JP2014511864A - 骨及び軟骨の自己ヒト成体多能性極小胚様(hVSEL)幹細胞再生 - Google Patents
骨及び軟骨の自己ヒト成体多能性極小胚様(hVSEL)幹細胞再生 Download PDFInfo
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Abstract
Description
本発明は、国立衛生研究所により認可された認可番号AR056893及びDK082481の政府援助により行われた。政府は、発明において一部の権利を有する。
本出願は、米国特許出願番号第61/473,420号、出願日2011年4月8日の優先権を主張し、斯かる出願は本願全体におい参照により組み込まれる。
本発明は、極小胚様(VSEL)幹細胞を含んで成る組成物、及びヒトにおける骨及び軟骨疾患を治療するための組成物の使用に関する。
本発明は、対象において骨軟骨組織を治療又は再生するための方法を供する。方法は、自己の極小胚様幹(VSELs)細胞集団を得る工程及び細胞を投与し骨軟骨組織を治療又は再生する又は新たな組織を産生する工程を含んでなる。VSELs細胞は、骨髄から得る、又は血液から動員及び収集することができる。投与に先立ち、VSELsは、濃縮又は精製によって通常調製され、支持マトリックスに取り込まれることができる。一部の実施形態において、発明のVSEL調製は、さらに1又は2以上の成長因子を含み、骨形態形成因子又はタンパク質(BMPs)を含むがそれらに限定されない。
以下の実施例は、当業者に本発明をどう実施し使用するかの完全な開示及び記載を供するものであり、発明者が発明として見なすものの範囲を限定するものではなく、また以下の実験が行った全てである又は唯一の実験であることを表すことを意図するものでもない。使用した数値(例えば、量、温度、等)に関して正確性を保証するために努力したが、一部に実験エラー及び偏差が、存在するかもしれない。他に表示しない限り、部は重量部であり、分子量は重量分子量であり、温度は摂氏温度であり、圧力は大気圧又は近大気圧である。
頭蓋冠を収集し、10%中性緩衝ホルマリン中に直ちに48時間固定した。骨検体を続いて8.93 μm ボクセル解像度でEVS Corp.、microCTスキャナー(London、Ontario、Canada)上で、1スキャンあたり合計667スライスでスキャンした。GEMS MicroView(登録商標)ソフトウェアを、斯かるセットからの3D再構築のために使用した。目的の領域(ROI)に関して各欠損を個体評価し、骨分析をミネラル化骨相を引き出すために使用される固定閾値(600)で行い、骨量画分(BVF)、骨密度(BMD)及び骨梁数(Th.N.)を算出した。
μCT分析後に、骨を10% EDTA(pH 7.4)に10日間脱灰させ、パラフィン中に取り込んだ。頭蓋冠の縦切片をカットし、ヘマトキシリン・エオシン(H&E)で又はマッソントリクローム染色を使用することによって染色し、光学顕微鏡で分析した。一部の場合、製造者のプロトコール(R&D Systems)に従って、スライドをヒトHLA抗原への抗体(抗HLA-ABC抗体(BioLegend、San Diego、CA))で又はHRPAEC染色系キットと併せてIgG対照(Sigma)で染色し、ヒト細胞を識別した。
サンドイッチMid-TactオステオカルシンEIA(Biomedical Technologies、Stoughton、MA)及びヒト組換え型オステオカルシン(Biomedical Technologies)を標準として使用することによって、ヒトオステオカルシンレベルを測定した。斯かるサンドイッチEIAは、インタクトのヒトオステオカルシン及び主要な(1-43)断片双方に非常に特異的である。血清中の生じるオステオカルシンレベルを規準化するために、ウシ血清アルブミン標準に対するRC-DCタンパク質アッセイキット(BioRad Laboratories)を使用することによって総タンパク質を測定した。
数的データを平均値± 標準偏差として表わす。統計分析をKruskal-Wallisの一方向分散分析によって、GraphPad Instat統計プログラム(GraphPad Software、San Diego, CA)を使用して行った。特異的な相違をMann-Whitney U検定によって測定した。有意性レベルをP < 0.05に設定する。
脱灰後に、組織学評価の準備において各欠損を介して連続切片を作成した。移植片物質は、高度の生体適合性を示し、非常に低レベルの炎症及び異物応答の証拠がないことが特徴であった。対照群において、コラーゲンGelfoam担体マトリックスは存続し、H&E又はマッソントリクローム染色で類骨又は成熟層状骨は観察できなかった(図7)。2,000-30,000 hVSEL 細胞を移植した実験群において、頭蓋冠欠損内に骨髄空間を含む層状骨が観察された(図7B-D)。担体マトリックスは大部分が欠損部位から再吸収され、層板骨を覆っている線維性結合組織内に包埋された残存小片はほとんどなかった。生じた骨は、主に成熟層状骨を含んだ(図7B-D)。
形成された骨が実際に移植されたヒト細胞によって産生されたことを確認するために、2つの独立した方法で評価した。まず、切片を汎ヒト特異的白血球抗原(HLA)抗体で染色した。媒体のみを移植しヒトVSELsを含まないたマウスは、ヒトHLAに交差反応を全く示さなかった(図8A)。ヒトVSEL細胞を移植したマウスは、骨芽細胞上及び骨細胞中に特異的に顕著なヒトHLA染色を示した(図8B-D)。
ヒトVSELsの移植部位から周辺への遊走を、定量的リアルタイムPCRを使用して、ヒト特異的Alu 配列に関して評価した。ヒトDNAの存在を、脾臓、大腿、肝臓の右葉及び全血由来の、代表的な組織試料から評価した。ヒト細胞移植していない動物及びマウス骨髄を移植した動物は、負の対照として機能した。マウス骨髄と混合(1:1,000)のヒト前立腺癌細胞系統(PC-3)は、正の対照として機能した。ヒト特異的Alu発現を、ヒトVSEL細胞を移植したレシピエント動物の血液で低レベルで同定した(図10)。ヒトDNAの証拠は、ヒトVSEL細胞を移植した動物の脾臓、大腿又は肝臓で見られなかったことは、欠損外に遊走したVSEL細胞のレベルが相対的に低かったことを示唆している。
一部の切片における組織学試験は、軟骨におけるヒトVSELsの存在を示した。一部の切片において、軟骨中に取り込まれた軟骨細胞を暗示する組織と共に織り込まれた骨が観察された。この細胞型が軟骨形成を示し得るコラーゲンII型を生じたかを決定するためにさらなる分析を行った。hVSEL細胞により形成された組織を、蛍光ヒト特異的汎ヒト白血球抗原(HLA)で免疫染色し、コラーゲンII型(Co II)を染色した。図11は、混合HLA、CO II、及び微分干渉(DIC)のイメージを示す。
1. Rodgerson, D.O. and Harris, A. (2011) A Comparison of Stem Cells for Therapeutic Use. Stem Cell Rev and Rep. Pub. on line DOI 10.1007/s12015-011-9241
2. Taichman, R.S., Wang, Z., Shiozawa, Y., Jung, Y., Song, J., Balduino, A., Wang, J., Patel, L.R., Havens, A., Kucia, M., Ratajczak, M., Krebsbach, P.H. Prospective Identification and Skeletal Localization of Cells Capable of Multi-Lineage Differentiation In Vivo. Stem Cells Dev. 2010.
3. Kucia, M., Wu, W., Ratajczak, M.Z. Bone marrow-derived very small embryonic-like stem cells: Their developmental origin and biological significance. Dev. Dyn. 2007.
4. Kucia, M., Zuba-Surma, E.K., Wysoczynski, M., Wu, W., Ratajczak, J., Machalinski, B., Ratajczak, M.Z. Adult marrow-derived very small embryonic-like stem cells and tissue engineering. [Review] [104 refs]. Expert Opinion on Biological Therapy 7(10):1499-514, 2007.
5. Kucia, M., Reca, R., Campbell, F.R., Zuba-Sunna, E., Majka, M., Ratajczak, J., Ratajczak, M.Z. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia 1920;857-869.
Claims (37)
- 対象において骨軟骨組織に対する損傷又は傷害を治療するための方法であって、極小胚様幹細胞(VSELs)を含んで成る組成物の有効量を該対象へ投与する工程を含んで成り、該VSELsが分化し骨軟骨組織を治療する、方法。
- 前記VSELsが、骨芽細胞へ分化する、請求項1に記載の方法。
- 前記VSELsが、軟骨細胞へ分化する、請求項1に記載の方法。
- 前記VSELsが、前記組織へ直接投与される、請求項1に記載の方法。
- 前記VSELsが、全身に投与される、請求項1に記載の方法。
- 前記組成物が、1mm3当たり約20〜約5 x 105 VSELsを含んでなる、請求項4に記載の方法。
- 前記組成物が、1mm3当たり約40〜約4,000 VSELsを含んでなる、請求項4に記載の方法。
- 前記組成物が、1mm2当たり約10〜約1 x 105 VSELsを含んでなる、請求項4に記載の方法。
- 前記組成物が、1mm2当たり約25〜約500 VSELsを含んでなる、請求項4に記載の方法。
- 前記組成物が、適したマトリックスを含んでなる、請求項4に記載の方法。
- 前記マトリックスが、生分解性である、請求項10に記載の方法。
- 前記組成物が、1又は2以上の骨形成タンパク質(BMPs)を含んでなる、請求項1に記載の方法。
- 前記骨軟骨組織が骨である、請求項1に記載の方法。
- 前記骨軟骨組織が軟骨である、請求項1に記載の方法。
- 前記骨軟骨組織が関節軟骨である、請求項1に記載の方法。
- 前記組成物が、少なくとも約50% VSELsである細胞を含んでなる、請求項1に記載の方法。
- 前記組成物が、少なくとも約70% VSELsである細胞を含んでなる、請求項1に記載の方法。
- 前記組成物が、少なくとも約90% VSELsである細胞を含んでなる、請求項1に記載の方法。
- 前記VSELsが、自己VSELsである、請求項1に記載の方法。
- 前記VSELsが、同種VSELsである、請求項1に記載の方法。
- 前記VSELsが、ヒト由来である、請求項1に記載の方法。
- 前記方法が、骨形成不全症を治療するために使用される、請求項1に記載の方法。
- 前記方法が、変形性関節症を治療するために使用される、請求項1に記載の方法。
- 前記方法が、骨粗しょう症を治療するために使用される、請求項1に記載の方法。
- 骨軟骨組織の再生又は修復に十分なVSELsの有効量を含んで成る、幹細胞組成物。
- 1mm3当たり約20〜約5 x 105 VSELsを含んでなる、請求項25に記載の幹細胞組成物。
- 1mm3当たり約40〜約4,000 VSELsを含んでなる、請求項25に記載の幹細胞組成物。
- 1mm2当たり約10〜約1 x 105 VSELsを含んでなる、請求項25に記載の幹細胞組成物。
- 1mm2当たり約25〜約500 VSELsを含んでなる、請求項25に記載の幹細胞組成物。
- 適したマトリックスを含んでなる、請求項25に記載の幹細胞組成物。
- 前記マトリックスが生分解性である、請求項30に記載の幹細胞組成物。
- 1又は2以上の骨形成タンパク質(BMPs)を含んでなる、請求項25に記載の幹細胞組成物。
- 骨芽細胞に分化可能である、請求項25に記載の幹細胞組成物。
- 軟骨細胞に分化可能である、請求項25に記載の幹細胞組成物。
- 少なくとも約50% VSELsである細胞を含んでなる、請求項25に記載の幹細胞組成物。
- 少なくとも約70% VSELsである細胞を含んでなる、請求項25に記載の幹細胞組成物。
- 少なくとも約90% VSELsである細胞を含んでなる、請求項25に記載の幹細胞組成物。
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US20160136203A1 (en) * | 2014-11-19 | 2016-05-19 | StemBios Technologies, Inc. | Somatic stem cells for treating bone defects |
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CN114732962B (zh) * | 2022-05-20 | 2023-06-20 | 武汉理工大学 | 一种可降解的抗菌引导骨再生膜及其制备方法和应用 |
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---|
JPN5014005958; TAICHMAN RUSSELL S: 'PROSPECTIVE IDENTIFICATION AND SKELETAL LOCALIZATION OF CELLS CAPABLE 以下備考' STEM CELLS AND DEVELOPMENT V19 N10, 201010, P1557-1570 * |
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RU2013147265A (ru) | 2015-05-20 |
AU2012239874A1 (en) | 2013-10-31 |
CN103748215A (zh) | 2014-04-23 |
BR112013025957A2 (pt) | 2016-09-20 |
EP2694641A1 (en) | 2014-02-12 |
US20140112891A1 (en) | 2014-04-24 |
WO2012139131A1 (en) | 2012-10-11 |
EP2694641A4 (en) | 2014-11-19 |
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