• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Soluble and microenvironmental factors that modulate myofibroblastic and calcific differentiation of valvular interstitial cells.
【24h】

Soluble and microenvironmental factors that modulate myofibroblastic and calcific differentiation of valvular interstitial cells.

机译：可溶性和微环境因素调节成纤维细胞和钙化的瓣膜间质细胞分化。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Calcific aortic stenosis is the cause of significant morbidity and mortality in the United States. Each year roughly 70,000 people undergo total valve replacement as a result of this disease 1, 2. In spite of this fact, valvular interstitial cells (VICs), the main cell-type of the cardiac leaflet, remain relatively understudied. This heterogeneous population of cells which include fibroblasts, myofibroblasts, and osteoblastic cells, plays an important role in the homeostasis of valve tissue 3-5. This thesis focuses on engineering instructive microenvironments that promote healthy myofibroblastic differentiation or pathological osteoblastic differentiation of VICs using controllable cues. The study of the interplay between myofibroblastic and calcific differentiation of VICs in simplified and controlled microenvironments is critical in developing more complex models of disease evolution and healthy tissue engineered valve substitutes. The overall goal of this thesis research was to study what factors are important in the design of controlled cellular microenvironments that regulate VIC dynamic differentiation between myofibroblastic and pathological osteoblastic phenotypes. First, the influence of exogenously delivered soluble factors, TGF-beta1 and statins, on myofibroblast and calcific differentiation was examined and found to be dependent on the presence and contractility of the myofibroblast marker, alpha smooth muscle actin (alphaSMA) 6. Secondly, the role of culture environment and mechanics, notably substrate stiffness, on VIC differentiation was investigated. Stiffer substrates were identified to be myofibroblast and osteoblastic promoting surfaces while softer substrates limited VIC activity 7. In addition to stiffness, the influence of matrix protein on VIC calcific differentiation was studied. Fibronectin, a ubiquitous extracellular matrix (ECM) protein, was shown to limit VIC calcification while fibrin, a wound healing protein structure accelerated VIC calcification 8. Lastly VIC myofibroblast differentiation was studied in two novel 3D hydrogel platforms based on both proteinaceous gelatin 9 and synthetic (poly (ethylene glycol)) photopolymerized hydrogels 10. In both cases VICs achieved spread morphology and differentiated in response to TGF-beta1. This research provides valuable information for those interested in valvular regenerative medicine and tissue engineering for regulating VIC myofibroblast differentiation, as well as those interested in studying VIC pathobiology and the evolution of valvular disease.;1. Mohler, E.R., et al., Bone formation and inflammation in cardiac valves. Circulation, 103, 1522-1528. (2001). 2. Shavelle, D.M., Otto, C.M., Cardiology - Chap. 9 Aortic Stenosis. 2 ed. H.C. Crawford, DiMarco, J.P., Paulus W.J. 2004: Harcourt International. 1660. 3. Filip, D.A., A. Radu, and M. Simionescu, Interstitial-Cells of the Heart-Valves Possess Characteristics Similar to Smooth-Muscle Cells. Circulation Research, 59, 310-320. (1986). 4. Messier, R.H., et al., Dual Structural and Functional Phenotypes of the Porcine Aortic-Valve Interstitial Population - Characteristics of the Leaflet Myofibroblast. Journal of Surgical Research, 57, 1-21. (1994). 5. Mohler, E.R., et al., Identification and characterization of calcifying valve cells from human and canine aortic valves. Journal Of Heart Valve Disease, 8, 254-260. (1999). 6. Benton, J.A., et al., Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth mucle actin expression. Arteriosclerosis, Thrombosis, and Vascular Biology, In Review. (2009). 7. Kloxin, A.M., J.A. Benton, and K.S. Anseth, In situ elasticity modulation with dynamic substrates directs cell phenotype. Proceedings Of The National Academy Of Sciences Of The United States Of America, In Review. (2009). 8. Benton, J.A., H.B. Kern, and K.S. Anseth, Substrate Properties Influence Calcification in Valvular Interstitial Cell Culture. Journal Of Heart Valve Disease, 17, 689-699. (2008). 9. Benton, J.A., et al., Photocrosslinking of gelatin macromers to synthesize porous hydrogels that promote valvular interstitial cell function. Tissue Engineering, In Press. (2009). 10. Benton, J.A., B.D. Fairbanks, and K.S. Anseth, Characterization of Valvular Interstitial Cell Function in Three Dimensional Matrix Metalloproteinase Degradable PEG Hydrogels. Biomaterials, In Review. (2009).
机译：在美国，钙化的主动脉瓣狭窄是引起大量发病和死亡的原因。由于这种疾病1、2，每年约有70,000人进行全瓣置换。尽管如此，瓣膜间质细胞（VIC）是心脏小叶的主要细胞类型，仍处于研究相对不足的状态。包括成纤维细胞，成肌纤维细胞和成骨细胞的细胞的这种异质群体在瓣膜组织3-5的稳态中起重要作用。本论文的重点是工程学指导性微环境，可通过可控线索促进健康的肌成纤维细胞分化或病理性成骨细胞分化。在简化和受控的微环境中研究VICs的肌纤维母细胞和钙化分化之间的相互作用对于开发更复杂的疾病演化模型和健康的组织工程瓣膜替代物至关重要。本研究的总体目标是研究哪些因素在设计可调控的细胞微环境中发挥重要作用，这些环境可调节肌成纤维细胞和病理性成骨细胞表型之间的VIC动态分化。首先，检查了外源递送的可溶性因子TGF-β1和他汀类药物对成肌纤维细胞和钙化分化的影响，发现这取决于成肌纤维细胞标志物α平滑肌肌动蛋白（alphaSMA）6的存在和收缩。研究了培养环境和力学（尤其是底物刚度）对VIC分化的作用。较坚硬的底物被确定为成肌纤维细胞和成骨细胞的促进表面，而较软的底物则限制了VIC的活性7。除了硬度，还研究了基质蛋白对VIC钙化分化的影响。纤连蛋白是一种普遍存在的细胞外基质（ECM）蛋白，可限制VIC钙化，而伤口愈合蛋白结构的纤维蛋白可加速VIC钙化8。最后，在两种基于蛋白质明胶9和合成蛋白的新型3D水凝胶平台中研究了VIC肌成纤维细胞分化（聚（乙二醇））光聚合水凝胶10.在两种情况下，VIC均实现了扩散形态并响应TGF-beta1而分化。这项研究为那些对调节VIC成肌纤维细胞分化的瓣膜再生医学和组织工程感兴趣的人，以及对研究VIC病理生物学和瓣膜疾病的发展感兴趣的人提供了有价值的信息。 Mohler，E.R.等人，心脏瓣膜的骨形成和炎症。循环，103，1522-1528。 （2001）。 2. Shavelle，D.M.，Otto，C.M。，心脏病学-第一章。 9主动脉瓣狭窄。 2版。 H.C. Crawford，DiMarco，J.P.，Paulus W.J. 2004：Harcourt International。 1660. 3. Filip，D.A.，A。Radu和M. Simionescu，心脏的间质细胞具有类似于平滑肌细胞的特征。循环研究，59，310-320。 （1986）。 4.Messier，R.H。等，猪主动脉瓣间质群体的双重结构和功能表型-小叶成肌纤维细胞的特征。外科研究杂志，57，1-21。 （1994）。 5.Mohler，E.R。等，人和犬主动脉瓣的钙化瓣膜细胞的鉴定和表征。心脏瓣膜疾病杂志，8，254-260。 （1999）。 6.Benton，J.A。等人，他汀类药物通过抑制α-平滑肌肌动蛋白的表达来阻断瓣膜间质细胞的钙化结节形成。动脉硬化，血栓形成和血管生物学综述。 （2009）。 7. Kloxin，A.M.，J.A.本顿和K.S. Anseth，动态底物的原位弹性调节指导细胞表型。美利坚合众国国家科学院院刊，评论。 （2009）。 8.本顿（J.A。），H.B。 Kern和K.S. Anseth，底物特性影响瓣膜间质细胞培养中的钙化。心脏瓣膜疾病杂志，17，689-699。 （2008）。 9.Benton，J.A。等人，明胶大分子的光交联以合成促进瓣膜间质细胞功能的多孔水凝胶。组织工程，印刷中。 （2009）。 10.本顿（B.D.）费尔班克斯和K.S. Anseth，三维基质金属蛋白酶可降解PEG水凝胶中瓣膜间质细胞功能的表征。生物材料，正在审查中。 （2009）。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号