Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Annexin A1 in the nervous and ocular systems

The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving effects of Annexin A1 are characteristic of pathologies involving the nervous system.In this review,we initially describe the expression sites of Annexin A1,then outline the mechanisms by which Annexin A1 maintains the neurological homeostasis through either formyl peptide receptor 2 or other molecular approaches;and,finally,we discuss the neuroregenerative potential qualities of Annexin A1.The eye and the nervous system are anatomically and functionally connected,but the association between visual system pathogenesis,especially in the retina,and Annexin A1 alterations has not been well summarized.Therefore,we explain the beneficial effects of Annexin A1 for ocular diseases,especially for retinal diseases and glaucoma on the basis of published findings,and we explore present and future delivery strategies for Annexin A1 to the retina.

缺血性脑卒中引发兴奋性氨基酸毒性激活RhoA通路抑制神经再生的机制研究

谷氨酸作为一种神经递质,在中枢神经系统信号传递中起着重要作用。缺血性脑卒中引起大量神经递质释放可造成兴奋性氨基酸毒性,神经元持续性去极化造成细胞骨架破坏,引起各项神经功能障碍。中枢神经受损后会分泌大量神经再生抑制分子激活RhoA蛋白通路,导致生长锥塌陷,抑制神经突起再生。干预生长锥塌陷途径,减轻兴奋性氨基酸毒性造成的神经突起损伤和促进神经突起再生成为当今研究热点。文章对谷氨酸损伤神经突起机制及促进神经突起再生机制展开深入讨论。

Acupuncture and neuroregeneration in ischemic stroke

Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke.Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate electroacupuncture parameters generates neuroprotective and neuroregenerative effects that increase cerebral blood flow,regulate oxidative stress,attenuate glutamate excitotoxicity,maintain bloodbrain barrier integrity,inhibit apoptosis,increase growth factor production,and induce cerebral ischemic tolerance.

Neuroregeneration and plasticity: a review of the physiological mechanisms for achieving functional recovery postinjury

Neuronal networks,especially those in the central nervous system(CNS),evolved to support extensive functional capabilities while ensuring stability.Several physiological"brakes"that maintain the stability of the neuronal networks in a healthy state quickly become a hinderance postinjury.These"brakes"include inhibition from the extracellular environment,intrinsic factors of neurons and the control of neuronal plasticity.There are distinct differences between the neuronal networks in the peripheral nervous system(PNS)and the CNS.Underpinning these differences is the trade-off between reduced functional capabilities with increased adaptability through the formation of new connections and new neurons.The PNS has"facilitators"that stimulate neuroregeneration and plasticity,while the CNS has"brakes"that limit them.By studying how these"facilitators"and"brakes"work and identifying the key processes and molecules involved,we can attempt to apply these theories to the neuronal networks of the CNS to increase its adaptability.The difference in adaptability between the CNS and PNS leads to a difference in neuroregenerative properties and plasticity.Plasticity ensures quick functional recovery of abilities in the short and medium term.Neuroregeneration involves synthesizing new neurons and connections,providing extra resources in the long term to replace those damaged by the injury,and achieving a lasting functional recovery.Therefore,by understanding the factors that affect neuroregeneration and plasticity,we can combine their advantages and develop rehabilitation techniques.Rehabilitation training methods,coordinated with pharmacological interventions and/or electrical stimulation,contributes to a precise,holistic treatment plan that achieves functional recovery from nervous system injuries.Furthermore,these techniques are not limited to limb movement,as other functions lost as a result of brain injury,such as speech,can also be recovered with an appropriate training program.

The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration: new pharmacological concepts for old and new drugs

Neurotrophins：Neurotrophins are peptides or proteins that are known to regulate neuronal viability,development,and function Beyond synaptic plasticity,neurotrophins protect neurons from apoptosis and also promote neurogenesis to recover neuronal defici even in adulthood.

Purinergic signalling in neuroregeneration

Purinergic signalling,adenosine 5′-triphosphate（ATP）as an extracellular signalling molecule,was proposed in 1972（Burnstock,1972）.However,it was not generally accepted until the early 1990s when receptors for ATP and its breakdown product adenosine were cloned and characterised（Ralevic and Burnstock,1998）.Four P1（adenosine）receptors are recognised（A1,A2A,A2B and A3）.

SNARE complex in axonal guidance and neuroregeneration

Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor （NSF） Attachment Protein Receptor （SNARE） proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.

Neuroregeneration using in vivo cellular reprogramming

Cellular reprogramming is an innovative technology used to artificlally convert a mature cell type into a different cell type by molecular＇manipulation. The general concept of cellular reprogramming is to use master transcription factors to override the endogenous transcriptome profile of a given cell type with the transcriptome profile of the target cell type, thereby altering the cellular function and identity.

eural Regeneration Research-- An interesting SCI-indexed journal in neuroregeneration

Neural Regeneration Research （NRR） is an international academic journal specialized in the field of neural regeneration research and published in English. The journal is supervised by the Ministry of Health, P.R. China, sponsored by the Chinese Association of Rehabilitation Medicine, and co-edited by the Editorial Department of Neural Regeneration Research and China Science Press.

Neural Regeneration Research--An interesting SCI-indexed journal in neuroregeneration

Neural Regeneration Research （NRR） is an international academic journal specialized in the field of neural regeneration research and published in English. The journal is supervised by the Ministry of Health, P.R. China, sponsored by the Chinese Association of Rehabilitation Medicine, and co-edited by the Editorial Department of Neural Regeneration Research and China Science Press.

Neuroregeneration in the visual cortex

Totally three articles focusing on “the expression of Nogo-A, Nogo receptor and NADPH-diaphorase in the developing rat visual cortex and the effects of levodopa methyl ester on nerve growth factor expression in visual cortex area 17 in strabismic amblyopia” are published in three issues. We hope that our readers find these papers useful to their research.

Editor's Choice——Experimental autoimmune encephalomyelitis and neuroregeneration

An experimental autolmmune encephalomyelitis model can be used to mimic pathological changes of multiple sclerosis from different angles. During the acute phase of experimental autolmmune encephalomyelitis, CD4＋ T-cells in the central nervous system infiltrate, proliferate, release large amounts of pro-inflammatory cytokines, and activate the inflammatory cascade, which ultimately leads to

How does zebrafish support new strategies for neuroprotection and neuroregeneration in hypoxia-related diseases?

Hypoxia is a condition found commonly in several disorders,such as ischemia,asthma,anemia and neonatal hypoxia.Individuals subjected suddenly to high altitude or extreme exercise are also challenged to low oxygen（O2）levels.Since the brain presents elevated basal O_2 consumption,this organ is readily affected by hypoxia.For this reason,

Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration

In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.

A benchtop brain injury model using resected donor tissue from patients with Chiari malformation

The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3 D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation(cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this ‘proof-of-concept’ study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.

运动干预诱导缺血性脑卒中后神经再生的机制

缺血性脑卒中(IS)具有高发病率、高致残率以及高病死率的特点,是当前脑血管疾病防治的难点,也是全球范围内重点关注的健康卫生问题。IS发生后,为了应对缺血、缺氧刺激诱发的脑梗死区神经元的输入丢失,机体会自发地启动自我修复机制,重组脑内神经元功能连接和神经通路。然而,神经功能的完全恢复仅仅依靠机体所具备的这种自我修复和功能重建是远远不够的,仍然需要通过有效的临床治疗手段最大化激发和强化这种能力。因此,探索一种能够有效促进神经元重塑、再生,改善神经元损伤诱导的功能障碍的治疗方法是防治IS的核心问题和首要研究方向。目前,运动干预作为临床应用可行性高、患者接受度高的康复治疗技术,已纳入到多种疾病的康复治疗计划中,是有效防治脑血管疾病的补充和替代疗法。本研究综述运动干预对IS后神经再生的调控机制,以期为运动防治IS提供理论基础。运动干预是以中枢神经系统可塑性为基础,可通过多层次、多途径、多靶向发挥脑神经保护作用,包括调控突触芽生、连接和传递效率,改善再生轴突和靶细胞间的功能联系,促进血管生成,保护神经血管单元完整性,调控相关抑制神经再生因素和诱导多种神经再生相关的神经生长因子表达,促进神经干细胞增殖等,参与调控中枢神经再生环境,改善缺血后受损的神经功能。

Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.

中枢神经系统干细胞研究进展

近年来 ,中枢神经系统干细胞的研究方法和其在临床应用方面的价值日益成为神经干细胞研究的焦点 ,本文对于神经干细胞的发现 ,最新的神经干细胞研究技术以及神经干细胞在中枢神经系统退变性疾病 ,缺血损伤和肿瘤治疗等方面的研究进展作一概述。

神经亲免素配体(NILs)的研究进展

介绍神经亲免素配体在设计、合成、构效关系以及促神经生长和神经保护研究方面的一些进展。