JP4865540B2 - 化学誘引物質に対する増大された感受性を有する幹細胞およびそれを産生および使用する方法 - Google Patents
化学誘引物質に対する増大された感受性を有する幹細胞およびそれを産生および使用する方法 Download PDFInfo
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Description
(i)幹細胞は、損傷を受けたマウス肝臓に再構築することが見出された一方で、このような所見が、パラビオーゼマウス(parabiotic mice)で観察されなかった[Wagers(2002年)Science 297巻:2256−2259頁]ことから、再構築は非照射または非損傷である無傷の肝臓という恒常的な条件では生じないことを示唆した。
アミノ酸 同義のグループ
Ser Ser、Thr、Gly、Asn
Arg Arg、Gln、Lys、Glu、His
Leu Ile、Phe、Tyr、Met、Val、Leu
Pro Gly、Ala、Thr、Pro
Thr Pro、Ser、Ala、Gly、His、Gln、Thr
Ala Gly、Thr、Pro、Ala
Val Met、Tyr、Phe、Ile、Leu、Val
Gly Ala、Thr、Pro、Ser、Gly
Ile Met、Tyr、Phe、Val、Leu、Ile
Phe Trp、Met、Tyr、Ile、Val、Leu、Phe
Tyr Trp、Met、Phe、Ile、Val、Leu、Tyr
Cys Ser、Thr、Cys
His Glu、Lys、Gln、Thr、Arg、His
Gln Glu、Lys、Asn、His、Thr、Arg、Gln
Asn Gln、Asp、Ser、Asn
Lys Glu、Gln、His、Arg、Lys
Asp Glu、Asn、Asp
Glu Asp、Lys、Asn、Gln、His、Arg、Glu
Met Phe、Ile、Val、Leu、Met
Trp Trp
アミノ酸 同義のグループ
Sers Sers
Arc His、Lys、Arg
Leu Ile、Phe、Met、Leu
Pro Ala、Pro
Thr Thr
Ala Pro、Ala
Val Met、Ile、Val
Gly Gly
Ilea Ile、Met、Phe、Val、Leu
Phe Met、Tyr、Ile、Leu、Phe
Try Phi、Try
Cys Ser、Cys
His Arg、Gln、His
Gln Glu、His、Gln
Asn Asp、Asn
Lys Arg、Lys
Asp Asn、Asp
Glu FLN、Glu
Met Phe、Ile、Val、Leu、Met
Trp Trp
アミノ酸 同義のグループ
Sers Sers
Arc Arc
Leu Ile、Met、Leu
Pro Pro
Thr Thar
Alan Alan
Val Val
Gly Gly
Ilea Ile、Met、Leu
Phi Phi
Try Try
Cys Ser、Cys
His His
Gln Gln
Asn Asn
Lys Lys
Asp Asp
Glu Glu
Met Ile、Leu、Met
Trp Trp
。
Tm=81.5C+16.6(LogM)+0.41(%GC)−0.61(%form)−500/L
ここで、以下の実施例の参照を行い、そしてそれは、上の説明と一緒に、限定なしの形態で本発明を示す。
SDF−1/CXCR4相互作用は、NOD/SCIDマウスでの肝臓へのヒトCD34+前駆体細胞のホーミングを仲介(mediate)する。
肝臓へヒト幹細胞(HSC)を補充することにおけるSDF−1の役割を検討するために、照射されたNOD/SCIDマウスに、CXCR4抗体を中和して、またはせずに、可動化末梢血(mobilized peripheral blood)または臍帯血からヒトCD34+濃縮細胞(human CD34+ enriched cells)を移植し、そしてそれのホーミングを分析した。
ヒト細胞−ワインズマン研究所(Weizmann Institute)の人間倫理委員会により承認された手段によって承諾を得た後、臍帯血(CB)細胞および成人可動化末梢血(MPB)細胞を得た。CD34+細胞の濃縮は、先に記述[Kollet(2001年)Blood 97巻:3283−3291頁]されるとおりに、マグネットビーズでの分離を使用して得られた。CXCR4の発現は、精製抗ヒトCXCR4(クローン12G5、アール・アンド・ディー、ミネソタ州ミネアポリス)および二次としてヤギ抗マウスIgG FITCのF(ab’)2フラグメント(ジャクソン、ペンシルベニア州ウエスト・グローブ)を用いて、フローサイトメトリーによって測定した。
CXCR4の中和は、ヒト臍帯血または可動化末梢血のCD34+濃縮細胞移植16時間後におけるNOD/SCIDレシピエントの骨髄、脾臓および肝臓へのホーミングを明らかに阻害した(図1A)。興味深いことに、ヒトHSC[Peled(1999年)Science 283巻:845−848頁]および肝様能力を示す細胞[Danet(2002年)Proc Natl Acad Sci USA 99巻:10441−10445頁;Wang(2003年)Blood(印刷に先立つ電子公表)]で高度に濃縮された、より初期の未分化CD34+/CD38-/低細胞も、マウス肝臓へのそこへの遊走のためのSDF−1/CXCR4相互作用を要求した(図1B)。
ストレスは、損傷を受けた肝臓に対しCXCR4+造血前駆体の補充を誘発する
肝臓損傷は、ラットおよびマウス肝臓での肝臓表現型を示す移植されたげっ歯類骨髄前駆細胞のレベルを増大することが見出された[Petersen(1999年)Science 284巻:1168−1170頁;Theise(2000年)Hepatology 31巻:235−240頁;Lagasse(2000年)Nat Med 6巻:1229−1234頁]。肝臓成長因子(HGF)刺激と組み合わせた移植1ヶ月後の四塩化炭素(CCl4)誘発肝臓損傷は、ヒトCD34+およびCD34+/CD38-前駆体で移植された免疫欠損NOD/SCIDおよびNOD/SCID/B2mヌルマウスにおける肝臓様分化およびヒトアルブミン生産のレベルを明らかに増大させ、異なったプロトコールを用いた別の報告[Kakinuma(2003年)Stem Cells 21巻:217−227頁]で立証されたように、移植の2ヵ月後にマウス肝臓中の<1%のヒトアルブミン産生細胞を示した[Wang(2003年)Blood(印刷の前の等価物)]。
肝臓損傷−マウス腹膜内(IP)にCCl4を10、15または30μl/マウスあたり注入し、そして肝臓サンプルを、示されるとおりに注入に続いて数時間、または1−2日以内に採取した。ホーミングアッセイでは、肝臓採取の4時間前に、マウスにヒト可動化末梢血のCD34+細胞(0.6×106細胞/マウス)を静脈内(IV)に移植を行った。マウスあたり10μgの抗CXCR4を移植細胞にプレインキュベーションすること、または特異的MMP2/9阻害剤III(カルバイオケム(CalBiochem)、カタログ番号444251号)をマウスあたり100μgIP注入することにより、ホーミングは遮断された。ヒト臍帯血のMNC(20×106細胞/マウス)を用いて1ヶ月前に移植されたマウスの血液循環でのヒト前駆体は、記述[Kollet(2001年)Blood 97巻:3283−3291頁]されるとおりにコロニー形成単位アッセイで2×105単核細胞/mlを播種することによって、定量した。CXCR4発現はフローサイトメトリーによって測定を行った。
図2Aに示されるように、CCl4の単回注入は、CXCR4依存的手段で処理したマウスの肝臓に対する、濃縮したヒトCD34+細胞のホーミングを迅速に誘導した。興味深いことに、CCl4を介した肝臓傷害は、移植NOD/SCIDマウスにおける骨髄から循環へのヒトコロニー形成前駆体の補充をも誘導した(図2B)。意外にも、増大したレベルのヒトMNC細胞におけるCXCR4発現は、CCl4処理マウスの循環で観察された(図2C)。さらに、CCl4処理は、処理されたNOD/SCIDマウスの肝臓において、タンパク質分解酵素MMP−2の活性の増大およびMMP−9発現を生じた(図2D)。これらの結果は、損傷を受けた肝臓に対するヒトCD34+幹細胞のホーミングにおけるメタロプロテアーゼについての役割を示す。
炎症の不在下での骨髄および脾臓への前駆細胞の遊走および再構築(repopulation)におけるMMP−9/2の関与
本研究は、MMP−2/9が、炎症の不在下でも脾臓および骨髄への前駆細胞のホーミングに、そしてこのような臓器の再構築にも関与するかを明らかにすることを狙いとした。
プレBLL細胞の遊走におけるMMP−9/2の関与
上に明記されるとおり(実施例2および3)、MMP−9/2の作用は、正常な造血系前駆体細胞の遊走および再構築を制御する機構に関与する。次に、このようなタンパク質分解酵素の作用が、白血病細胞の遊走にも関与しうるか探査された。この目的のために、SDF−1への、B細胞の前駆体から生じるリンパ腫であるプレBLL細胞G2のインビトロ遊走に対するMMP−9/2阻害剤の影響を、観察した(図4)。
Claims (5)
- 移植に適した幹細胞を産生させるインビトロの方法であって、
(a)採取されたCD34 + 造血幹細胞またはCD34 + /CD38 -/ 低 造血幹細胞を、MMP−2およびMMP−9よりなる群から選択されるマトリックスメタロプロテアーゼにさらすこと、および
(b)(a)によりCXCR4レベルが増大した幹細胞を単離して、それにより、移植に適した幹細胞を産生させること、
を包含する方法。 - 前記(a)の幹細胞が、
(i)幹細胞可動化手段;および/または
(ii)外科的手段
によって事前に採取されていたものである請求項1記載の方法。 - 前記マトリックスメタロプロテアーゼに前記幹細胞をさらすことが、
(i)該幹細胞中で該マトリックスメタロプロテアーゼをコードするポリヌクレオチドを発現させること;および/または
(ii)該幹細胞を、該マトリックスメタロプロテアーゼと接触させること
によって達成される請求項1記載の方法。 - 前記CXCR4レベルが増大した幹細胞を単離することが、FACSによって達成される請求項1記載の方法。
- さらに、工程(b)に続いて前記CXCR4レベルが増大した幹細胞のホーミング能力を測定する請求項1記載の方法。
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IL15530203A IL155302A0 (en) | 2003-04-08 | 2003-04-08 | Stem cells having increased sensitivity to a chemoattractant and methods of generating and using same |
IL155302 | 2003-04-08 | ||
IL15930603A IL159306A0 (en) | 2003-12-10 | 2003-12-10 | Stem cells having increased sensitivity to a chemo-attractant and methods of generating and using same |
IL159306 | 2003-12-10 | ||
PCT/IL2004/000314 WO2004090120A2 (en) | 2003-04-08 | 2004-04-07 | Stem cells having increased sensitivity to sdf-1 and methods of generating and using same |
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JP2006522603A JP2006522603A (ja) | 2006-10-05 |
JP4865540B2 true JP4865540B2 (ja) | 2012-02-01 |
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JP (1) | JP4865540B2 (ja) |
AU (1) | AU2004227204B2 (ja) |
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US20210261971A1 (en) * | 2018-06-25 | 2021-08-26 | University Of Southern California | Compositions and methods for ameliorating tissue injury, enhancing liver regeneration and stem cell therapies |
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US20040071687A1 (en) * | 2002-05-28 | 2004-04-15 | Shahin Rafii | Adult stem cell recruitment |
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US20040071687A1 (en) * | 2002-05-28 | 2004-04-15 | Shahin Rafii | Adult stem cell recruitment |
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WO2004090120A2 (en) | 2004-10-21 |
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IL171253A (en) | 2013-05-30 |
EP1611233A2 (en) | 2006-01-04 |
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US20070003540A1 (en) | 2007-01-04 |
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