Sensory Inputs Stimulate Progenitor Cell Proliferation in an Adult Insect Brain

AbstractAlthough most brain neurons are produced during embryonic and early postnatal development, recent studies clearly demonstrated in a wide range of species from invertebrates to humans that new neurons are added to specific brain structures throughout adult life. Hormones, neurotransmitters, and growth factors as well as environmental conditions modulate this neurogenesis [1–9]. In this study, we address the role of sensory inputs in the regulation of adult neural progenitor cell proliferation in an insect model. In some insect species, adult neurogenesis occurs in the mushroom bodies [10], the main sensory integrative centers of the brain, receiving multimodal information [11, 12] and often considered as the analog of the vertebrate hippocampus. We recently showed that rearing adult crickets in enriched sensory and social conditions enhanced neuroblast proliferation in the mushroom bodies [13]. Here, by manipulating hormonal levels and affecting olfactory and/or visual inputs, we show that environmental regulation of neurogenesis is in direct response to olfactory and visual stimuli rather than being mediated via hormonal control. Experiments of unilateral sensory deprivation reveal that neuroblast proliferation can be inhibited in one brain hemisphere only. These results, obtained in a relatively simple brain, emphasize the role of sensory inputs on stem cell division

Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production

International audienceMyelin destruction is followed by resident glia activation and mobilization of endogenous progenitors (OPC) which participate in myelin repair. Here we show that in response to demyelination, mature oligodendrocytes (OLG) bordering the lesion express Ndst1, a key enzyme for heparan sulfates (HS) synthesis. Ndst1+ OLG form a belt that demarcates lesioned from intact white matter. Mice with selective inactivation of Ndst1 in the OLG lineage display increased lesion size, sustained microglia and OPC reactivity. HS production around the lesion allows Sonic hedgehog (Shh) binding and favors the local enrichment of this morphogen involved in myelin regeneration. In MS patients, Ndst1 is also found overexpressed in oligodendroglia and the number of Ndst1-expressing oligodendroglia is inversely correlated with lesion size and positively correlated with remyelination potential. Our study suggests that mature OLG surrounding demyelinated lesions are not passive witnesses but contribute to protection and regeneration by producing HS

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

Post lesional mobilization of subventricular zone cells in the adult brain (the role of Reelin)

La migration des cellules souches / progénitrices neurales (CSPN) dans le cerveau adulte est cruciale pour la réparation cérébrale. Reeline (Rln) est une protéine de la matrice extracellulaire, régulant le positionnement des neurones pendant la croticogénèse. Nous révélons un rôle nouveau de Rln chez l'adulte. In vitro, Rln est chémocinétique mais pas chémoattractante. In vivo, Rln induit le détachement et la dispersion des CSNP de la zone sousventriculaire (SVZ) hors du courant rostral de migration (RMS) où elles sont sinon confinées. Rln potentialise le recrutement spontané des CSPN vers les lésions démyélinisantes où un tiers deviennent oligodendrocytaires. L'expression endogène de Rln est stimulée après lésion. Les animaux sans voie de signalisation Rln ont un recrutement réduit des CSPN vers les lésions.Ces résultats révèlent que Rln est un arbitre clef de la migration post-lésionnelle des CSPN et que permettre au CSPN de sortir du RMS est une stratégie thérapeutique prometteuse.Neural stem/ progenitor cell (NSPC) migration in the adult brain is crucial for brain repair. Reelin (Rln) is an extracellular matrix protein regulating neuron positioning during coricogenesis. We reveal new roles of Rln in adult NSPC migration. In vitro, Rln promotes detachment, is chemokinetic but not chemoattractant. After Rln ectopic overexpression in the healthly brain, subventricular zone (SVZ) NSPC detach from the rostal migratory stream (RMS) in which they are normally restricted, and disperse in adjacent fiber tracts. Rln over-expression potentiates spontaneous cell recruitment to demyelinated lesion and one third of the NSPC recruited adopt an oligodendrocytic phenotype. Rln expression is spontaneously upregulated after lesion, and disruption of its signaling pathway results in reduced NSPC recruitment toward lesion. Our study reveals that Rln is a key player of post-lesional NSPC migration and that allowing NSPC to escape from RMS is a promising therapeutic approachAIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Etude comparative des facteurs régulateurs de la neutrogenèse chez le rongeur et l'insecte adulte

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Promouvoir la mobilisation des cellules souches neurales adultes pour la réparation de lésions demyélinisantes (effet de l'environnement et de l'EGF)

La persistance de zones germinatives dans le cerveau adulte a permis de concevoir des stratégies thérapeutiques basées sur le potentiel réparateur des cellules souches adultes. En effet, il a été montré qu en cas de lésion dans le cerveau, des cellules de la zone sousventriculaire (ZSV) augmentent leur prolifération et changent leur chemin migratoire pour rejoindre l endroit de la lésion et se différencier dans le type cellulaire affecté. Dans le cas des lésions démyélinisantes, certaines cellules sont capables de différencier en oligodendrocytes dans une tentative de remyélinisation. Cependant leur nombre reste faible et ne permet pas d obtenir une réparation complète de la lésion. Ainsi, une stratégie thérapeutique envisageable peut être de promouvoir la mobilisation des cellules souches de la ZSV. Mon travail de thèse a consisté à identifier des conditions et des facteurs qui peuvent stimuler le recrutement des cellules de la ZSV dans le cas des lésions démyélinisantes dans le cerveau de souris adultes. Dans une première étude, j ai contribué à montrer que l exercice et l enrichissement environnemental (EE) promeuvent le recrutement des cellules de la ZSV et favorisent la récupération fonctionnelle de souris atteintes d encéphalite expérimentale auto-immune (EAE). L EE promeut également le destin ligodendrocytaire des cellules de la ZSV recrutées dans les lésions d EAE. Dans le deuxième travail, nous avons montré que l administration intra-nasale du facteur de croissance HB-EGF permet de stimuler non seulement la prolifération des cellules de la ZSV mais également leur migration vers une lésion focale de démyélinisation. En revanche, HB-EGF favorise la différenciation astrocytaire des cellules sur le site lésionnel. Dans l ensemble ces deux études montrent qu il est possible de modifier la prolifération et la migration des progéniteurs de la ZSV par des approches non invasives, et de favoriser ainsi leur mobilisation et le remplacement oligodendrocytaire dans des lésions de démyélinisation.The identification of neural stem cells in the adult rodent and human central nervous system opens new perspectives for self-repair of brain damage. In the adult subventricular zone (SVZ), these cells proliferate and generate progenitors that migrate along the rostral migratory stream to the olfactory bulb, where they differentiate into interneurons. These cells can also be recruited spontaneously to damaged brain areas to replace lost cells, including oligodendrocytes in demyelinated lesions. However, this process only leads to partial recovery. My Ph.D. research has focused on the identification of conditions and factors that could enhance the self-repair capacity of endogenous SVZ cells in demyelinating lesions in the adult mouse. In a first study, I have contributed to show that exercise and environmental enrichment (EE), known to induce regional increases in neurotrophin levels in the rodent brain, promote recruitment of SVZ cells and favour recovery in demyelination models. EE also favored the oligodendrocyte fate of SVZ-recruited cells in the experimental autoimmune encephalomyelitis lesions. In a second study, I have focused on epidermal growth factor (EGF) influences on SVZ cell participation to brain repair in the context of demyelinated lesions. Indeed, previous studies have suggested that EGF is able to stimulate proliferation, migration and glial differentiation of SVZ progenitors. We induced a focal demyelinated lesion in the corpus callosum by lysolecithin injection and showed that intranasal heparinbinding epidermal growth factor (HB-EGF) administration induces a significant increase in SVZ cell proliferation together with a stronger SVZ cell mobilization towards the lesions. Besides, HB-EGF causes a shift of SVZ-derived cell differentiation towards the astrocytic lineage. These results suggest that SVZ cell proliferation and migration can be stimulated by non invasive approaches that could be part of future strategies to promote cell replacement from endogenous SVZ stem / progenitor cells, notably in demyelinated lesions.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Commentary: "Promoting Myelin Repair through In vivo Neuroblast Reprogramming"

International audienc

Promoting Myelin Repair through In Vivo Neuroblast Reprogramming

International audienceDemyelination is frequently observed in a variety of CNS insults and neurodegenerative diseases. In rodents, adult neural stem cells can generate oligodendrocytes and participate to myelin repair. However, these cells mainly produce migratory neuroblasts that differentiate in the olfactory bulb. Here, we show that, in the demyelination context, a small subset of these neuroblasts can spontaneously convert into myelinating oligodendrocytes. Furthermore, we demonstrate that the contribution of neuroblasts to myelin repair can be improved by in vivo forced expression of two transcription factors: OLIG2 and SOX10. These factors promote directed fate conversion of endoge-nous subventricular zone neuroblasts into mature functional oligodendrocytes, leading to enhanced remyelination in a cuprizone-induced mouse model of demyelination. These findings highlight the unexpected plasticity of committed neuroblasts and provide proof of concept that they could be targeted for the treatment of demyelinated lesions in the adult brain

Region and dynamic specificities of adult neural stem cells and oligodendrocyte precursors in myelin regeneration in the mouse brain

Myelin regeneration can occur in the brain following demyelination. Parenchymal oligodendrocyte progenitors (pOPC) are known to play a crucial role in this process. Neural stem cells (NSC) residing in the ventricular-subventricular zone (V-SVZ) also have the ability to generate oligodendrocytes but their contribution to endogenous myelin repair was so far considered to be negligible. Here, we addressed the relative contribution of pOPC and V-SVZ-derived neural progenitors (SVZdNP) to remyelination in cuprizone mouse models of acute or chronic corpus callosum (CC) demyelination. Using genetic tracing, we uncover an unexpected massive and precocious recruitment of SVZdNP in the anterior CC after acute demyelination. These cells very quickly adopt an oligodendrocytic fate and robustly generate myelinating cells as efficiently as pOPC do. In more posterior areas of the CC, SVZdNP recruitment is less important whereas pOPC contribute more, underlining a regionalization in the mobilization of these two cell populations. Strikingly, in a chronic model when demyelination insult is sustained in time, SVZdNP minimally contribute to myelin repair, a failure associated with a depletion of NSC and a drastic drop of progenitor cell proliferation in V-SVZ. In this context, pOPC remain reactive, and become the main contributors to myelin regeneration. Altogether our results highlight a region and context-dependent contribution of SVZdNP to myelin repair that can equal pOPC. They also raise the question of a possible exhaustion of V-SVZ proliferation potential in chronic pathologies

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 / remyelinations process. Finally, we will synthetize the results of studies searching for factors able to modulate spontaneous myelin repair