脑缺血后运动疗法的神经再生与血管再生机制

缺血性卒中后的病理生理反应很复杂,单纯注重挽救神经元在临床研究中并不能有效达到神经保护作用。神经血管单位中的“血管龛”假说强调神经再生和血管再生之间复杂的相互作用,从而有效修复脑缺血损伤。本综述中主要简述了运动锻炼对缺血性卒中的保护和治疗作用,运动疗法的保护机制包括增加脑灌注、促进神经再生、侧支循环、血管再生等。本综述旨在认识血管再生的重要性,可望其成为缺血性卒中治疗的新途径。     

间充质干细胞治疗缺血性卒中动物实验进展

间充质干细胞具有较低的免疫原性、较强的细胞增殖分化能力,在缺血性卒中的治疗方面显示出巨大潜力。间充质干细胞主要源自骨髓、脂肪和胎盘,具有调节免疫炎症反应、神经保护、促血管生成等作用,常见注射方式为脑内注射、静脉注射和动脉注射等,同时联合缺氧预处理等物理疗法可增强其治疗缺血性卒中的效果。本文综述间充质干细胞治疗缺血性卒中的动物实验进展,从细胞种类、作用机制、注射方式以及增强疗效的物理疗法等角度,阐述间充质干细胞对缺血性卒中的治疗作用,为缺血性卒中的临床治疗提供新的思路。     

激肽释放酶-激肽系统促进脑缺血后血管新生的机制

脑缺血后的神经、血管调节机制较为复杂,其中激肽释放酶一激肽系统起重要作用。它主要通过具有血管活性的激肽与其特异受体结合,影响一系列因子及细胞,发挥扩血管,神经保护,促进局部血管新生和神经再生的作用,从而促进神经功能的改善。本文总结了激肽释放酶一激肽系统促进新血管生成的多种机制,为缺血性卒中的治疗提供新的思     

专题论坛：卒中转化医学

编者按卒中不仅仅损伤神经元,更重要的是对神经血管单元和与此相关的微环境造成破坏,损伤细胞功能和细胞之间的信号传递。以往相关的科研只注重单一的神经元保护研究,现在越来越重视神经血管单元功能的修复和重塑以恢复神经功能的研究。目前,实验性卒中干预方法较多,如应用药物小分子、基因、干细胞以及基于基因的干细胞治疗等,其主要目的是通过促进卒中后神经再生和血管新生以修复     

大脑老化与神经再生和卒中

大脑老化是神经退行性疾病的主要诱因。而卒中不仅是老年人的神经系统常见疾病,而且也是70岁以上老年人致残和死亡的重要原因,因此,大脑老化与卒中发病息息相关。已经证实,老年卒中患者其缺血性脑组织损伤更加严重、脑梗死面积更大、缺血后的神经功能障碍也更加显著。尽管研究已证实老龄大脑的神经再生减少,但卒中可以诱导神经再生并能有效促进神经功能恢复,这就为神经再生治疗卒中开辟了良好的途径。本文重点就大脑老化及老化后神经再生、缺血性卒中作一简要综述。     

缺血性脑损伤和神经再生

脑缺血可诱导中枢神经系统神经细胞再生,脑缺血后神经再生常见于海马和SVZ,可能与缺血性脑损伤后的记忆恢复有关。脑缺血后神经再生与兴奋性氨基酸受体、神经营养因子、5-HT、炎症和凋亡等有关,干细胞移植能改善缺血性脑损伤模型动物的神经损伤症状。     

缺血性卒中后血管新生的细胞和分子调节机制

卒中是由脑供血异常引起的急性神经功能缺损,其中缺血性卒中占60%～80%。脑组织对缺血缺氧十分敏感,卒中后缺血中心区脑细胞迅速大量死亡,及时抢救缺血半暗带区脑细胞可减轻脑损伤,卒中后期血管新生亦在为神经再生和脑组织修复创建良好环境中发挥重要作用,如何调控卒中后血管新生是目前缺血性卒中治疗探索热点之一,而目前其调节机制仍处于研究之中,因此本文就缺血性卒中后     

缺血性脑卒中后微血管形成

缺血性脑卒中的发病率及致残率高,严重危害了人类健康。尽快恢复缺血区的血供,挽救濒死的神经元、神经胶质细胞和神经内皮细胞是治疗缺血性脑卒中的关键。治疗性血管新生为其提供了新思路。有关脑缺血后新血管形成的病理过程、机制及其调控因素已成为研究的热点。本文就缺血性脑卒中后微血管形成及治疗性血管新生的有关问题综述如下。     

内皮祖细胞在缺血性脑血管疾病治疗中的研究进展

近年来,成人外周血中鉴定出一类具有前体内皮细胞特性的细胞,称之为内皮祖细胞(EPC)。对于这种细胞的研究表明其具有干细胞特性,参与了神经再生和再血管化,在脑血管疾病中发挥正性作用,能够帮助缺血性卒中后的神经功能恢复。目前临床治疗缺血性脑血管疾病手段单一且疗效不确切,内皮祖细胞的修复潜力越来越受到关注。本文讨论了目前关于内皮祖细胞特性的研究进展,以及它对于缺血性脑血管疾病的治疗作用及其临床应用前景。     

微小RNA调节缺血诱导的内源性神经再生研究进展

成年哺乳动物的脑内存在神经干细胞,能够被脑缺血等刺激激活,诱导内源性神经再生。微小RNA(miRNA)能够在转录后水平调控蛋白质的表达,参与调节缺血性脑卒中的各个环节,在疾病的病理过程中发挥关键作用。miR-124和miR-9可能是脑缺血诱导的内源性神经再生的核心调控因子,研究miRNA对内源性神经再生的调节作用有助于阐明内源性神经修复机制和发现新的治疗靶点。利用药物或非药物手段调节特异性miRNA增强内源性神经再生可能是中风的有效治疗途径。     

干细胞移植治疗缺血性脑卒中的研究与现状

近年来，随着成年个体神经系统内神经干细胞的发现以及对其研究的不断深入，应用干细胞治疗缺血性脑卒中受到各国学者的广泛关注。大量的实验研究表明，干细胞可从不同程度上改善脑卒中后的神经功能，具有良好的临床应用前景。目前此类研究主要集中于2种途径，其一是利用内源性神经干细胞的激活治疗脑卒中，其二是利用外源性干细胞移植治疗脑卒中。文章就近年来应用各种干细胞治疗缺血性脑卒中的动物及临床实验研究现状进行综述，并对其存在的问题进行了分析和展望。     

Angiogenesis and neuronal remodeling after ischemic stroke

Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models.This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke.Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit.In this mini-review,we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia.Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery.Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery.First,new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling.Second,blood vessels are thought to enhance neurogenesis in three stages:1)Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals,2)microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen,nutrients,and soluble factors as well as serving as a scaffold for migration,and 3)oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons.Thus,the regions of angiogenesis and surrounding tissue may be coupled,representing novel treatment targets.     

Adult neurogenesis and the ischemic forebrain.

The recent identification of endogenous neural stem cells and persistent neuronal production in the adult brain suggests a previously unrecognized capacity for self-repair after brain injury. Neurogenesis not only continues in discrete regions of the adult mammalian brain, but new evidence also suggests that neural progenitors form new neurons that integrate into existing circuitry after certain forms of brain injury in the adult. Experimental stroke in adult rodents and primates increases neurogenesis in the persistent forebrain subventricular and hippocampal dentate gyrus germinative zones. Of greater relevance for regenerative potential, ischemic insults stimulate endogenous neural progenitors to migrate to areas of damage and form neurons in otherwise dormant forebrain regions, such as the neostriatum and hippocampal pyramidal cell layer, of the mature brain. This review summarizes the current understanding of adult neurogenesis and its regulation in vivo, and describes evidence for stroke-induced neurogenesis and neuronal replacement in the adult. Current strategies used to modify endogenous neurogenesis after ischemic brain injury also will be discussed, as well as future research directions with potential for achieving regeneration after stroke and other brain insults.     

Injury‐induced neural stem/progenitor cells in post‐stroke human cerebral cortex

Increasing evidence points to accelerated neurogenesis after stroke, and support of such endogenous neurogenesis has been shown to improve stroke outcome in experimental animal models. The present study analyses post‐stroke cerebral cortex after cardiogenic embolism in autoptic human brain. Induction of nestin‐ and musashi‐1‐positive cells, potential neural stem/progenitor cells, was observed at the site of ischemic lesions from day 1 after stroke. These two cell populations were present at distinct locations and displayed different temporal profiles of marker expression. However, no surviving differentiated mature neural cells were observed by 90 days after stroke in the previously ischemic region. Consistent with recent reports of neurogenesis in the cerebral cortex after induction of stroke in rodent models, the present current data indicate the presence of a regional regenerative response in human cerebral cortex. Furthermore, observations underline the potential importance of supporting survival and differentiation of endogenous neural stem/progenitor cells in post‐stroke human brain.     

Ischemia-induced neural stem/progenitor cells express pyramidal cell markers

Adult brain-derived neural stem cells have acquired a lot of interest as an endurable neuronal cell source that can be used for central nervous system repair in a wide range of neurological disorders such as ischemic stroke. Recently, we identified injury-induced neural stem/progenitor cells in the poststroke murine cerebral cortex. In this study, we show that, after differentiation in vitro, injury-induced neural stem/progenitor cells express pyramidal cell markers Emx1 and CaMKIIα, as well as mature neuron markers MAP2 and Tuj1. 5-bromo-2-deoxyuridinine-positive neurons in the peristroke cortex also express such pyramidal markers. The presence of newly regenerated pyramidal neurons in the poststroke brain might provide a noninvasive therapeutic strategy for stroke treatment with functional recovery.     

Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain

Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2′-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen Neu N, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2′-deoxyuridine-positive ? anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.     

脑梗死后VEGF及bFGF对神经干细胞增殖分化的机制研究进展

缺血性卒中因其发病机制复杂,迄今为止,仍未发现确切有效治疗方法。随着研究深入, 神经干细胞（neural stem cells,NSCs）作为新的研究靶点,为卒中的治疗提供了新的前景。目前脑梗 死后促进内源神经干细胞增殖分化的影响因素众多,但有研究表明碱性成纤维细胞生长因子（basic fibroblast growth factor,bFGF）及血管内皮生长因子（vascular endothelial growth factor,VEGF）对NSCs 的增殖及分化起到了不容忽视的作用。通过研究VEGF和bFGF在脑缺血后NSCs增殖分化中的作用机 制,为临床脑缺血的靶向治疗提供理论基础。     

Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here

This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.     

Adult stem cell therapy in stroke

PURPOSE OF REVIEW: Acute cerebral infarction causes irreversible locally restricted loss of the neuronal circuitry and supporting glial cells with consecutive functional deficits and disabilities. The currently available and effective therapy targets fast vessel recanalization accompanied by symptomatic measures. Research activities focusing on stem cells, which represent a promising source for organotypic cell replacement and functional recovery after stroke, have gained momentum in recent years, making regenerative cell-based therapies a much more feasible realistic approach. This review provides an update about preclinical and clinical cell-based studies in stroke focusing on stem cells derived from the adult central nervous and hematopoetic systems. RECENT FINDINGS: Endogenous neural stem cells, which have been shown to reside throughout life in the central nervous system, have the capacity to replace lost neurons in models for numerous disorders, including cerebral ischemia. Considering adult neural stem cell transplantation as a regenerative strategy after stroke, progress has been made in isolating human adult neural stem cells and demonstrating the feasibility of autologous neural stem cell transplantation. An increasing number of studies provide evidence that hematopoietic stem cells, either after stimulation of endogenous stem cell pools or after exogenous hematopoietic stem cell application (transplantation), improve functional outcome after ischemic brain lesions. Various underlying mechanisms such as transdifferentiation into neural lineages, neuroprotection through trophic support, and cell fusion have been deciphered. SUMMARY: Many preclinical studies employing adult stem cell-based strategies hold great promise. For endogenous approaches the correlate of cell replacement underlying functional improvement needs to be demonstrated. Transplantation approaches on the experimental level need further development before clinical application can be considered.     

Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice

The CNS has the potential to marshal strong reparative mechanisms, including activation of endogenous neurogenesis, after a brain injury such as stroke. However, the response of neural stem/progenitor cells to stroke is poorly understood. Recently, neural stem/progenitor cells have been identified in the cerebral cortex, as well as previously recognized regions such as the subventricular or subgranular zones of the hippocampus, suggesting that a contribution of cortex-derived neural stem/progenitor cells may repair ischemic lesions of the cerebral cortex. In the present study, using a highly reproducible murine model of cortical infarction, we have found nestin-positive cells in the post-stroke cerebral cortex, but not in the non-ischemic cortex. Cells obtained from the ischemic core of the post-stroke cerebral cortex formed neurosphere-like cell clusters expressing nestin; such cells had the capacity for self-renewal and differentiated into electrophysiologically functional neurons, astrocytes and myelin-producing oligodendrocytes. Nestin-positive cells from the stroke-affected cortex migrated into the peri-infarct area and differentiated into glial cells in vivo . Although we could not detect differentiation of nestin-positive cells into neurons in vivo , our current observations indicate that endogenous neural stem/progenitors with the potential to become neurons can develop within post-stroke cerebral cortex.