Genetic control of neurogenesis in the developing neocortex

Le néocortex est composé de six couches neuronales contenant divers sous-types de neurones excitateurs qui s’assemblent en circuits responsables de nos capacités cognitives et sensorielles. Ces neurones naissent séquentiellement lors du développement embryonnaire à partir de progéniteurs apicaux. Dans ce travail, nous avons combiné des outils technologiques de pointe afin de déterminer le scénario transcriptionnel engagé lors de la corticogenèse. Nous avons constaté que les progéniteurs apicaux étaient moléculairement et fonctionnellement dynamiques au cours de la neurogenèse, ils progressent d’un état épigénétiquement réprimé vers un état sensible aux signaux environnementaux. Les marques transcriptionnelles temporelles sont transmises des cellules mères progénitrices vers les cellules filles neuronales qui sont alors soumises à un programme de différentiation conservé et indépendant du stade développemental. Leur identité neuronale adulte est ensuite acquise suite à l’intégration de signaux externes. Ainsi, l’origine de la diversité neuronale résulte de marques transcriptionnelles transmises par des progéniteurs apicaux temporellement dynamiques

Principles of progenitor temporal patterning in the developing invertebrate and vertebrate nervous system

During the development of the central nervous system, progenitors successively generate distinct types of neurons which assemble into the circuits that underlie our ability to interact with the environment. Spatial and temporal patterning mechanisms are partially evolutionarily conserved processes that allow generation of neuronal diversity from a limited set of progenitors. Here, we review examples of temporal patterning in neuronal progenitors in the Drosophila ventral nerve cord and in the mammalian cerebral cortex. We discuss cell-autonomous mechanisms and environmental influences on the temporal transitions of neuronal progenitors. Identifying the principles controlling the temporal specification of progenitors across species, as highlighted here, may help understand the evolutionary constraints over brain circuit design and function. © 2019 Elsevier Lt

Bone marrow mesenchymal and neural crest-derived stem cells have distinct secretomes, which are both relevant for spinal cord injury therapy.

Objectives: Spinal cord injury (SCI) treatment represents a critical issue in clinical research and patient care. Stem cell-based replacement therapies have already been proposed worldwide, especially studying stem cells from the adult bone marrow stroma. Previous studies focusing on those cells did not specifically consider their intrinsic embryonic heterogeneity, thus intermingling different stem cells subpopulations to treat experimental SCI or even injured patients. In this study, we decided to compare adult bone marrow neural crest-derived stem cells (NCSC) and mesenchymal stem cells (MSC), and highlight which of their specific properties could be relevant in therapeutic perspectives. Material and methods: In that purpose, we compared NCSC and MSC isolated from adult mouse bone marrow. We then compared the effects that both cell types could exert once grafted inside an injured spinal cord. Cells were injected into the spinal cord of mice that right after a spinal cord contusion at the T11-12 spinal level. Results: Both MSC and NCSC-injected mice recovered locomotion abilities faster than control mice (as assessed by BMS scoring). Additionally, we observed that after 28 days post-injury, the lesion volume tended to decrease in mice that received cell graft compared to control group. Interestingly, it appeared that MSC seemed to be able to modulate inflammation inside the lesion, more than NCSC. Indeed, MSC-graft increased early neutrophil and macrophage recruitment in the bloodstream and inside the spinal cord, and increased the number of arginase-1-expressing cells remaining in the spinal cord after 28 days. In parallel, we compared the secretome of both NCSC and MSC, and noticed some interesting differences: MSC secreted several chemokines reflecting possible immunomodulating properties, while NCSC secreted products might be able to enhance neurite outgrowth. Conclusions: Preliminary data showed that NCSC induced neuritogenesis on primary neurons in vitro. Altogether, those results should help to improve and optimize cell-based therapies parameters and/or to define precise and efficient pharmacological treatments for SCI patients

Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury

Introduction: Stem cells from adult tissues were considered for a long time as promising tools for regenerative therapy of neurological diseases, including spinal cord injuries (SCI). Indeed, mesenchymal (MSCs) and neural crest stem cells (NCSCs) together constitute the bone marrow stromal stem cells (BMSCs) that were used as therapeutic options in various models of experimental SCI. However, as clinical approaches remained disappointing, we thought that reducing BMSC heterogeneity should be a potential way to improve treatment efficiency and reproducibility. Methods: We investigated the impact of pure populations of MSCs and NCSCs isolated from adult bone marrow in a mouse model of spinal cord injury. We then analyzed the secretome of both MSCs and NCSCs, and its effect on macrophage migration in vitro. Results: We first observed that both cell types induced motor recovery in mice, and modified the inflammatory reaction in the lesion site. We also demonstrated that NCSCs but especially MSCs were able to secrete chemokines and attract macrophages in vitro. Finally, it appears that MSC injection in the spinal cord enhance early inflammatory events in the blood and spinal cord of SCI mice. Conclusions: Altogether, our results suggest that both cell types have beneficial effects in experimental SCI, and that further investigation should be dedicated to the regulation of the inflammatory reaction following SCI, in the context of stem cell-based therapy but also in the early-phase clinical management of SCI patients

Specific properties of bone marrow mesenchymal and neural crest-derived stem cells: Relevance in spinal cord injury therapy.

Spinal cord injury (SCI) treatment represents a critical issue in clinical research and patient care. Stem cell-based replacement therapies have already been proposed worldwide, especially studying stem cells from the adult bone marrow stroma. Previous studies focusing on those cells did not specifically consider their intrinsic embryonic heterogeneity, thus intermingling different stem cells subpopulations to treat experimental SCI or even injured patients. In this study, we decided to compare adult bone marrow neural crest-derived stem cells (NCSC) and mesenchymal stem cells (MSC), and highlight which of their specific properties could be relevant in therapeutic perspectives. In that purpose, we compared NCSC and MSC isolated from adult mouse bone marrow. We then compared the effects that both cell types could exert once grafted inside an injured spinal cord. Cells were injected into the spinal cord of mice that right after a spinal cord contusion at the T11-12 spinal level. Our results indicate that both MSC and NCSC-injected mice recovered locomotion abilities faster than control mice (as assessed by BMS scoring). Additionally, we observed that after 28 days post-injury, the lesion volume tended to decrease in mice that received cell graft compared to control group. Interestingly, it appeared that MSC seemed to be able to modulate inflammation inside the lesion, more than NCSC. Indeed, MSC-graft increased early neutrophil and macrophage recruitment in the bloodstream and inside the spinal cord, and increased the number of arginase-1-expressing cells remaining in the spinal cord after 28 days. In parallel, we compared the secretome of both NCSC and MSC, and noticed some interesting differences: MSC secreted several chemokines reflecting possible immunomodulating properties, while NCSC secreted products might be able to enhance neurite outgrowth. Indeed, preliminary data showed that NCSC induced neuritogenesis on primary neurons in vitro. Altogether, those results should help to improve and optimize cell-based therapies parameters and/or to define precise and efficient pharmacological treatments for SCI patients

Human bone marrow harbors cells with neural crest-associated characteristics like human adipose and dermis tissues.

Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or bone marrow have been described in rodent, as sources of NCSC. However, very little information is available concerning their correspondence in human tissues, and more precisely for human bone marrow. The main objective of this study was therefore to characterize NCSC from adult human bone marrow. In this purpose, we compared human bone marrow stromal cells to human adipose tissue and dermis, already described for containing NCSC. We performed comparative analyses in terms of gene and protein expression as well as functional characterizations. It appeared that human bone marrow, similarly to adipose tissue and dermis, contains NESTIN+ / SOX9+ / TWIST+ / SLUG+ / P75NTR+ / BRN3A+/ MSI1+/ SNAIL1+ cells and were able to differentiate into melanocytes, Schwann cells and neurons. Moreover, when injected into chicken embryos, all those cells were able to migrate and follow endogenous neural crest migration pathways. Altogether, the phenotypic characterization and migration abilities strongly suggest the presence of neural crest-derived cells in human adult bone marrow

Additional file 3: Figure S2. of Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury

Phenotypic profile of RAW264.7 macrophages is not modified in presence of MSC-CM and NCSC-CM. We observed that when placed in serum-free DMEM, or in MSC- or NCSC-CM, RAW264.7 macrophages all express arginase 1, CD11b, Iba1, CX3CR1, CD206, CD68. Moreover, their secretion profile is not significantly modified. (TIFF 3075 kb

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinsons disease.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut