Biology subjects

Neveu, P.

Publications and source records attributed to Neveu, P..

9 recordsLinked to original sources

bioRxiv2026

Pattern-dependent low-intensity repetitive magnetic stimulation enhances spinal cord repair through modulation of neuroinflammation

Spinal cord injuries (SCI) are traumatic lesions of the spinal cord that commonly result from physical trauma. They can lead to severe and permanent impairments in motor, sensory, and/or autonomic functions, often resulting in paraplegia or tetraplegia. Despite advances in this field, effective restorative treatments for SCI remain limited. Over the past few years, several therapeutic strategies have been investigated to promote functional recovery after SCI, including neuromodulation approaches. Repetitive magnetic stimulation has emerged as a promising non-invasive strategy, with encouraging results when the stimulation is applied directly over the spinal cord. However, most studies have focused on high-intensity stimulation, while the key parameters underlying its therapeutic efficacy remain poorly understood. In this study, we investigated the effects of low-intensity repetitive trans-spinal magnetic stimulation (LI-rTSMS) following SCI in mice, using BMS, histological and RNA sequencing approaches. We aimed to determine the optimal protocol by comparing three stimulation patterns (10 Hz, iTBS and BHFS) and two coil sizes. Our results show that LI-rTSMS modulates the injured spinal cord in a pattern- and coil size-dependent manner, with distinct effects on fibrotic, neural, and inflammatory responses. Notably, the BHFS pattern produced the most marked tissue-remodeling effects, reducing fibrosis, reactive astrogliosis, and phagocytosis of myelin debris. This reduction in phagocytosis was also observed with a smaller coil, supporting an effect of LI-rTSMS on this process. We also identified distinct inflammatory signatures depending on the stimulation pattern and time after injury. Transcriptomic analyses revealed a common early inflammatory response to LI-rTSMS, whereas each stimulation pattern subsequently led to distinct molecular signatures after 2 weeks stimualtion. In addition, ependymal cells are known to retain endogenous regenerative potential following SCI. We found that LI-rTSMS increased ependymal cell proliferation and migration toward the lesion site, without detectable changes in their differentiation. Finally, we assessed c-Fos expression as a marker of early transcriptional changes in neurons. LI-rTSMS did not result in significant changes, suggesting that the observed effects were unlikely to be mediated by early, widespread neuronal activation. Altogether, this study provides mechanistic insights into the pattern-dependent effects of LI-rTSMS and highlights its potential role for future clinical translation.

neuroscience↗

bioRxiv2025

Repetitive Trans-spinal magnetic stimulation Promotes Repair in Inflammatory Spinal Cord Injury Through Sex-Dependent Immune Modulation

Spinal cord injuries (SCI), whether traumatic or inflammatory such as transverse myelitis (TM), are characterized by severe neuroinflammation, demyelination, and long-term disabilities. Current treatments remain limited, highlighting the need for novel non-invasive therapeutic approaches. Repetitive magnetic stimulation (RMS) has emerged as a promising strategy, but its mechanisms and efficacy in inflammatory contexts remain poorly described. Here, we investigated the effects of RMS applied as trans-spinal RMS (rTSMS) in a mouse model of focal spinal cord demyelination induced by lysophosphatidylcholine (LPC). When applied one day after LPC injection, rTSMS reduced inflammation, demyelination, and fibroglial scar formation, while promoting early locomotor recovery in both sexes. In contrast, when treatment was initiated three days after LPC injection, corresponding to the peak of motor deficits, rTSMS conferred tissue protection and functional benefits only in female mice. RNA sequencing analyses revealed sex-dependent immune modulation: in females, rTSMS primarily regulated adaptive T cell-related pathways, whereas in males, it mainly targeted innate immune responses such as neutrophil activity and phagocytosis. Complementary in vitro experiments using microglial and macrophage cultures further demonstrated that RMS modulates transcriptomic responses differently depending on cell type and inflammatory state. Specifically, RMS attenuated IL-1-induced pro-inflammatory signaling in macrophages and completely abolished these effects in microglia. Altogether, our findings establish rTSMS as a non-invasive therapy capable of reducing neuroinflammation and demyelination in inflammatory SCI, with pronounced sex-dependent effects. By uncovering distinct immune pathways engaged in male and female mice, this study provides mechanistic insights into rTSMS action and opens perspectives for its translational use in neuroinflammatory diseases.

neuroscience↗

bioRxiv2025

Anti-PD-1/PD-L1 Therapy Triggers Cognitive Deficits and Anxiety-Like Behaviors Through Tumor-Initiated Neuroinflammatory Niches in Male Mice

Checkpoint inhibitors are promising immunotherapy to treat cancer patients, but their cognitive impact has not been evaluated despite several neurological adverse events. We studied the impact of immune desert or inflamed cancers when combined with immune checkpoint inhibitors (ICI) anti-PD-1/anti-PD-L1 on mouse behaviors and brain immune cells infiltration/homeostasis, and neuroinflammation in male mice. We showed that systemic inflammation, brain-barriers permeability accompanying meningeal infiltration of peripheral macrophages and neuroinflammation as well as deficits in cognition or emotional reactivity, depending on immuno-inflammatory or immune-desert cancer type. Combined with cancers, anti-PD-1 and PD-L1 treatments exacerbated the decline in executive functions and hippocampal vascular inflammation. PD-L1 specifically relayed the infiltration of the T{gamma}{delta} lymphocytes subpopulation in choroid plexus and leptomeninges implicated, whose systemic neutralization counteracted anti-PDL1-induced cognitive deficits and anxiety in mice bearing immune-inflamed cancer. Our findings highlight new systemic biomarkers of cold or hot cancer, treated with anti-PD-1/anti-PDL-1, and associated with cognitive and emotional alterations in mice; guiding ways of intervention to secure the cancer curation and improve patients quality of life under ICI treatment. Competing Interest StatementThe authors have declared no competing interest. One Sentence SummaryImpact of cancer and checkpoint inhibitors on cognitive functions

cancer biology↗

bioRxiv2025

Altered therapeutic capacities of olfactory ensheathing cells caused by a lesion in an autologous transplantation model for the treatment of spinal cord injury.

Spinal cord injury (SCI) causes irreversible loss of motor, sensory, and autonomic functions and currently has no cure. Beyond local damage, SCI induces systemic inflammation, including cerebral inflammation that impairs neurogenesis. While cell therapies show promising effects in animal models, such as scar reduction and neuroprotection, their benefits in humans remain limited. One key difference lies in the transplantation strategy: animals receive healthy donor cells, whereas humans require autologous transplants. This led us to investigate how the lesion context affects the neuro-reparative potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs. To this end, we cultured OECs from healthy animals and from animals that had undergone SCI one week earlier. We then transplanted both types of OECs into recipient animals after SCI for therapeutic purposes. Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. Indeed, transplantation of cells from previously injured animals does not modulate the fibrotic and glial scar, or the demyelinated areas at the lesion site, and therefore fails to improve functional recovery; unlike cells derived from healthy donors. Moreover, our in vitro studies show that cells derived from SCI animals secrete pro-inflammatory molecules that promote the polarization of microglia toward a pro-inflammatory phenotype. Altogether, these innovative findings provide new insights into the potential of cell transplantation in the context of autologous therapy after SCI. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/660789v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2e9b52org.highwire.dtl.DTLVardef@1d75bfaorg.highwire.dtl.DTLVardef@1d7af58org.highwire.dtl.DTLVardef@138f1b8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Brain inflammation and cognitive decline induced by spinal cord injury can be reversed by spinal cord cell transplants

Spinal cord injuries (SCIs) affect between 250,000 and 500,000 people worldwide each year, most commonly due to road accidents or falls. These injuries result in permanent disabilities, the severity and impact of which are directly related to the extent and location of the injury. Recent studies have also shown that SCIs can lead to cognitive disorders due to inflammation in the brain. From a therapeutic perspective, numerous treatments have been explored, including cell therapy. It has been established that a common mechanism across various cellular transplant models is the modulation of inflammation at the injury site. However, it remains unclear whether the immunomodulatory effects observed in the spinal cord also extend to the brain. To test this hypothesis, we induced SCI in wild-type mice and treated them with transplants of differentiated cells, specifically olfactory ensheathing cells, or stem cells, such as mesenchymal stem cells. Our results demonstrate that both types of transplants can reverse cognitive disorders induced by SCI. Additionally, we found that these cellular transplants modulate brain inflammation and increase neuronal density in the hippocampus. To our knowledge, this is the first study to show that cells transplanted into the spinal cord can modulate the inflammatory response in the brain, thereby reversing the negative effects of injury on brain function following SCI. These findings underscore the complex interactions between the brain and spinal cord under both physiological and pathological conditions.

neuroscience↗

bioRxiv2024

Spinal cord injury: What are the lesion effects on transplanted cells in an autograft model?

AbstractSpinal cord injury (SCI) is a serious pathology of the central nervous system that results in loss of motor, sensory and autonomic functions below the level of the lesion and for which, unfortunately, there is currently no cure. In addition to the loss of function, SCI induces a systemic inflammation that is not confined to the spinal cord and whose effects are increasingly well characterized. In particular, SCI causes cerebral inflammation, which is responsible for the impairment of hippocampal and bulbar neurogenesis. Many therapies have been tested as potential treatments for SCI. In animal models, cell therapies have shown interesting effects such as spinal scar reduction, anti-inflammatory properties, axonal regrowth or neuronal survival, allowing better functional recovery. However, in human studies, their therapeutic capacities are less significant. Beyond obvious differences in pathophysiology and cell culture procedures, a key paradigm of cell transplantation differs between humans and animals. In animal models, transplanted cells are systematically taken from healthy individuals, whereas in humans the immune incompatibility leads to the realization of autologous transplantation. Therefore, we were interested in the lesion effects on the neuro-repairing potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs. Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. These innovative results shed new light on the future use of cell transplantation in autologous transplantation after SCI.

neuroscience↗

bioRxiv2022

Lipotype acquisition during neural development in vivo is not recapitulated in stem cell-derived neurons

During development, different tissues acquire distinct lipotypes that are coupled to tissue function and homeostasis. In the brain, where complex membrane trafficking systems are required for neural function, specific glycerophospholipids, sphingolipids, and cholesterol are highly abundant, and defective lipid metabolism is associated with abnormal neural development and neurodegenerative disease. Notably, the production of tissue-specific lipotypes requires appropriate programming of the underlying lipid metabolic machinery, but when and how this occurs is unclear. To address this, we used high-resolution mass spectrometry-based (MSALL) lipidomics to perform a quantitative and comprehensive analysis of mouse brain development covering early embryonic and postnatal stages. We discovered a distinct bifurcation in the establishment of the neural lipotype, whereby the canonical brain lipid biomarkers 22:6-glycerophospholipids and 18:0-sphingolipids begin to be produced in utero, whereas cholesterol attains its characteristic high levels after birth. In contrast, when profiling rodent and human stem cell-derived neurons, we observed that these do not acquire a brain lipotype per se. However, upon probing the lipid metabolic wiring by supplementing brain lipid precursors, we found that the stem cell-derived neurons were partially able to establish a brain-like lipotype, demonstrating that the cells are partially metabolically committed. Altogether, our report provides an extensive lipidomic resource for brain development and highlights a potential challenge in using stem cell-derived neurons for mechanistic studies of lipid biochemistry, membrane biology and biophysics that can be mitigated by further optimizing in vitro differentiation protocols. Significance StatementWe report an extensive time-resolved resource of lipid molecule abundances across mouse brain development, starting as early as 10 days post-fertilization. The resource reveals a bifurcation in the establishment of the neural lipotype where the canonical 22:6-glycerophospholipid and 18:0-sphingolipid biomarkers are attained in utero, whereas cholesterol is attained after birth. Furthermore, we uncover that the neural lipotype is not established in rodent and human stem cell-derived neurons in vitro.

developmental biology↗

bioRxiv2019

Cell surface mechanics gate stem cell differentiation

Cell differentiation typically occurs with concomitant shape transitions to enable specialized functions. To adopt a different shape, cells need to change the mechanical properties of their surface. However, whether conversely cell surface mechanics control the process of differentiation has been relatively unexplored. Here, we show that membrane mechanics gate the exit from naive pluripotency of mouse embryonic stem cells. By measuring membrane tension during differentiation, we find that naive stem cells release their plasma membrane from the underlying actin cortex when transitioning to a primed state. By mechanically tethering the plasma membrane to the cortex with a synthetic signalling-inert linker, we demonstrate that preventing this detachment forces stem cells to retain their naive pluripotent state. We thus identify a decrease in membrane-to-cortex attachment as a new cell-intrinsic mechanism that is essential for stem cells to exit pluripotency.

biophysics↗

bioRxiv2019

Optogenetic inhibition of Delta reveals digital Notch signaling output during tissue differentiation

Spatio-temporal regulation of signalling pathways plays a key role in generating diverse responses during the development of multicellular organisms. The role of signal dynamics in transferring signalling information in vivo is incompletely understood. Here we employ genome engineering in Drosophila melanogaster to generate a functional optogenetic allele of the Notch ligand Delta (opto-Delta), which replaces both copies of the endogenous wild type locus. Using clonal analysis, we show that optogenetic activation blocks Notch activation through cis-inhibition in signal-receiving cells. Signal perturbation in combination with quantitative analysis of a live transcriptional reporter of Notch pathway activity reveals differential tissue- and cell-scale regulatory modes. While at the tissue-level the duration of Notch signalling determines the probability with which a cellular response will occur, in individual cells Notch activation acts through a switch-like mechanism. Thus, time confers regulatory properties to Notch signalling that exhibit integrative digital behaviours during tissue differentiation.

developmental biology↗