Oligodendrogenesis from neural stem cells: Perspectives for remyelinating strategies

Mobilization of remyelinating cells spontaneously occurs in the adult brain. These cellular resources are specially active after demyelinating episodes in early phases of multiple sclerosis (MS). Indeed, oligodendrocyte precursor cells (OPCs) actively proliferate, migrate to and repopulate the lesioned areas. Ultimately, efficient remyelination is accomplished when new oligodendrocytes reinvest nude neuronal axons, restoring the normal properties of impulse conduction. As the disease progresses this fundamental process fails. Multiple causes seem to contribute to such transient decline, including the failure of OPCs to differentiate and enwrap the vulnerable neuronal axons. Regenerative medicine for MS has been mainly centered on the recruitment of endogenous self-repair mechanisms, or on transplantation approaches. The latter commonly involves grafting of neural precursor cells (NPCs) or neural stem cells (NSCs), with myelinogenic potential, in the injured areas. Both strategies require further understanding of the biology of oligodendrocyte differentiation and remyelination. Indeed, the success of transplantation largely depends on the pre-commitment of transplanted NPCs or NSCs into oligodendroglial cell type, while the endogenous differentiation of OPCs needs to be boosted in chronic stages of the disease. Thus, much effort has been focused on finding molecular targets that drive oligodendrocytes commitment and development. The present review explores several aspects of remyelination that must be considered in the design of a cell-based therapy for MS, and explores more deeply the challenge of fostering oligodendrogenesis. In this regard, we discuss herein a tool developed in our research group useful to search novel oligodendrogenic factors and to study oligodendrocyte differentiation in a time- and cost-saving manner.     

嗅球切除对成年大鼠侧脑室外侧壁神经生发活动的影响

目的研究成年大鼠嗅球切除后侧脑室外侧壁（SVZ）的形态学变化,探讨嗅球对成年大鼠SVZ神经生发活动的影响。方法建立成年SD雄性大鼠右侧嗅球切除模型,并分别存活2、4、8、12周;利用Nissl染色、多唾液酸神经细胞黏附分子（PSA—NCAM）、GFAP免疫组织化学染色的方法,分别观察成年SD大鼠嗅球切除后存活不同时间两侧SVZ的组织结构和免疫组织化学特征;计数模型动物脑两侧SVZ细胞总数及PSA-NCAM、GFAP免疫阳性细胞数,并进行统计学分析。结果嗅球切除4周后,嗅球切除侧SVZ的细胞总数增加,PSA—NCAM免疫阳性细胞数增加,但GFAP免疫阳性细胞数没有明显变化;SVZ的细胞总数及PSA-NCAM免疫阳性细胞数的增加有从SVZ嘴侧向尾侧蔓延的趋势。结论嗅球切除后在SVZ仍有新生神经元不断产生,说明SVZ的神经生发活动可能并不依赖于嗅球的存在。     

Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone

Abstract: Melatonin, a circadian rhythm–promoting molecule secreted mainly by the pineal gland, has a variety of biological functions and neuroprotective effects including control of sleep–wake cycle, seasonal reproduction, and body temperature as well as preventing neuronal cell death induced by neurotoxic substances. Melatonin also modulates neural stem cell (NSC) function including proliferation and differentiation in embryonic brain tissue. However, the involvement of melatonin in adult neurogenesis is still not clear. Here, we report that precursor cells from adult mouse subventricular zone (SVZ) of the lateral ventricle, the main neurogenic area of the adult brain, express melatonin receptors. In addition, precursor cells derived from this area treated with melatonin exhibited increased proliferative activity. However, when cells were treated with luzindole, a competitive inhibitor of melatonin receptors, or pertussis toxin, an uncoupler of Gi from adenylate cyclase, melatonin‐induced proliferation was reduced. Under these conditions, melatonin induced the differentiation of precursor cells to neuronal cells without an upregulation of the number of glia cells. Because stem cell replacement is thought to play an important therapeutic role in neurodegenerative diseases, melatonin might be beneficial for stimulating endogenous neural stem cells.     

Presence of nerve growth factor and TrkA expression in the SVZ of EAE rats: evidence for a possible functional significance

Nerve growth factor (NGF) is a well-characterized neurotrophic factor that plays a crucial role during development in the growth, differentiation, and maintenance of brain neurons as well as in the reparative response of the adult brain to neuronal damage. Recent studies have shown that acute axonal loss occurs in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), and that NGF suppresses clinical symptoms of EAE in nonhuman primates. Aim of the present study was to investigate the role of NGF in the regenerative response of the adult brain to neuronal damage occurring in EAE. Using EAE rats, we have found that exogenous NGF injection and NGF deprivation (NGF autoimmunization) can act on growth and differentiation of brain precursor cells in the subventricular zone (SVZ) of EAE rats. Moreover, NGF administration in brain of EAE rats stimulates the expression of early neuronal markers on proliferating precursor cells of the SVZ. The data obtained demonstrated that NGF and its antibody affect bromodeoxyuridine (BrdU) incorporation and NGF receptor expression by SVZ progenitor cells in the brain of EAE rats.     

Buyang Huanwu Decoction can improve recovery of neurological function,reduce infarction volume,stimulate neural proliferation and modulate VEGF and Flk1 expressions in transient focal cerebral ischaemic rat brains

Buyang Huanwu Decoction is a classic formula for treating stroke-induced disability in traditional Chinese medicine (TCM). To explore its pharmacological basis, we investigated the effects of the whole formula and its herbal components on the neurological behavior performance and infarction volume in focal cerebral ischaemia rats. The neurological deficit scores and infarction volume were measured at days 3, 7 and 14 after 30 min of occlusion of middle cerebral artery. The results showed that Buyang Huanwu Decoction and its herbal components significantly improved the neurological behavior performances and reduced the infarction volume in the ischaemic brains. To elucidate the potential therapeutic mechanisms, we investigated the proliferation of progenitors by detecting the immunohistochemical staining of thymidine analog 5-bromo-2′-deoxyuridine (BrdU) and found that the formula stimulated the proliferation of the progenitors at hippocampus and subventricular zone (SVZ) in the ischaemic brains. As vascular endothelial growth factor (VEGF) and its receptor fetal liver kinase (Flk1) are important neurotrophic, neuroprotective and neuroproliferative factors, we studied the expressions of VEGF and Flk1 in the hippocampus, SVZ and cortex in the ischaemic brains and found that the formula led to increase the numbers of VEGF-positive and Flk1-positive cells in the SVZ and cortex in the ischaemic brains. The results indicate that the therapeutic effects of Buyang Huanwu Decoction for recovery of neurological deficits are associated with the stimulation of the proliferation of progenitors and the enhancement of the expressions of VEGF and Flk in ischaemic brains.     

The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders

Accumulating laboratory studies have implicated the mobilization of bone marrow (BM)-derived stem cells in brain plasticity and stroke therapy. This mobilization of bone cells to the brain is an essential concept in regenerative medicine. Over the past ten years, mounting data have shown the ability of bone marrow-derived stem cells to mobilize from BM to the peripheral blood (PB) and eventually enter the injured brain. This homing action is exemplified in BM stem cell mobilization following ischemic brain injury. Various BM-derived cells, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and very small embryonic-like cells (VSELs) have been demonstrated to exert therapeutic benefits in stroke. Here, we discuss the current status of these BM-derived stem cells in stroke therapy, with emphasis on possible cellular and molecular mechanisms of action that mediate the cells' beneficial effects in the ischemic brain. When possible, we also discuss the relevance of this therapeutic regimen in other central nervous system (CNS) disorders.     

Modeling premature brain injury and recovery

Premature birth is a growing and significant public health problem because of the large number of infants that survive with neurodevelopmental sequelae from brain injury. Recent advances in neuroimaging have shown that although some neuroanatomical structures are altered, others improve over time. This review outlines recent insights into brain structure and function in these preterm infants at school age and relevant animal models. These animal models have provided scientists with an opportunity to explore in depth the molecular and cellular mechanisms of injury as well as the potential of the brain for recovery. The endogenous potential that the brain has for neurogenesis and gliogenesis, and how environment contributes to recovery, are also outlined. These preclinical models will provide important insights into the genetic and epigenetic mechanisms responsible for variable degrees of injury and recovery, permitting the exploration of targeted therapies to facilitate recovery in the developing preterm brain.     

Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice

The neuropeptide Y (NPY) is widely expressed in the central nervous system and has been shown to stimulate neurogenesis in the hippocampus and the olfactory epithelium. Here, we demonstrate that intracerebroventricular injection of NPY stimulates proliferation of neural precursors in the mice subventricular zone (SVZ), one the most neurogenic areas of the brain. Newly generated neuroblasts migrate through the rostral migratory stream to the olfactory bulb and also directly to the striatum, as evidenced by BrdU labelling and cell phenotyping. Using knock-out mice, specific NPY receptor agonists and antagonists, we report that this neuroproliferative effect is mediated by the Y1 receptor subtype that we found to be highly expressed in the SVZ both at the mRNA and protein levels. Our data suggest that stimulating endogenous SVZ neural stem cells by NPY may be of a potential interest in cell replacement based therapies of neurodegenerative diseases affecting the striatum such as Huntington's disease.     

The ADAMs family: coordinators of nervous system development, plasticity and repair

A disintegrin and metalloprotease (ADAM) transmembrane proteins have metalloprotease, integrin-binding, intracellular signaling and cell adhesion activities. In contrast to other metalloproteases, ADAMs are particularly important for cleavage-dependent activation of proteins such as Notch, amyloid precursor protein (APP) and transforming growth factor alpha (TGFalpha), and can bind integrins. Not surprisingly, ADAMs have been shown or suggested to play important roles in the development of the nervous system, where they regulate proliferation, migration, differentiation and survival of various cells, as well as axonal growth and myelination. On the eleventh anniversary of the naming of this family of proteins, the relatively unknown ADAMs are emerging as potential therapeutic targets for neural repair. For example, over-expression of ADAM10, one of the alpha-secretases for APP, can prevent amyloid formation and hippocampal defects in an Alzheimer mouse model. Another example of this potential neural repair role is the finding that ADAM21 is uniquely associated with neurogenesis and growing axons of the adult brain. This comprehensive review will discuss the growing literature about the roles of ADAMs in the developing and adult nervous system, and their potential roles in neurological disorders. Most excitingly, the expanding understanding of their normal roles suggests that they can be manipulated to promote neural repair in the degenerating and injured adult nervous system.     

Selective serotonin depletion does not regulate hippocampal neurogenesis in the adult rat brain: differential effects of p-chlorophenylalanine and 5,7-dihydroxytryptamine

Serotonin is suggested to regulate adult hippocampal neurogenesis, and previous studies with serotonin depletion reported either a decrease or no change in adult hippocampal progenitor proliferation. We have addressed the effects of serotonin depletion on distinct aspects of adult hippocampal neurogenesis, namely the proliferation, survival and terminal differentiation of hippocampal progenitors. We used the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) to deplete serotonin levels. 5,7-DHT selectively decreased hippocampal serotonin levels, while PCPA resulted in a significant decline in both serotonin and norepinephrine levels. We observed a robust decline in the proliferation and survival of adult hippocampal progenitors following PCPA treatment. This was supported by a decrease in the number of doublecortin-positive cells in the neurogenic niche in the hippocampus. In striking contrast, 5,7-DHT did not alter the proliferation or survival of adult hippocampal progenitors and did not alter the number of doublecortin-positive cells. The terminal differentiation of adult hippocampal progenitors was not altered by either PCPA or 5,7-DHT treatment. An acute increase in serotonin levels also did not influence adult hippocampal progenitor proliferation. These results suggest that selective serotonin depletion or an acute induction in serotonin levels does not regulate adult hippocampal neurogenesis, whereas treatment with PCPA that induces a decline in both serotonin and norepinephrine levels results in a significant decrease in adult hippocampal neurogenesis. Our results highlight the need for future studies to examine the role of other monoamines in both the effects of stress and antidepressants on adult hippocampal neurogenesis.