人骨髓间充质干细胞体外向心肌样细胞诱导分化机制的研究

发布时间：2018-05-10 08:17

本文选题：干细胞 + 分化　；参考：《吉林大学》2012年硕士论文

【摘要】：冠心病(coronary heart disease,CHD)是心血管疾病的的一个主要病种，在我国每年导致超过一百万患者死亡。冠状动脉狭窄引起心肌缺血，导致心肌细胞的供氧和供能不足，心肌细胞代谢受阻，不能够支持心脏的正常工作，并引起心绞痛。长期的供氧供能不足导致心肌细胞（Cardiomyocytes,CMs）受损，死亡，数量减少，引起疤痕组织形成，导致心室重构，从而进一步引起心脏功能受损甚至危害生命。传统观念认为心肌细胞是不可再生细胞，一旦发生损害就无法修复，心肌损伤后的心肌细胞如何补充修复是困扰医学界的一个难题。在目前的治疗方案中，，药物治疗确实能够延缓心肌细胞的损伤和死亡，减慢心脏的衰竭，但是药物并不能够从根本上解决问题。目前唯一有效的可行的治疗心脏衰竭的途径是心脏移植，然而，供体心脏的不足和移植后免疫排斥反应严重的限制了心脏移植对解决广大患者的应用。心肌细胞再生可以提供一个当前可行的解决方案，是目前科学家和临床医生们解决包含冠心病等多种心血管疾病的希望与挑战。近些年来，随着细胞治疗技术研究的深入，利用细胞移植的方法来替代补充机体损伤或死亡的细胞来修复受损组织的方法，已经成为当今医学研究领域中的一个重点研究方向。大量研究表明，人骨髓间充质干细胞(human bone marrow mesenchymal stem cells，hBMSCs)具有高度增殖、自我更新能力及多分化潜能,在不同的诱导条件下可分化为各种不同类型的组织细胞。BMSCs可以分化为心肌细胞(cardiomyocytes cell，CMs)，但其机制尚不明了。目前体外骨髓间充质干细胞向心肌细胞诱导分化研究主要限于通过5-Aza（5-氮杂胞苷）对其进行成心肌细胞诱导。虽然通过5-Aza的诱导，hBMSCs可以诱导分化为心肌细胞，但间充质干细胞的可塑性依赖于其所处的微环境，然而体外诱导实验并没有完全模拟冠状动脉狭窄后心肌细胞处于缺血缺氧的微环境，这种微环境的变化引起心肌细胞氧化应激损伤。氧化应激时，细胞活性氧的产生与清除之间的平衡被打破，机体内堆积大量的超氧阴离子、羟自由基和过氧化氢(H_2O_2)等自由基，这些氧自由基能够对人体的正常功能产生很大的危害。近些年来随着研究的逐步深入，世界各地的生物医学领域的科研工作者对与冠心病相关的心肌细胞缺血、心肌细胞氧化应激损伤等复杂的病理生理变化进行了更为深入的科学研究。本实验以体外培养人来源骨髓间充质干细胞（hBMSCs）为对象，探讨5-Aza诱导hBMSCs向心肌细胞分化的机制及氧化应激损伤的hBMSCs分化为心肌细胞的可能性。 H2O2可以模拟局部缺氧、氧化应激的微环境，在这种微环境下研究5-Aza还能否继续诱导hBMSCs向心肌细胞分化。本实验将为hBMSCs修复替代受损心肌等的细胞移植提供实验依据及理论基础,从而为冠心病等心血管疾病的治疗开辟新的方法。
[Abstract]:Coronary heart disease (heart) is one of the major cardiovascular diseases, which causes more than 1 million deaths in China every year. Coronary artery stenosis causes myocardial ischemia, which leads to insufficient oxygen supply and energy supply, blocked metabolism of myocardial cells, and can not support the normal operation of the heart and cause angina pectoris. Long-term lack of oxygen supply leads to the damage of cardiomyocytes-CMs, death, decrease in the number, scar tissue formation, ventricular remodeling, and further damage to heart function and even endanger life. The traditional view is that myocardial cells are non-renewable cells, once damage can not be repaired, how to repair myocardial cells after myocardial injury is a difficult problem in medical field. In the current treatment, drug therapy can delay myocardial cell injury and death, slow down heart failure, but drugs can not solve the problem fundamentally. At present, the only effective and feasible way to treat heart failure is heart transplantation. However, the shortage of donor heart and the post-transplant immune rejection seriously limit the application of heart transplantation to solve patients. Cardiomyocyte regeneration can provide a feasible solution for scientists and clinicians to solve the challenges of cardiovascular diseases including coronary heart disease. In recent years, with the development of cell therapy technology, it has become an important research direction in the field of medical research to replace the method of cell transplantation to repair damaged tissue by replacing the damaged or dead cells. A large number of studies have shown that human bone marrow mesenchymal stem cells hBMSCs have high proliferation, self-renewal and multi-differentiation potential. Under different induction conditions, BMSCs could differentiate into different types of tissue cells. BMSCs could differentiate into cardiomyocytes, but its mechanism was not clear. At present, the study on the differentiation of bone marrow mesenchymal stem cells into cardiomyocytes in vitro is mainly limited to the induction of cardiac myocytes by 5-Azaan5-azacytidine (5-Aza-5-azacytidine). Although hBMSCs can be induced to differentiate into cardiomyocytes by 5-Aza, the plasticity of mesenchymal stem cells depends on their microenvironment. However, in vitro induction experiments did not completely mimic the ischemic and hypoxic microenvironment of myocardial cells after coronary artery stenosis, which resulted in oxidative stress injury of cardiomyocytes. During oxidative stress, the balance between the production and elimination of reactive oxygen species was broken, and a large number of superoxide anions, hydroxyl radicals and H _ S _ 2O _ 2 were accumulated in the body. These oxygen free radicals can do great harm to the normal function of human body. In recent years, with the gradual deepening of research, researchers in the biomedical field around the world have done research on myocardial ischemia related to coronary heart disease. The complex pathophysiological changes of myocardial cells such as oxidative stress injury have been studied more deeply. Human bone marrow mesenchymal stem cells (hBMSCs) were cultured in vitro to investigate the mechanism of hBMSCs differentiation into cardiomyocytes induced by 5-Aza and the possibility of oxidative stress induced hBMSCs differentiation into cardiomyocytes. H2O2 can simulate the microenvironment of hypoxia and oxidative stress in which 5-Aza can continue to induce the differentiation of hBMSCs into cardiomyocytes. This study will provide experimental basis and theoretical basis for hBMSCs repair and replacement of damaged myocardium cells, thus opening up a new method for the treatment of cardiovascular diseases such as coronary heart disease.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R329

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