Biology subjects

Riou, G.

Publications and source records attributed to Riou, G..

7 recordsLinked to original sources

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↗

bioRxiv2025

Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Cardiac lymphatics have emerged as potential targets in cardiovascular diseases (CVDs). However, we recently reported that despite extensive lymphatic expansion during experimental cardiac pressure-overload, lymphatic drainage remained insufficient. To unravel the cellular and molecular mechanisms underlying lymphatic dysfunction in CVDs, we applied cardiac single-cell (sc) analyses in a murine heart failure model. Transaortic constriction (TAC), in C57BL/6J and BALB/c mice, was used to model chronic pressure-overload-induced cardiac hypertrophy and heart failure, respectively. Cardiac lymphatic (LEC) and blood vascular (BECs) endothelial cells were analyzed by scRNAseq (10XGenomics). Lymphatic targets were validated by immunohistochemistry and wholemount-imaging, and in vitro using human LEC cultures. We identified three distinct cardiac lymphatic subpopulations, capillary (LEC1), precollector (LEC2), and valvular (LEC3) clusters, and several BECs clusters, including venous BEC (vBEC). Chronic pressure-overload led to expansion of lymphatic capillaries and loss of valves in BALB/c, but not C75BL6/J. Analysis of differentially expressed genes (DEG) post-TAC revealed reduction only in BALB/c of lymphatic cell-junction components. In contrast, LEC expression of anchoring filaments, immune cell-adhesion molecules, and chemokines was preserved, or increased, indicating functional lymphatic-mediated immune cell uptake post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)-1{beta}-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier properties may underly poor drainage capacity during pressure-overload, despite potent lymphangiogenesis and preserved LEC immune attraction. Further studies are needed to address how to restore lymphatic health to accelerate resolution of both inflammation and edema in CVDs.

cell biology↗

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↗

bioRxiv2021

Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimers disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of A{beta} peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of A{beta} secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variations on SorLA protein indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

cell biology↗

bioRxiv2021

Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure

RationaleLymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphatics in non-ischemic cardiomyopathy induced by pressure-overload remains to be determined. ObjectiveInvestigate cardiac lymphangiogenesis following transverse aortic constriction (TAC) in adult male or female C57Bl/6J or Balb/c mice, and in patients with end-stage HF. Methods & ResultCardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, edema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis, respectively. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice. The gender- and strain-dependent mouse cardiac hypertrophic response to TAC, especially increased ventricular wall stress, led to lymphatic expansion in the heart. Our experimental findings that ventricular dilation triggered cardiac lymphangiogenesis was mirrored by observations in clinical HF samples, with increased lymphatic density found in patients with dilated cardiomyopathy. Surprisingly, the striking lymphangiogenesis observed post-TAC in Balb/c mice, linked to increased cardiac Vegfc, did not suffice to resolve myocardial edema, and animals progressed to dilated cardiomyopathy and HF. Conversely, selective inhibition of the essentially Vegfd-driven capillary lymphangiogenesis observed post-TAC in male C57Bl/6J mice did not significantly aggravate cardiac edema. However, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, while the TAC-triggered development of interstitial cardiac fibrosis was unaffected by anti-VEGFR3, inhibition of lymphangiogenesis increased perivascular fibrosis and accelerated the development of left ventricular dilation and cardiac dysfunction. ConclusionsWe demonstrate for the first time that endogenous cardiac lymphangiogenesis limits pressure-overload-induced cardiac inflammation and perivascular fibrosis, thus delaying HF development. While these findings remain to be confirmed in a larger study of HF patients, we propose that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development.

physiology↗