Myriam Cayre

Neurogenesis in adult insect mushroom bodies.

The occurrence of neurogenesis in mushroom bodies of adult insects belonging to several orthopteroid and coleopteran families is described. Using injections of 5‐bromo, T2′‐deoxy we showed that neuroblasts, which are progenitors of Kenyon cells during preimaginal instars continue to divide in adult Acheta domesticus. Their progeny constitute a central column in mushroom body cortices of 3‐week‐old females. Other Gryllidae, Gryllus bimaculatus and Gryllomorpha dalmatina, show the same pattern of neuroblast activity and migration of their progeny. Immunocytochemical staining of glial cells failed to reveal any immunoreactivity, either in proliferating regions or in the resulting cells.

A2B5 Cells from Human Glioblastoma have Cancer Stem Cell Properties

Glioblastomas, like other cancers, harbor small cell populations with the capability of sustaining tumor formation. These cells are referred to as cancer stem cells. We isolated cells expressing the surface marker A2B5 from three human glioblastomas (GBM) and showed that after grafting into nude mice, they generated dense and highly infiltrative tumors. Then, we extensively studied A2B5+ cells isolated from 11 human GBM. These cells display neurosphere‐like, self‐renewal, asymmetrical cell division properties and have multipotency capability. Stereotactic xenografts of dissociated A2B5+‐derived secondary spheres revealed that as few as 1000 cells produced a tumor. Moreover, flow cytometry characterization of A2B5+‐derived spheres revealed three distinct populations of cells: A2B5+/CD133+, A2B5+/CD133‐ and A2B5‐/CD133‐, with striking proportion differences among GBM. Both A2B5+/CD133+ and A2B5+/CD133‐ cell fractions displayed a high proliferative index, the potential to generate spheres and produced tumors in nude mice. Finally, we generated two green fluorescent protein‐cell lines that display—after serum induction—distinct proliferative and migratory properties, and differ in their CD133 level of expression. Taken together, our results suggest that transformed A2B5+ cells are crucial for the initiation and maintenance of GBM, although CD133 expression is more involved in determining the tumors behavior.

The common properties of neurogenesis in the adult brain: from invertebrates to vertebrates

Until recently, it was believed that adult brains were unable to generate any new neurons. However, it is now commonly known that stem cells remain in the adult central nervous system and that adult vertebrates as well as adult invertebrates are currently adding new neurons in some specialized structures of their central nervous system. In vertebrates, the subventricular zone and the dentate gyrus of the hippocampus are the sites of neuronal precursor proliferation. In some insects, persistent neurogenesis occurs in the mushroom bodies, which are brain structures involved in learning and memory and considered as functional analogues of the hippocampus. In both vertebrates and invertebrates, secondary neurogenesis (including neuroblast proliferation and neuron differentiation) appears to be regulated by hormones, transmitters, growth factors and environmental cues. The functional implications of adult neurogenesis have not yet been clearly demonstrated and comparative study of the various model systems could contribute to better understand this phenomenon. Here, we review and discuss the common characteristics of adult neurogenesis in the various animal models studied so far.

Oligodendrogenesis in the normal and pathological central nervous system

Oligodendrocytes (OLGs) are generated late in development and myelination is thus a tardive event in the brain developmental process. It is however maintained whole life long at lower rate, and myelin sheath is crucial for proper signal transmission and neuronal survival. Unfortunately, OLGs present a high susceptibility to oxidative stress, thus demyelination often takes place secondary to diverse brain lesions or pathologies. OLGs can also be the target of immune attacks, leading to primary demyelination lesions. Following oligodendrocytic death, spontaneous remyelination may occur to a certain extent. In this review, we will mainly focus on the adult brain and on the two main sources of progenitor cells that contribute to oligodendrogenesis: parenchymal oligodendrocyte precursor cells (OPCs) and subventricular zone (SVZ)-derived progenitors. We will shortly come back on the main steps of oligodendrogenesis in the postnatal and adult brain, and summarize the key factors involved in the determination of oligodendrocytic fate. We will then shed light on the main causes of demyelination in the adult brain and present the animal models that have been developed to get insight on the demyelination/remyelination process. Finally, we will synthetize the results of studies searching for factors able to modulate spontaneous myelin repair.

Enriched environment promotes adult neural progenitor cell mobilization in mouse demyelination models

Since the discovery of adult neural stem cells, mobilization of endogenous stem cells from the subventricular zone (SVZ) emerges as a promising strategy to promote brain repair. Here, we examined the effect of environment enrichment on SVZ cell mobilization in demyelinating pathologies. We showed that enriched housing conditions reduced functional impairment in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Furthermore, both in a focal demyelination model (lysolecithine injection) and in the inflammatory EAE model, SVZ mitotic activity and the number of SVZ‐derived cells in demyelinated areas were significantly increased by environment enrichment. Enriched housing conditions also promoted the oligodendrocyte fate of SVZ‐recruited cells in the EAE lesions. Altogether our results show that environment enrichment provides beneficial conditions to promote the mobilization of neural progenitors into demyelinating lesions and to favour functional recovery.

Reelin Controls Progenitor Cell Migration in the Healthy and Pathological Adult Mouse Brain

Understanding the signals that control migration of neural progenitor cells in the adult brain may provide new therapeutic opportunities. Reelin is best known for its role in regulating cell migration during brain development, but we now demonstrate a novel function for reelin in the injured adult brain. First, we show that Reelin is upregulated around lesions. Second, experimentally increasing Reelin expression levels in healthy mouse brain leads to a change in the migratory behavior of subventricular zone-derived progenitors, triggering them to leave the rostral migratory stream (RMS) to which they are normally restricted during their migration to the olfactory bulb. Third, we reveal that Reelin increases endogenous progenitor cell dispersal in periventricular structures independently of any chemoattraction but via cell detachment and chemokinetic action, and thereby potentiates spontaneous cell recruitment to demyelination lesions in the corpus callosum. Conversely, animals lacking Reelin signaling exhibit reduced endogenous progenitor recruitment at the lesion site. Altogether, these results demonstrate that beyond its known role during brain development, Reelin is a key player in post-lesional cell migration in the adult brain. Finally our findings provide proof of concept that allowing progenitors to escape from the RMS is a potential therapeutic approach to promote myelin repair.

Development of cricket mushroom bodies.

Mushroom bodies are recognized as a multimodal integrator for sensorial stimuli. The present study analyzes cricket mushroom body development from embryogenesis to adulthood. In the house cricket, Kenyon cells were born from a group of neuroblasts located at the apex of mushroom bodies. Our results demonstrate the sequential generation of Kenyon cells: The more external they are, the earlier they were produced. BrdU treatment on day 8 (57% stage) of embryonic life results, at the adult stage, in the labelling of the large Kenyon cells at the periphery of the mushroom body cortex. These cells have specific projections into the posterior calyx, the gamma lobe, and an enlargement at the inner part of the vertical lobe; they represent a part of mushroom bodies of strictly embryonic origin. The small Kenyon cells were formed from day 9 (65% stage) of the embryonic stage onward, and new interneurons are produced throughout the entire life of the insect. They send their projections into the anterior calyx and into the vertical and medial lobes. Mushroom body development of Acheta should be considered as a primitive template, and cross‐taxonomic comparisons of the mushroom body development underscore the precocious origin of the gamma lobe. As a result of continuous neurogenesis, cricket mushroom bodies undergo remodeling throughout life, laying the foundation for future studies of the functional role of this developmental plasticity. J. Comp. Neurol. 452:215–227, 2002.

A novel role for polyamines in adult neurogenesis in rodent brain

Although neurogenesis in the adult is known to be regulated by various internal cues such as hormones, growth factors and cell‐adherence molecules, downstream elements underlying their action at the cellular level still remain unclear. We previously showed in an insect model that polyamines (putrescine, spermidine and spermine) play specific roles in adult brain neurogenesis. Here, we demonstrate their involvement in the regulation of secondary neurogenesis in the rodent brain. Using neurosphere assays, we show that putrescine addition stimulates neural progenitor proliferation. Furthermore, in vivo depletion of putrescine by specific and irreversible inhibition of ornithine decarboxylase, the first key enzyme of the polyamine synthesis pathway, induces a consistent decrease in neural progenitor cell proliferation in the two neurogenic areas, the dentate gyrus and the subventricular zone. The present study reveals common mechanisms underlying birth of new neurons in vertebrate and invertebrate species.

Migrating and myelinating potential of subventricular zone neural progenitor cells in white matter tracts of the adult rodent brain

Adult neural stem cells in the subventricular zone (SVZ) produce neuronal progenitors that migrate along the rostral migratory stream (RMS) and generate olfactory interneurons. Here, we evaluate the migratory potential of SVZ cells outside the RMS and their capacity to generate oligodendrocytes in the adult brain. We show that SVZ cells migrate long distances when grafted into white matter tracts such as the cingulum (Ci) and corpus callosum (CC). Furthermore, 22 days postinjection, most present morphologic and phenotypic characteristics of cells committed to the oligodendrocyte lineage. Cells grafted in shiverer CC and Ci become MBP-positive oligodendrocytes, abundantly myelinating these white matter tracts. Type A progenitors are involved in this myelinating process. Altogether, this study reveals the migrating and myelinating potential of SVZ cells in a new environmental context. Therefore, SVZ cells stand as interesting candidates for the development of novel therapeutic strategies for demyelinating diseases.

Olesoxime accelerates myelination and promotes repair in models of demyelination.

Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo.