Biology subjects

Lebron-Galan, R.

Publications and source records attributed to Lebron-Galan, R..

4 recordsLinked to original sources

bioRxiv2024

Circulating Myeloid-Derived Suppressor Cell load and disease severity are associated to an enhanced oligodendroglial production in a murine model of multiple sclerosis

BackgroundMultiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) that is highly heterogeneous in terms of disease severity and tissue damage extent. Improving myelin restoration is essential to prevent neurodegeneration and the associated disability in MS patients. However, remyelinating therapies are failing in clinical trials, in part, due to the absence of classifying biomarkers of different endogenous regenerative capacities amongst enrolled patients. We previously reported that circulating monocytic myeloid-derived suppressor cells (M-MDSCs) at the onset of the murine model of MS experimental autoimmune encephalomyelitis (EAE) are associated with milder disease courses and less degree of demyelination and axonal damage in spinal cord lesions, while at peak are indicative of a better symptom recovery. Moreover, M-MDSCs are able to promote in vitro oligodendrocyte precursor cell (OPC) proliferation and differentiation towards mature oligodendrocytes (OLs) through the release of the soluble factor osteopontin. ResultsHere, we show a relationship between disease severity and a gradient of OPCs between the rim and the core in mixed active-inactive lesions of MS patients, along with a positive correlation between M-MDSC density and OPC abundance in the same lesions. We also show that EAE disease severity negatively influences the density of total and newly generated OPCs found associated to the demyelinated lesions of the spinal cord at the peak of the disease. In addition, disease severity also impacts the abundance of newly generated OLs originated either during the effector phase or during the early recovery phase. We also demonstrate the positive association between infiltrated M-MDSCs and the abundance of OPCs in the periplaque of demyelinating lesions at the peak of EAE. Interestingly, circulating M-MDSCs at EAE onset and peak of the disease are directly associated to a higher density of newly generated OLs in the plaque and periplaque, respectively. ConclusionDisease severity clearly impacts oligodendrocyte generation during a neuroinflammatory insult like EAE. Our results set the basis for further studies on M-MDSCs as a promising new biomarker that identify a CNS prone to the generation of new OLs that may contribute to restore myelin.

neuroscience↗

bioRxiv2023

GRAPHENE OXIDE AS A NOVEL IMMUNOTHERAPY TOOL FOR THE MODULATION OF MYELOID-DERIVED SUPPRESSOR CELL ACTIVITY IN THE CONTEXT OF MULTIPLE SCLEROSIS

Multiple Sclerosis (MS) is a chronic, inflammatory disease of the central nervous system. Despite the pharmacological arsenal approved for MS, there are treatment-reluctant patients for whom cell therapy appears as the only therapeutic alternative. Myeloid-derived suppressor cells (MDSCs) are immature cells of the innate immune response able to immunosuppress T lymphocytes and to promote oligodendroglial differentiation in experimental autoimmune encephalomyelitis (EAE), a preclinical model for MS. Culture devices need to be designed so that MDSCs maintain a state of immaturity and immunosuppressive function similar to that exerted in the donor organism. Graphene oxide (GO) has been described as a biocompatible material with the capacity to biologically modulate different cell types, including immune cells. In the present work, we show how MDSCs isolated from immune organs of EAE mice maintain an immature phenotype and highly immunosuppressive activity on T lymphocytes after being cultured on 2D reduced GO films (rGO200) compared to those grown on glass. This activity is depleted when MDSCs are exposed to slightly rougher and more oxidized GO substrates (rGO90). The greater reduction in cell size of cells exposed to rGO90 compared to rGO200 is associated with the activation of apoptosis processes. Taken together, the exposure of MDSCs to GO substrates with different redox state and roughness appears as a good strategy to control MDSC activity in vitro. This versatility of GO nanomaterials and the impact of their physico-chemical properties in immunomodulation open the door to its possible selective therapeutic use for pathologies where MDSCs need to be enhanced or inhibited.

immunology↗

bioRxiv2022

Extracellular matrix protein anosmin-1 overexpression regulates dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in MPTP model of Parkinson disease

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. Furthermore, overexpression of A1 in vivo gives rise to higher number of dopaminergic neurons in the olfactory bulb. Here, using A1 overexpressing mice (A1-mice), we studied the effects of A1 on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). A1 overexpression increases the number of dopaminergic SNpc neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice do not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, these analyses confirm A1 as a principal regulator of the FGF pathway in the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.

neuroscience↗

bioRxiv2022

Myeloid-Derived Suppressor Cells are relevant factors to predict the severity of multiple sclerosis

Multiple Sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Previous retrospective investigations in the MS model, experimental autoimmune encephalomyelitis (EAE), highlighted the important relationship between monocytic-myeloid-derived suppressor cells (M-MDSCs) and the experimented severity of the clinical course. In this work, we show for the first time cells resembling M-MDSCs associated to MS lesions, whose abundance was related to milder MS clinical courses. Moreover, Ly-6Chi cells (which are indistinguishable from circulating M-MDSCs in mice) are useful biomarkers to predict a milder severity of the EAE disease course and a lesser tissue damage extent. Finally, the abundance of M-MDSCs in blood from untreated MS patients at their first relapse was inversely correlated with EDSS at baseline and relapse recovery one-year later. In summary, our data point to M-MDSC load as a promising biomarker of patients clinical course severity. TeaserThe abundance of myeloid-derived suppressor cells is related to a milder clinical course in multiple sclerosis patients.

neuroscience↗