干细胞治疗糖尿病下肢动脉病变

一、糖尿病下肢动脉病变的危害 下肢动脉病变(peripheral arterial disease,PAD)是周围动脉病变的一个组成部分,是全身动脉粥样硬化的局部临床表现.动脉内膜粥样斑块形成后可逐渐向血管腔内发展,使管腔变窄甚至闭塞,也可因为斑块内出血或局部血栓形成导致血流中断[1].与非糖尿病患者比较,糖尿病患者PAD更易累及股深动脉及胫前动脉等中小动脉[2].PAD在普通人群中的患病率为3%～10%,且随着年龄的增长而增加.据报道,超过15%的60岁以上老年人罹患PAD[3].同时,由于导致PAD的相关危险因素(如人口老龄化、糖尿病、肥胖和高血压等)在持续增加,预计PAD患病率在将来会进一步增加.     

Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells

OBJECTIVE: Interferon-gamma (IFN-gamma), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN-gamma in GAD. METHODS: Wild-type (WT), IFN-gamma-/-, or recombination-activating-gene-1-/- (RAG-1-/-; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN-gamma expression by infiltrating cells. RESULTS: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-gamma expression by both infiltrating T cells and macrophages. No GAD developed in IFN-gamma-/- or in RAG-1-/- hosts, nor was any IFN-gamma expression evident. RAG-1-/- hosts receiving na?ve WT or IFN-gamma-/- T cells (10(7)) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1-/- recipients yielded GAD, with associated IFN-gamma expression by the transferred T cells and the host macrophages. Transfer of IFN-gamma-/- T cells induced neither GAD nor host macrophage IFN-gamma expression. CONCLUSIONS: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-gamma plays a critical role in GAD pathogenesis.     

The role of chemokines in transplant graft arterial disease

Despite the development of effective immunosuppressive therapy, transplant graft arterial disease (GAD) remains the major limitation to long-term graft survival. Multiple immune and nonimmune risk factors contribute to this vasculopathic intimal hyperplastic process. Thus, initial interplay between host inflammatory cells and donor endothelial cells triggers alloimmune responses, whereas alloantigen-independent factors such as prolonged ischemia, surgical manipulation, ischemia-reperfusion injury, and hyperlipidemia enhance the antigen-dependent events. Intrinsic to all stages of this process are chemokines, a family of 8- to 10-kDa proteins mediating directional migration of immune cells to sites of inflammation and injury. Beyond their role in immune-cell chemotaxis, chemokines also contribute to cellular activation, vascular remodeling, and angiogenesis. Expression of chemokines and their cognate receptors in allografts correlates with acute organ rejection, as well as GAD. Moreover, chemokine or chemokine receptor blockade prolongs graft survival and attenuates GAD in experimental models. Further studies will likely confirm a substantial utility for antichemokine therapy in human organ transplantation.     

Stem cells in cardiovascular disease: from cell biology to clinical therapy

Human life begins as a single fertilized cell. As adult human beings we are profoundly complex. This journey from single cell to complex being is attributable to the role of stem cells (i.e. cells that produce all the different types of cells and tissues that make up the human body). Recent interest has focused on the development of stem cells as a therapeutic option in the treatment of disease. Due to their ability both to replace and/or repair damaged tissue, stem cell therapy provides an ideal means to improve therapy for cardiac disorders associated with heart muscle injury. In particular, pre-clinical studies in animal models of acute myocardial infarction have shown great promise for both repairing damaged cardiac muscle and generating new blood vessel formation in the infarcted area. Stem-cell research therefore holds great therapeutic potential and is relevant, not only to basic science researchers, but also to clinicians (who may need to consider such cell-based therapy in the future) and to their patients.     

Stem cells for lung disease

Respiratory diseases remain one of the main causes of morbidity and mortality in the world. Interest has increased as to the possibility of optimizing the repair of the lung with the manipulation of stem cells. Embryonic and adult stem cells have been suggested as possibilities. Adult stem cells have traditionally been thought of as having limited differentiation ability and to be organ specific. However, a series of exciting reports over the last 5 to 10 years have suggested that adult bone marrow-derived stem cells may have more plasticity and are able to differentiate into bronchial and alveolar epithelium, vascular endothelium, and interstitial cell types, making them prime candidates for repair. This article critically reviews the evidence for this plasticity and the use of predominantly adult stem cells to help with lung regeneration and repair and assesses how this technology may be utilized in clinical medicine.     

自体干细胞治疗缺血性心脏病临床研究

干细胞具有自我更新、自我复制的多向分化潜能使其成为治疗缺血性心脏病的研究热点.而自体干细胞移植不涉及伦理学问题,不存在免疫排斥反应,细胞易获得,已在临床应用并获得了一定疗效.     

Stem cell therapy in ischemic heart disease

Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be addressed. To name a few: 1) Which patient population should be considered for stem cell therapy? 2) What type of stem cell should be used? 3) What is the best route for cell delivery? 4) What is the optimum number of cells that should be used to achieve functional effects? 5) Is stem cell therapy safer and more effective than conventional therapies? The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of ischemia, species of donors and recipients, techniques of cell delivery, cell types, cell numbers and timing of the experiments have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseases in the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Non‐ischemic cardiomyopathy, peripheral vascular disease, and aging may be treated by stem cells. Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with pharmacological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.     

Stem cell therapy for vascular disease

Endothelial dysfunction/loss is a key event in the development of vascular diseases, including native atherosclerosis, angioplasty-induced restenosis, transplant arteriosclerosis, and vein bypass graft atherosclerosis. In challenge to the traditional concept that lost endothelial cells were replaced by neighboring endothelial replication, recent studies have shown that stem cells in blood and the vessel wall have the ability to repair endothelial cells after extensive loss. Concomitantly, accumulating data indicate that stem cell therapy is a promising option for the treatment of vascular diseases and might, in the future, contribute to tissue regeneration, that is, the restoration of endothelium lining the arteries to recover the function of the vascular system. In the present review, we will focus on the progress of stem cell therapy, discuss the mechanisms of stem cell differentiation into endothelial cells, and point out the clinical potential of stem cell therapy in the future.     

Stem cell transplantation for Crohn's disease

There is much interest in the possibility that haematopoietic stem cell transplantation might benefit patients with inflammatory bowel disease, with an emphasis on Crohn's disease. Case reports of patients with Crohn's disease undergoing stem cell transplantation for other reasons, or specifically for Crohn's disease, support the view that major improvements can be achieved, with even the possibility of a cure in a small number of, but certainly not all, cases. The development of Crohn's disease in a previously normal patient receiving an allogeneic transplant from an individual with the NOD2 mutation illustrates the importance of the genotype of the immune system. Population of the lamina propria by myofibroblasts with the donor's phenotype shows that non-immune mechanisms make also play a part. A clinical trial to determine the value of stem cell transplantation in Crohn's disease has been set up under the supervision of the European Group for Blood and Marrow Transplantation.     

Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions

Smooth muscle cell (SMC) accumulation in the inner layer of the vessel wall is a key event in the pathogenesis of atherosclerosis in vein grafts, but the origin of the cells in these lesions has yet to be shown. Herein, we use animal models of vein grafts in transgenic mice to clearly identify the sources of SMCs in atherosclerosis. Vena cava segments were isografted to carotid arteries between four types of transgenic mice, including SM-LacZ expressing beta-galactosidase (beta-gal) in vascular SMCs, SM-LacZ/apoE(-/-), ROSA26 expressing beta-gal in all tissues, and wild-type mice. beta-gal-positive cells were observed in neointimal and atherosclerotic lesions of all vein segments grafted between LacZ transgenic and wild-type mice. Double staining for beta-gal and cell nuclei revealed that about 40% of SMCs originated from hosts and 60% from the donor vessel. This was confirmed by double labeling of the Y-chromosome and alpha-actin in the lesions of sex-mismatched vein grafts. The possibility that bone marrow cells were the source of SMCs in grafts was eliminated by the absence of beta-gal staining in atherosclerotic lesions of chimeric mice. Furthermore, vein SMCs of SM-LacZ mice did not express beta-gal in situ, but did so when these cells appeared in atherosclerotic lesions in vivo, suggesting that hemodynamic forces may be crucial for SMC differentiation. Thus, we provide the first evidence of SMC origins in the atherosclerotic lesions of vein grafts, which will be essential for providing insight into new types of therapy for the disease. The full text of this article is available at http://www.circresaha.org.     

Stem cells and kidney disease.

Functional recovery in acute renal failure is well known, and the adult kidney is generally recognized to have the capacity to regenerate and repair. Several groups have reported the contribution of bone marrow-derived cells in this process, and others have confirmed the existence of adult stem cells in the kidney, including slow-cycling cells, side population cells, CD133+ cells and rKS56 cells. However, recent data demonstrated that in vivo differentiation of bone marrow-derived cells into renal tubular cells may not occur at all, or is at most a minor component of the repair process. Moreover, it is now generally accepted that stem cells and multipotent cells contribute to the regenerative process by producing protective and regenerative factors rather than by directly differentiating to replace damaged cells. Therefore, for clinical regenerative medicine in kidney disease, the focus of stem cell biology will shift from multiple differentiation of cells or cell-therapy to multiple functions of the cells, such as the production of bone morphologic protein-7 and other regenerative factors.     

Increased intimal hyperplasia in experimental vein graft stenting compared to arterial stenting: comparisons in a new rabbit model of stent injury

BACKGROUND: In-stent restenosis due to intimal hyperplasia is an important clinical problem. Animal models of stent injury are limited by inconsistent arterial responses to stenting, and less intimal hyperplasia than diseased human vessels. To address these issues, we aimed to compare the degree of intimal hyperplasia in stented rabbit jugular-carotid interposition grafts (vein grafts) versus stented carotid arteries. METHODS: Jugular-carotid vein grafts were constructed in rabbits, then stented or left unstented. Carotid arteries were treated with similar stents or left instrumented only. After 3 or 28 days, vessels were perfusion fixed, embedded in resin, and sections were cut with a diamond saw. Intimal and medial thicknesses were measured in stained sections. RESULTS: After 3 days, inflammatory changes were observed in the intima of all stented vessels. After 28 days, intimal thickness in stented vein grafts was 2-fold greater than in control vein grafts and approximately 4-fold greater than in stented carotid arteries. In addition, the intimal hyperplasia response was markedly more consistent in stented vein grafts compared with stented carotid arteries. CONCLUSIONS: Stent deployment in experimental vein grafts results in increased and more reproducible smooth muscle cell intimal hyperplasia than carotid arterial stenting. This is a promising small-animal model for investigating the intimal response to stenting.     

Stem cell differentiation and human liver disease

Human stem cells are scalable cell populations capable of cellular differentiation. This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells. Such an approach has the potential to improve our understanding of human biology and treating disease. In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases. In recent years, efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own. In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.