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Tenogenic Differentiation of Tendon Derived Stem Cells (TDSCs) and Application for Tendon Repair.

机译：肌腱衍生干细胞（TDSC）的肌腱分化及其在肌腱修复中的应用。

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摘要

Tendon injuries are common and tendon healing outcome is poor, because tendon contains few cells with limited capacities for self-repair/regeneration. The current treatments on tendon injuries including drugs, physiotherapy, and surgery are not ideal and there is a need for the development of novel tissue-engineering strategies for tendon repair.;Previous studies have shown positive effects of bone marrow-derived mesenchymal stem cells (BMSCs), dermal fibroblast, tenocytes, and embryonic stem cells-derived MSCs for tendon repair/regeneration. However, these cells have limitations including insufficient differentiation; risk of teratoma and ectopic bone formation etc. Recently, stem cells have been isolated from tendons of human, mouse, rat and rabbit and considered as a new alternative cell source for tendon tissue engineering (TDSCs). For tenogenic differention of MSCs, connective tissue growth factor (CTGF) and ascorbic acid (one form of vitamin C) are reported to play important roles in promoting collagen and other extracellular matrixes (ECM) production, and regulating the MSCs differentiation towards tenogenic pathway.;The aims of the current study are: (1) To investigate the use of TDSCs in tendon repair in a rat acute patellar tendon injury model; (2) To test the effects of CTGF and ascorbic acid on tenogenic differentiation of TDSCs in vitro; (3) To construct scaffold-free tendon-like tissues in vitro using tenogenically differentiated TDSCs; (4) To promote tendon healing by engineered tendon-like tissues in a rat acute patellar tendon injury model.;In the rat acute patellar tendon injury model, in contract to control group, TDSCs treated group showed better alignment of collagen fibers and the significantly higher ultimate stress and Young's modulus, indicating TDSCs may be an alternative cell source for tendon repair. The effects of CTGF and ascorbic acid on tenogenic differentiation of TDSCs were also confirmed with higher expression of tendon related markers such as Tenomodulin, Scleraxis, Thbs4, Type I Collagen, etc.; with higher production of collagenous proteins. After treatment with CTGF and ascorbic acid for 2 weeks, TDSCs can form cell sheets, which can be harvested, rolled up on a U-shaped spring to form tendon-like tissues in culture, which had loose extracellular matrices and randomly distributed TDSCs and also expressed Tenomodulin, Type I & III collagen. Following transplantation of the engineered tendon-like tissue in nude mice for 8 and 12 weeks, neo-tendon tissues were formed, with thin and parallel collagen fibrils and extracellular matrices of Tenomodulin, Type I & III collagen. Finally in the rat patellar tendon window injury model, data suggested that the engineered tendon-like tissue could promote tendon healing with significantly improved histological features and biomechanical properties comparing to the control group.;In conclusion, our study has indicated that TDSCs can be an alternative cell source in tendon tissue engineering for tendon regeneration. The tenogenic differentiation of TDSCs, induced by CTGF and ascorbic acid in vitro, produces cell sheets, which can be constructed tendon-like tissues in vitro; to form neo-tendon and repair tendon injuries in vivo. The use of engineered scaffold-free tendon tissue for tendon tissue engineering has potentials in clinical application for tendon repair/regeneration.
机译：肌腱损伤很常见，肌腱的愈合效果很差，因为肌腱中的细胞很少，自我修复/再生的能力有限。目前对肌腱损伤的治疗包括药物，理疗和手术尚不理想，因此需要开发新的组织工程策略来修复肌腱。;先前的研究表明，骨髓间充质干细胞具有积极的作用（ BMSC），真皮成纤维细胞，肌腱细胞和源自胚胎干细胞的MSC用于肌腱修复/再生。然而，这些细胞具有局限性，包括分化不足。最近，已经从人，小鼠，大鼠和兔子的肌腱中分离出干细胞，并被认为是肌腱组织工程（TDSC）的新的替代细胞来源。对于MSC的腱变性，据报道结缔组织生长因子（CTGF）和抗坏血酸（一种维生素C形式）在促进胶原蛋白和其他细胞外基质（ECM）的产生，以及调节MSC向腱途径的分化中起重要作用。 ；本研究的目的是：（1）研究TDSCs在大鼠急性pa骨腱损伤模型中的肌腱修复中的应用； （2）检测CTGF和抗坏血酸对TDSCs体外成肌分化的影响； （3）利用肌源性分化的TDSCs体外构建无支架的肌腱样组织； （4）通过工程化的肌腱样组织促进大鼠急性pa腱损伤模型中的肌腱愈合。在大鼠急性pa腱损伤模型中，与对照组相比，TDSCs治疗组的胶原纤维排列更好，胶原纤维明显。更高的极限应力和杨氏模量，表明TDSC可能是肌腱修复的替代细胞来源。肌腱相关标志物如Tenomodulin，Scleraxis，Thbs4，I型胶原蛋白等的高表达也证实了CTGF和抗坏血酸对TDSCs的肌腱分化的影响。具有更高的胶原蛋白产量。用CTGF和抗坏血酸处理2周后，TDSC可以形成细胞片，可以将其收集起来，在U形弹簧上卷起，形成培养物中的肌腱样组织，其细胞外基质松散，TDSC随机分布，并且表达Tenomodulin，I型和III型胶原。在裸鼠中将工程化的肌腱样组织移植8周和12周后，形成了新的肌腱组织，其中有薄而平行的胶原纤维和Tenomodulin，I和III型胶原的细胞外基质。最后，在大鼠pa肌腱窗损伤模型中，数据表明，与对照组相比，工程化的肌腱样组织可以促进肌腱愈合，并具有明显改善的组织学特征和生物力学特性。肌腱组织工程中用于肌腱再生的替代细胞源。 CTGF和抗坏血酸在体外诱导的TDSCs的肌腱分化产生细胞片，可以在体外构建肌腱样组织。在体内形成新肌腱并修复肌腱损伤。将无工程改造的无支架肌腱组织用于肌腱组织工程在肌腱修复/再生的临床应用中具有潜力。

著录项

  • 作者

    Ni, Ming.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Health Sciences Medicine and Surgery.;Biology Cell.;Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 154 p.
  • 总页数 154
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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