Concise review: Spinal cord injuries: how could adult mesenchymal and neural crest stem cells take up the challenge?

Since several years, adult/perinatal mesenchymal and neural crest stem cells have been widely used to help experimental animal to recover from spinal cord injury. More interestingly, recent clinical trials confirmed the beneficial effect of those stem cells, which improve functional score of patients suffering from such lesions. However, a complete understanding of the mechanisms of stem cell-induced recovery is seriously lacking. Indeed, spinal cord injuries gathered a wide range of biochemical and physiopathological events (such as inflammation, oxidative stress, axonal damage, demyelination, etc.) and the genuine healing process after cell transplantation is not sufficiently defined. This review aims to sum up recent data about cell therapy in spinal cord lesions using mesenchymal or recently identified neural crest stem cells, by describing precisely which physiopathological parameter is affected and the exact processes underlying the observed changes. Overall, although significant advances are acknowledged, it seems that further deep mechanistic investigation is needed for the development of optimized and efficient cell-based therapy protocols.

Neutrophil contribution to spinal cord injury and repair.

Spinal cord injuries remain a critical issue in experimental and clinical research nowadays, and it is now well accepted that the immune response and subsequent inflammatory reactions are of significant importance in regulating the damage/repair balance after injury. The role of macrophages in such nervous system lesions now becomes clearer and their contribution in the wound healing process has been largely described in the last few years. Conversely, the contribution of neutrophils has traditionally been considered as detrimental and unfavorable to proper tissue regeneration, even if there are very few studies available on their precise impact in spinal cord lesions. Indeed, recent data show that neutrophils are required for promoting functional recovery after spinal cord trauma. In this review, we gathered recent evidence concerning the role of neutrophils in spinal cord injuries but also in some other neurological diseases, highlighting the need for further understanding the different mechanisms involved in spinal cord injury and repair.

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

[This corrects the article DOI: 10.1371/journal.pone.0177962.].

Color Categorization Independent of Color Naming.

Color is continuous, yet we group colors into discrete categories associated with color names (e.g., yellow, blue). Color categorization is a case in point in the debate on how language shapes human cognition. Evidence suggests that color categorization depends on top-down input from the language system to the visual cortex. We directly tested this hypothesis by assessing color categorization in a stroke patient, RDS, with a rare, selective deficit in naming visually presented chromatic colors, and relatively preserved achromatic color naming. Multimodal MRI revealed a left occipito-temporal lesion that directly damaged left color-biased regions, and functionally disconnected their right-hemisphere homologs from the language system. The lesion had a greater effect on RDS's chromatic color naming than on color categorization, which was relatively preserved on a nonverbal task. Color categorization and naming can thus be independent in the human brain, challenging the mandatory involvement of language in adult human cognition.

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.

Systematic expression analysis of Hox genes at adulthood reveals novel patterns in the central nervous system.

Hox proteins are key regulators of animal development, providing positional identity and patterning information to cells along the rostrocaudal axis of the embryo. Although their embryonic expression and function are well characterized, their presence and biological importance in adulthood remains poorly investigated. We provide here the first detailed quantitative and neuroanatomical characterization of the expression of the 39 Hox genes in the adult mouse brain. Using RT-qPCR we determined the expression of 24 Hox genes mainly in the brainstem of the adult brain, with low expression of a few genes in the cerebellum and the forebrain. Using in situ hybridization (ISH) we have demonstrated that expression of Hox genes is maintained in territories derived from the early segmental Hox expression domains in the hindbrain. Indeed, we show that expression of genes belonging to paralogy groups PG2-8 is maintained in the hindbrain derivatives at adulthood. The spatial colinearity, which characterizes the early embryonic expression of Hox genes, is still observed in sequential antero-posterior boundaries of expression. Moreover, the main mossy and climbing fibres precerebellar nuclei express PG2-8 Hox genes according to their migration origins. Second, ISH confirms the presence of Hox gene transcripts in territories where they are not detected during development, suggesting neo-expression in these territories in adulthood. Within the forebrain, we have mapped Hoxb1, Hoxb3, Hoxb4, Hoxd3 and Hoxa5 expression in restricted areas of the sensory cerebral cortices as well as in specific thalamic relay nuclei. Our data thus suggest a requirement of Hox genes beyond their role of patterning genes, providing a new dimension to their functional relevance in the central nervous system.

Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

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.

Disruption of temporally extended self-memory system following traumatic brain injury.

We investigated for the first time the episodic/semantic distinction in remembering the past and imagining the future in traumatic brain injury (TBI), and explored cognitive mechanisms that may underlie their deficits. Fifteen severe TBI patients and 15 control participants performed a battery of neuropsychological tests and a set of verbal fluency tasks designed to assess semantic (personality traits knowledge and general events), and episodic (specific events and details) facets of self-representations according to three time periods (remote/retrograde past, recent/anterograde past, future). Compared to controls, TBI patients showed deficits in both semantic and episodic self-representations, regardless of the time period, and controlling for basic cognitive functions. By contrast, a subjective evaluation of self-concept measuring the degree of certitude and the valence of self did not differ between patients and controls. The deficits were mainly predicted by altered executive function (i.e., updating) for past periods, as well as by general semantic and feature binding in working memory for the future period, independently of the injury characteristics. For controls, only episodic self-representation for each time period was mediated by executive or working memory functions, while semantic self-representation was mediated by the certitude of the self. This study highlights the dual role of semantic and episodic representations in temporally extended self, and shows the global disruption of self-representations across extended time in severe TBI. This encourages the extension of past and future thinking research to TBI populations to provide important insights into the nature and origin of these deficits and their role in recovery and to suggest future lines of research on rehabilitation procedures.

Concise review: adult mesenchymal stem cells, adult neural crest stem cells, and therapy of neurological pathologies: a state of play.

Adult stem cells are endowed with in vitro multilineage differentiation abilities and constitute an attractive autologous source of material for cell therapy in neurological disorders. With regard to lately published results, the ability of adult mesenchymal stem cells (MSCs) and neural crest stem cells (NCSCs) to integrate and differentiate into neurons once inside the central nervous system (CNS) is currently questioned. For this review, we collected exhaustive data on MSC/NCSC neural differentiation in vitro. We then analyzed preclinical cell therapy experiments in different models for neurological diseases and concluded that neural differentiation is probably not the leading property of adult MSCs and NCSCs concerning neurological pathology management. A fine analysis of the molecules that are secreted by MSCs and NCSCs would definitely be of significant interest regarding their important contribution to the clinical and pathological recovery after CNS lesions.

Adult bone marrow neural crest stem cells and mesenchymal stem cells are not able to replace lost neurons in acute MPTP-lesioned mice.

Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC) or mesenchymal stem cells (MSC) survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management.

[What about the mental time travel and age-related effects?]. / Quid du voyage mental dans le temps subjectif et effets de l'âge ?

According to Tulving, episodic memory allows humans to travel mentally through subjective time into either the past or the future, this ability being at the origin of adaptation, organization and planning of future behavior. The main aim of this review is to present a state of art of episodic mental time travel and a lifespan perspective from children to elderly people. We examine the numerous similarities between remembering the past and envisioning the future which have been highlighted in cognitive, neuroimaging, and neuropsychological studies. We also present studies that have given evidence that remembering the past and imagining the future differ somewhat. We focus on demonstrating that hippocampal dysfunction is associated with disturbances in the recall of episodic autobiographical details in past memories, but also in the imagining of episodic detailed future events. More specifically, we discuss that the future seems to involve higher semantic processes mediated by the inferior frontal and lateral temporal gyri. We propose that the study of mental travel in personal time could be undertaken in line with the distinction between the memory of (episodic) experiences and (semantic) personal knowledge of one's life, which constitutes a major part of the self and constraints what we have been, what we are now, and what we might yet become.

Exploring the roles of the executive and short-term feature-binding functions in retrieval of retrograde autobiographical memories in severe traumatic brain injury.

Conway's autobiographical memory (AM) model postulates that memories are not stored in a crystallised form in long-term memory but are reconstructed at time of retrieval via executive and binding processes, to create a temporary multimodal representation from different AM knowledge. Traumatic brain injury (TBI) impairs AM recollection. However, no study has yet considered the distinct roles of executive and short-term feature-binding functions in the retrieval deficits of retrograde AMs after TBI. Examining a group of 33 TBI patients and 33 controls, our study addresses these roles through a first-ever exploration of the links between performance on an AM verbal fluency evaluation that distinguishes four levels of representation, from semantic to episodic (lifetime periods, general events, specific events, specific details of a specific event), and three executive functions (shifting, inhibition and updating) and two short-term feature-binding functions (short-term formation and maintenance of multimodal representations). The results showed that TBI patients were impaired compared to controls in the retrieval of both semantic and episodic retrograde AM representations, but especially for the most episodic level of AM, in the three executive functions and the short-term maintenance of multimodal representations. Regression analyses indicated that the executive predictors (mainly updating) mediated a large proportion (over 70%) of TBI-related deficit on the retrieval of lifetime periods, general events and specific events, in contrast with the main impairment on generation of specific details which were only mildly (just 12%) predicted by the short-term maintenance of multimodal representations. Additional analyses in a subgroup of patients point to episodic memory abilities and time since injury in predicting the retrieval of specific events and details. In summary, the present study mainly emphasizes that the executive deficits in TBI are involved in the disruption of the first levels of AM generative processes that give access to the multiple episodic details recollection.

Reduced specificity of autobiographical memory and aging: do the executive and feature binding functions of working memory have a role?

Autobiographical memory (AM) is built up from various kinds of knowledge, from general to specific, via generative processes. Aging seems to particularly affect the episodic autobiographical information while preserving information that is more semantic. However, the mechanism of this deficit has not yet been thoroughly tested in relation to working memory. This study is designed to investigate, in a group of 100 subjects, the relationships between age, accessibility to different levels of AM specificity, and two main components of working memory: the central executive and the episodic buffer. We used a new task composed of four embedded verbal autobiographical fluencies (VAF) - from low to highest specificity levels - exploring lifetime periods, general events, specific events, and details, plus tasks exploring free recall of episodic AM and updating, shifting, inhibition, and feature binding in working memory. The results demonstrate that age-related difficulties increase with level of specificity of autobiographical knowledge, i.e., from semantic to episodic aspects. Moreover, regression analyses mainly show that increase in age-related deficit with level of specificity of AM is largely mediated by performance on executive functions (updating and inhibition) and to a lesser extent feature binding in working memory. The results confirm in episodic AM the executive/working memory aging hypothesis, and for the first time highlight the role of episodic buffer in associating the various different details of specific events that elicit the conscious recollection.