒト前駆細胞の集団が、帯の脈管構造から誘導される細胞を本質的に含まない、請求項1〜8および11〜15に記載の方法。
- 該集団が、帯の血管構造から誘導される細胞を本質的に含まない、請求項9及び10のいずれかに記載の単離された細胞集団。
- ヒト前駆細胞を含んでなりそしてヒト臍帯の脈管構造に近接するウォートンジェリーの酵素消化により得られる、ウォートンジェリー抽出物。
- 臍帯血の細胞を本質的に含まない、請求項18記載のウォートンジェリー抽出物。
- 近接ウォートンジェリーを担う臍帯脈管構造を適切な細胞抽出媒体内で酵素消化させて得られる、請求項18または19記載のウォートンジェリー抽出物。
- 酵素消化の工程が、ウォートンジェリーのコラーゲンマトリックスから細胞の開放をもたらす、請求項18〜20記載のウォートンジェリー抽出物。
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- 2009-06-11 US US12/482,963 patent/US8481311B2/en active Active
- 2009-11-25 IL IL202331A patent/IL202331A/en not_active IP Right Cessation
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2013
- 2013-05-28 US US13/903,575 patent/US9567564B2/en active Active
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2015
- 2015-10-15 US US14/884,339 patent/US9611456B2/en not_active Expired - Lifetime
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2017
- 2017-02-23 US US15/440,170 patent/US20170157180A1/en not_active Abandoned
Patent Citations (4)
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FR2578743A1 (fr) * | 1985-03-13 | 1986-09-19 | Bontemps Raymond | Procede de fabrication d'une preparation medicamenteuse a base de substance mesenchymateuse du type microsepteurs |
SU1708328A1 (ru) * | 1989-07-11 | 1992-01-30 | Кемеровский государственный медицинский институт | Способ изготовлени сосудистого протеза |
WO1998017791A1 (en) * | 1996-10-23 | 1998-04-30 | Advanced Tissue Sciences, Inc. | Production of cartilage tissue using cells isolated from wharton's jelly |
RU2174016C1 (ru) * | 2000-06-14 | 2001-09-27 | Оренбургская государственная медицинская академия | Способ получения тимпанопластического трансплантата |
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BRPI0407221A (pt) | 2006-01-31 |
CA2515469C (en) | 2013-12-17 |
US20090269318A1 (en) | 2009-10-29 |
CA2515469A1 (en) | 2004-08-26 |
KR20050115862A (ko) | 2005-12-08 |
WO2004072273A1 (en) | 2004-08-26 |
US20170157180A1 (en) | 2017-06-08 |
US20130259840A1 (en) | 2013-10-03 |
IL170221A (en) | 2010-11-30 |
US20050148074A1 (en) | 2005-07-07 |
EP2277992A2 (en) | 2011-01-26 |
ATE478941T1 (de) | 2010-09-15 |
US9611456B2 (en) | 2017-04-04 |
AU2008261123A1 (en) | 2009-01-15 |
US8481311B2 (en) | 2013-07-09 |
JP2006517102A (ja) | 2006-07-20 |
IL202331A (en) | 2011-08-31 |
AU2004210891A1 (en) | 2004-08-26 |
KR101077760B1 (ko) | 2011-10-27 |
PT1594957E (pt) | 2010-11-30 |
EP2277992A3 (en) | 2011-03-02 |
US20160032241A1 (en) | 2016-02-04 |
EP1594957A1 (en) | 2005-11-16 |
DE602004028803D1 (de) | 2010-10-07 |
HK1084417A1 (en) | 2006-07-28 |
US7547546B2 (en) | 2009-06-16 |
US9567564B2 (en) | 2017-02-14 |
EP1594957B1 (en) | 2010-08-25 |
ES2351386T3 (es) | 2011-02-03 |
AU2004210891B2 (en) | 2008-09-25 |
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