骨髓间充质干细胞移植调节心肌梗死后炎症反应的研究现状

探讨骨髓间充质干细胞移植调节心肌梗死后免疫炎症反应。急性心肌梗死往往伴随强烈的免疫炎症反应。近来研究表明,骨髓间充质干细胞具有免疫炎症调节作用,移植到体内后可以调节免疫炎症反应,可以延缓心肌梗死后心室重塑。现就心肌梗死后免疫炎症反应及骨髓间充质干细胞移植后调节免疫炎症反应做一简要综述。     

间充质干细胞调控巨噬细胞极化在ALI/ARDS中作用的研究进展

急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是由多种原因引起的一种临床急危重症,发展非常迅速,病死率极高。肺泡巨噬细胞M1/M2免疫失衡参与ALI/ARDS的发生发展。间充质干细胞可通过调控巨噬细胞由促炎性M1型向抗炎性M2型极化,抑制下游炎症反应,促进组织修复和再生,达到治疗ALI/ARDS的目的。因此,深入...     

骨髓间充质干细胞移植对心肌缺血/再灌注大鼠心肌胶原与血管新生的影响

目的通过心肌缺血/再灌注模型观察大鼠骨髓间充质干细胞心肌移植对心肌细胞外胶原、小血管新生和心功能变化的影响,并探讨其机制。方法分离、原代培养Wistar大鼠骨髓间充质干细胞,建立缺血/再灌注动物模型,分为假手术组、心肌梗死 骨髓间充质干细胞移植组、心肌梗死对照组,观察骨髓间充质干细胞移植后动物模型血流动力学指标、心肌梗死面积和心肌细胞形态、心肌间质、血管密度、心室膨展指数、心肌细胞横截面积和心肌胶原变化。结果(1)骨髓间充质干细胞心肌移植可缩小60min缺血/再灌注大鼠28d心肌梗死面积;(2)骨髓间充质干细胞移植可减轻心肌梗死动物左心室重塑,但心功能改善作用不明显;(3)骨髓间充质干细胞移植发挥细胞外基质抑制、促血管生成作用,心肌间质胶原含量、胶原分数下降,心肌毛细血管、小动脉密度增加。结论骨髓间充质干细胞移植可改善心肌梗死后心室重塑、促进血管新生和降低心肌胶原作用。     

间充质干细胞治疗心肌梗死的现状及展望

间充质干细胞存在于骨髓、脂肪等多种成熟组织,易于体外分离培养。很多临床前及临床研究已经证实其可以通过分化为心肌样细胞、促血管生成、旁分泌等作用参与心肌梗死后组织修复,改善心脏功能。间充质干细胞是理想的心肌再生治疗的细胞来源,现就相关领域研究现状及进展做一综述。     

造血干细胞治疗心肌梗死的机制研究进展

造血干细胞(hematopoietic stem cells,HSCs)获取相对容易,应用时无组织相容性问题及伦理争议,在再生医学的研究及应用中具有较大的潜力。研究证明,HSCs具有促进心肌损伤后修复,改善受损心脏功能的作用。心肌梗死后多种细胞因子等生物活性分子及相关信号通路参与HSCs动员、归巢至心脏。同时,研究表明多种机制可能促进HSCs发挥心肌修复作用,如转分化、细胞融合、旁分泌、促进心外膜细胞发生上皮间充质转化等,但其确切机制尚有争议。本文就近年来关于HSCs在心肌梗死后动员及发挥修复作用的机制研究进展作全面概述。     

炎症在梗死心肌损伤与修复中的作用

炎症在心肌梗死后心肌损伤与修复中扮演着重要的角色,其中Ly6C~(Lo)单核细胞、M2巨噬细胞及CC类趋化因子受体2(CCR2)阴性巨噬细胞可能有助于心肌梗死后心肌再生修复。同时,心肌梗死后单核/巨噬细胞释放大量的炎症因子,如白细胞介素-1β(IL-1β)、IL-6、肿瘤坏死因子-α(TNF-α)、IL-10、CCR2等,它们也发挥重要作用。研究已经表明心肌梗死后强烈的炎症反应是造成心肌组织继发性损伤的重要因素,因此通过药物等外界手段抑制心肌梗死后的炎症反应,减轻心脏损伤,保护心肌组织,可能会为心肌梗死后的心肌再生修复提供新的策略。     

缺血性心脏病干细胞治疗的争论热点与最新进展

文章讨论了细胞修复治疗在缺血性心脏病中的应用。介绍了不同类型细胞的心脏修复效应。重点介绍了胚胎干细胞(ESCs)及诱导型多能干细胞(iPS)临床应用障碍,而ESC及iPS源心脏前体细胞,心肌源性干细胞等修复心肌的最新进展。尤其重点描述了来自于人胚外或胚胎中胚层的脐带华通胶源间充质干细胞的细胞生物学特性,如：兼有胚胎干细胞及间充质干细胞标志特征,无伦理道德问题,多向分化而无致肿瘤性,多代增殖保持干性特征,独特的免疫调节功能等,使之WJ MSCs将成为心脏再生医学中最具希望的种子细胞。     

骨髓单个核细胞移植治疗缺血性心脏病临床研究的现状

骨髓单个核细胞(BMMNCs)是由多种细胞组成的混合细胞群,主要包括间充质干细胞、内皮祖细胞和造血干细胞。目前,大量的临床试验都表明自体BMMNCs经冠状动脉或心内膜等途径移植可分化为心肌细胞、内皮细胞和平滑肌细胞,从而修复再生心肌细胞,改善心功能,为缺血性心脏病提供新的治疗途径。本文就目前自体BMMNCs移植治疗缺血性心脏病的临床试验进行综述。     

骨髓间充质干细胞治疗缺血性卒中的机制

近年来研究表明,间充质干细胞可促进缺血性卒中后的神经修复并改善神经功能.作为间充质干细胞的主要来源,骨髓间充质干细胞用于治疗缺血性卒中有着潜在的广阔前景.文章对骨髓间充质干细胞的来源及特点、骨髓间充质干细胞移植治疗缺血性卒中的机制进行了综述.     

脐血间充质干细胞的研究进展

脐血干细胞作为间充质干细胞的一种,具有间充质干细胞的多向分化潜能、免疫调控及自我复制等特点,可以在体内或体外特定的诱导分化脂肪、骨、软骨、肌肉、肌腱、韧带、神经、肝、心肌、内皮等多种组织细胞,连续传代培养和冷冻保存后仍具有多向分化潜能且免疫原性低。     

巨噬细胞在心肌梗死后的作用研究进展

心肌梗死后会在缺血区域引发强烈的炎症反应,各种炎性细胞浸润其中发挥作用。巨噬细胞作为固有免疫反应中重要组成,在心肌损伤后组织修复过程中至关重要。随着心肌梗死的发展,巨噬细胞可以分化成各种亚型,在吞噬凋亡细胞、血管新生、纤维化及瘢痕成熟等各个方面发挥作用。研究巨噬细胞对心肌梗死的影响,有助于探索改善心肌梗死预后及其诊治。本篇综述将围绕心肌梗死后巨噬细胞浸润、极化及功能变化展开讨论。     

组胺与固有免疫细胞分化在冠心病研究中的新认识

冠状动脉粥样硬化性心脏病(CHD)是一种常见的临床慢性心脏疾病。上世纪九十年代提出的动脉粥样硬化(As)"炎症学说",已成为心血管领域的基础和转化医学研究热点之一。炎症与免疫反应在As的炎症微环境形成中发挥了关键的作用,异常的免疫反应促进了As的发生,影响了急性心肌梗死后的心肌损伤和组织修复。组胺(histamine)是一个具有多种生物学活性的小分子化学物质,参与机体多样的生理和病理作用。组胺对固有免疫细胞和适应免疫细胞的分化和功能均有重要的调控作用,参与CHD的发生发展。组胺及其细胞内下游信号分子,成为CHD靶向药物研发的重要参考。     

NK细胞与冠心病的关系

冠心病（CHD）是动脉粥样硬化导致器官病变的最常见类型,也是危害人类健康的常见病,近年来研究表明炎症免疫反应与CHD的发生、发展及心梗后的损伤修复密切相关。NK细胞作为先天性免疫系统的重要组成成分,参与了CHD的发生、发展及缺血后的心肌重塑。本文简要概括了NK细胞与CHD的研究进展,以期为CHD的治疗提供新的思路。     

单核-巨噬细胞与缺血性心脏病:心梗引起心梗？

急性冠脉综合征后发生死亡、再梗及卒中等后续不良事件风险增加是缺血性心脏病的研究热点。单核-巨噬细胞广泛参与动脉粥样硬化斑块形成、破裂及心肌缺血损伤、修复。心肌梗死(MI)后交感神经激活,骨髓和脾脏造血作用增强,导致循环中炎性单核细胞激增,改变斑块中巨噬细胞的表型及供应链,从而加速动脉粥样斑块的发展,可能导致再梗或再缺血的发生。本文将对MI如何通过单核-巨噬细胞途径加重动脉粥样硬化进行综述。     

Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains?

The important contribution of monocytes and macrophages to cardiovascular disease and heart failure pathophysiology has attracted significant attention in the past several years. Moreover, subsets of these cells have been shown to partake in the initiation and exacerbation of several cardiovascular pathologies including atherosclerosis, myocardial infarction, pressure overload, cardiac ischemia and fibrosis. This review focuses on the role of monocytes and macrophages along the continuum to heart failure and the contribution of different cell subsets in promoting or inhibiting cardiac injury or repair. It outlines a primary role for the monocyte/macrophage system as an important regulator of cardiac inflammation and extracellular matrix remodelling in early and late stage heart disease with particular focus on phenotypic plasticity and the inflammatory and fibrotic functions of these cells. It also summarizes evidence from pre-clinical and clinical studies evaluating monocyte type regulation and its functional significance for development of cardiovascular disease and heart failure. Finally, current and prospective therapeutic approaches based on monocyte and macrophage manipulation for the treatment of cardiovascular disease and heart failure are discussed. Based on these data, future work in this fertile research area may aid in identifying potential diagnostic biomarkers and novel therapies for chronic heart failure.     

Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction

Given the established anti-inflammatory properties of mesenchymal stromal cells (MSCs), we investigated their effect on inflammatory cell infiltration of ischemic cardiac tissue and cardiac function. We employed two types of MSCs, human bone marrow-derived (BM) MSCs and human umbilical cord perivascular cells in an experimental acute myocardial infarction (MI) model with the immune-deficient NOD/SCID gamma null mouse. Cells were infused 48 h after induction of MI and mice assessed 24 h later (72 h after MI) for bone marrow (BM), circulating and cardiac tissue-infiltrating monocytes/macrophages. We showed that in the presence of either MSC type, overall macrophage/monocyte levels were reduced, including pro-inflammatory M1-type macrophages, while the proportion of alternatively activated M2-type macrophages was significantly increased in the circulation and heart but not the BM. Moreover, we found decreased expression of IL-1β and IL-6, increased IL-10 expression and fewer apoptotic cardiomyocytes without changes in angiogenesis in the infarct area. Fractional shortening was enhanced 2 weeks after cell infusion but was similar to medium controls 16 weeks after MI. In vitro studies showed that BM MSCs increased the frequency of alternatively activated monocytes/macrophages, in part by MSC-mediated secretion of IL-10. Our data suggest a new mechanism for MSC-mediated enhancement of cardiac function, possibly via an IL-10 mediated switch from infiltration of pro-inflammatory to anti-inflammatory macrophages at the infarct site. Additional studies are warranted confirming the role of IL-10 and augmenting the anti-inflammatory effects of MSCs in cardiac regeneration.     

Challenges in allogeneic mesenchymal stem cell-mediated cardiac repair

Autologous mesenchymal stem cells (MSCs) have been proven safe in phase I and II clinical trials in patients who have suffered a myocardial infarction. However, their potential for proliferation and differentiation decreases with age, which limits their efficacy in elderly patients. Allogeneic MSCs offer several key advantages over autologous MSCs, including a high regenerative potential and availability for clinical use without the delay required for expansion. It was believed that allogeneic MSCs were immune privileged and thus able to escape the recipient's immune system. In several preclinical studies, allogeneic MSCs were successful in regenerating the myocardium, and the transplanted MSCs improved heart function early after implantation. However, the long-term ability of allogeneic MSCs to preserve heart function is limited because of a transition from an immune privileged to an immunogenic phenotype after the cells differentiate. The initial phase I/II clinical study using allogeneic MSCs in patients with acute myocardial infarction was safe, and no side effects were observed. However, the long-term safety and efficacy of allogeneic MSCs remain to be established. In this review, we discuss the challenges of using allogeneic MSCs for cardiac repair and present strategies to prevent the immune rejection of allogeneic MSCs to increase their potential for use in cardiac patients.     

肥大细胞与缺血性心脏病

心脏中存在肥大细胞。在心肌缺血状态下,心脏肥大细胞密度增多并处于功能活跃状态。肥大细胞通过释放细胞因子、炎症介质、蛋白酶等内容物,参与动脉粥样硬化、心肌梗死、充血性心力衰竭等疾病的病理过程。现就当前对肥大细胞与缺血性心脏病关系的相关研究进行综述。     

Ischemia/reperfusion injury: The role of immune cells

Ischemia/reperfusion (I/R) injury is an inflammatory condition that is characterized by innate immunity and an adaptive immune response. This review is focused on the acute inflammatory response in I/R injury, and also the adaptive immunological mechanisms in chronic ischemic disease that lead to increased vulnerability during acute events, in relation to the cell types that have been shown to mediate innate immunity to an adaptive immune response in I/R, specifically myocardial infarction. Novel aspects are also highlighted in respect to the mechanisms within the cardiovascular system and cardiovascular risk factors that may be involved in the inflammatory response accompanying myocardial infarction. Experimental myocardial I/R has suggested that immune cells may mediate reperfusion injury. Specifically, monocytes, macrophages, T-cells, mast cells, platelets and endothelial cells are discussed with reference to the complement cascade, toll-like receptors, cytokines, oxidative stress, renin-angiotensin system, and in reference to the microvascular system in the signaling mechanisms of I/R. Finally, the findings of the data summarized in this review are most important for possible translation into clinical cardiology practice and possible avenues for drug development.     

Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector.

OBJECTIVES: The goal of this study was to modify mesenchymal stem cells (MSCs) cells with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid to enhance the survival of MSCs in acute myocardial infarction (MI) heart. BACKGROUND: Although stem cells are being tested clinically for cardiac repair, graft cells die in the ischemic heart because of the effects of hypoxia/reoxygenation, inflammatory cytokines, and proapoptotic factors. Heme oxygenase-1 is a key component in inhibiting most of these factors. METHODS: Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ plasmids. Cell apoptosis was assayed in vitro after hypoxia-reoxygen treatment. In vivo, 1 x 10(6) of male MSC(HO-1), MSC(LacZ), MSCs, or medium was injected into mouse hearts 1 h after MI (n = 16/group). Cell survival was assessed in a gender-mismatched transplantation model. Apoptosis, left ventricular remodeling, and cardiac function were tested in a gender-matched model. RESULTS: In the ischemic myocardium, the MSC(HO-1) group had greater expression of HO-1 and a 2-fold reduction in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells compared with the MSC(LacZ) group. At seven days after implantation, the survival MSC(HO-1) was five-fold greater than the MSC(LacZ) group; MSC(HO-1) also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts two weeks after MI. CONCLUSIONS: A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.