Dall Christopher, Khan Mahmood, Chen Chun-An, Angelos Mark G
Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Davis Heart Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Life Sci. 2016 May 15;153:124-31. doi: 10.1016/j.lfs.2016.04.011. Epub 2016 Apr 14.
Heart disease represents the leading cause of death among Americans. There is currently no clinical treatment to regenerate viable myocardium following myocardial infarction, and patients may suffer progressive deterioration and decreased myocardial function from the effects of remodeling of the necrotic myocardium. New therapeutic strategies hold promise for patients who suffer from ischemic heart disease by directly addressing the restoration of functional myocardium following death of cardiomyocytes. Therapeutic stem cell transplantation has shown modest benefit in clinical human trials with decreased fibrosis and increased functional myocardium. Moreover, autologous transplantation holds the potential to implement these therapies while avoiding the immunomodulation concerns of heart transplantation. Despite these benefits, stem cell therapy has been characterized by poor survival and low engraftment of injected stem cells. The hypoxic tissue environment of the ischemic/infracting myocardium impedes stem cell survival and engraftment in myocardial tissue. Hypoxic preconditioning has been suggested as a viable strategy to increase hypoxic tolerance of stem cells. A number of in vivo and in vitro studies have demonstrated improved stem cell viability by altering stem cell secretion of protein signals and up-regulation of numerous paracrine signaling pathways that affect inflammatory, survival, and angiogenic signaling pathways. This review will discuss both the mechanisms of hypoxic preconditioning as well as the effects of hypoxic preconditioning in different cell and animal models, examining the pitfalls in current research and the next steps into potentially implementing this methodology in clinical research trials.
心脏病是美国人死亡的主要原因。目前尚无临床治疗方法可在心肌梗死后再生有活力的心肌，患者可能会因坏死心肌重塑的影响而出现病情逐渐恶化和心肌功能下降。新的治疗策略有望为患有缺血性心脏病的患者带来希望，通过直接解决心肌细胞死亡后功能性心肌的恢复问题。治疗性干细胞移植在临床人体试验中已显示出一定益处，可减少纤维化并增加功能性心肌。此外，自体移植有可能实施这些疗法，同时避免心脏移植中的免疫调节问题。尽管有这些益处，但干细胞治疗的特点是注入的干细胞存活率低且植入率低。缺血/梗死心肌的缺氧组织环境阻碍了干细胞在心肌组织中的存活和植入。缺氧预处理被认为是提高干细胞缺氧耐受性的可行策略。许多体内和体外研究表明，通过改变干细胞蛋白质信号的分泌以及上调影响炎症、存活和血管生成信号通路的众多旁分泌信号通路，可以提高干细胞的活力。本综述将讨论缺氧预处理的机制以及缺氧预处理在不同细胞和动物模型中的作用，探讨当前研究中的缺陷以及在临床研究试验中潜在实施该方法的下一步措施。
