Biology subjects

Gomez-Sanchez, J. A.

Publications and source records attributed to Gomez-Sanchez, J. A..

8 recordsLinked to original sources

bioRxiv2026

Inflammation-induced epigenetic memory restores oligodendrocyte progenitor cell regenerative capacity in the aged central nervous system

Although remyelination, a central nervous system (CNS) regenerative process mediated by oligodendrocyte progenitor cells (OPCs), takes place in an inflammatory environment the long-term impact of inflammation on OPC remyelination capacity remains unclear. Here, we studied the short- and long-term impact of systemic inflammation on adult OPCs to assess whether transient inflammation triggers enduring chromatin remodelling indicative of inflammatory memory in OPCs. We observed long-lasting epigenetic modifications in response to both lipopolyssaccharide (LPS) and polyinosinic:polycytidylic acid (Poly(I:C)), but only LPS induced a tolerance-like memory. LPS-mediated tolerance-like memory enhanced OPC differentiation after demyelination in aged mice, reducing axonal damage. Our findings reveal OPC epigenetic memory of inflammation as a mechanism by which adult OPCs adapt to inflammatory challenges, which could be harnessed to reduce neuroinflammation and enhance remyelination efficiency in ageing and neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Cell-type Specific Extracellular Vesicles in Mouse Brain: Proteomic Signatures Highlight Astrocytic GlialCAM Network and GPCR Enrichment

Extracellular vesicles (EVs) mediate intercellular communication in the central nervous system (CNS) and are emerging as biomarkers of brain health and disease. However, the molecular composition of cell type-specific brain EVs, particularly astrocyte-derived EVs (ADEVs), remains poorly defined. We performed comparative proteomic analysis of neuronal (NDEVs), microglial (MDEVs), and astrocytic (ADEVs) from mouse brain using magnetic immunocapture and LC-MS/MS proteomic profiling. Each EV subtype displayed distinct molecular fingerprints. NDEVs were enriched in synaptic and neurogenesis-related proteins (e.g., APP, SNAP25, GPR158 and BDNF), whereas MDEVs contained immune and phagocytic markers (e.g., TMEM119, CX3CR1, CD11B). Strikingly, the ADEV proteome closely mirrored the recently characterized GlialCAM interactome from leukodystrophy research, encompassing GlialCAM/MLC1 and associated partners involved in ion and water homeostasis (EAAT1/2, AQP4, GJA1), together with GPCRs such as GPRC5B. This overlap suggests that ADEVs encapsulate a molecular scaffold characteristic of astrocytic endfeet, potentially extending their signaling functions to the extracellular space. In conclusion, our study provides a detailed comparative proteomic characterization of brain cell type-specific EVs, revealing that ADEVs contain the GlialCAM/MLC1 network and GPCRs. These findings highlight ADEVs as promising candidates for biomarker development and mechanistic studies of blood-brain barrier integrity and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Assessment of Motoneuronal Regeneration and Wallerian Degeneration Following Axotomy in Postnatal Mice

Nerve injuries during early postnatal stages results in markedly different outcomes compared to adult injury, with significant motoneuronal death masking potential regenerative capacity. This study systematically evaluated motoneuronal survival, axonal regeneration, and Wallerian degeneration following peripheral nerve injury at distinct postnatal stages (P4, P10, and P30) in mice. Using ChAT-Cre/Ai9(RCL-tdT) and ChAT-Cre/RiboTag transgenic models, we assessed both histological and transcriptomic responses after sciatic nerve lesions. Injury at P4 induced substantial motoneuron death (1150%), whilst P10 and P30 animals showed minimal neuronal loss. However, when correcting for neuronal survival, P4 mice demonstrated the highest regenerative capacity, with surviving neurons achieving 100% axonal regeneration. Motoneuron-specific translatome analysis revealed that P30 animals activated a robust regeneration-associated gene (RAG) programme, including classical markers such as Atf3, Gap43, and Ngfr. In contrast, P4 neurons showed minimal RAG upregulation, suggesting they retain an intrinsic growth state that facilitates regeneration without requiring transcriptional reprogramming. P10 animals exhibited a transitional phenotype with impaired RAG activation and reduced regenerative capacity. Wallerian degeneration proceeded efficiently across all developmental stages, with age-specific differences in myelin clearance kinetics and macrophage recruitment. Transcriptomic analysis confirmed consistent downregulation of myelination programmes and upregulation of pro-regenerative markers following injury, regardless of age. These findings indicate that regenerative capacity is primarily determined by the intrinsic growth state of motoneurons rather than extrinsic factors. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/691768v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9079b4org.highwire.dtl.DTLVardef@12640b7org.highwire.dtl.DTLVardef@62e763org.highwire.dtl.DTLVardef@1453180_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

In vivo Morphological Dynamics of Single Laser-Axotomized Corneal Nerve Fibers in Sarm1-Null Adult Mice

Axonal regeneration represents a pivotal aspect of the adult peripheral nervous system (PNS). When an injury occurs, peripheral axons are able to regenerate and reestablish connections with their original targets. Although several precision techniques for severing axons in various non-mammalian model organisms have allowed to study the dynamics of regeneration after injury, similar axonal injury models have yet to be fully developed in mammals. In this study, we introduced a novel experimental method for laser-induced axotomy of single corneal sensory subbasal nerve fibers. This method enables the in vivo monitoring and quantification of axonal degeneration and regeneration morphological dynamics in adult mice. Results revealed that the degeneration of the distal stump of the subbasal fiber was delayed in mice lacking the protein SARM1, which promotes degenerative process after injury. Meanwhile, the proximal stump maintained the regenerative dynamics of the subbasal fiber, but regeneration of its nerve terminals was impaired. The present study introduces a valuable model for the in vivo study of the morphological plasticity dynamics of peripheral axons after injury in genetically tractable adult mammals.

neuroscience↗

bioRxiv2022

SARM1 detection in oligodendrocytes but not Schwann cells though sarm1/Sarm1 deletion does not perturb CNS nor PNS myelination in zebrafish and mice.

SARM1 is a central regulator of programmed axon death and is required to initiate axon self-destruction after traumatic and toxic insults to the nervous system. Abnormal activation of this axon degeneration pathway is increasingly recognized as a contributor to human neurological disease and SARM1 knockdown or inhibition has become an attractive therapeutic strategy to preserve axon loss in a variety of disorders of the peripheral and central nervous system. Despite this, it remains unknown whether Sarm1/SARM1 is present in myelinating glia and whether it plays a role in myelination in the PNS or CNS. It is important to answer these questions to understand whether future therapies inhibiting SARM1 function may have unintended deleterious impacts on myelination. Here we show that Sarm1 mRNA is present in oligodendrocytes in zebrafish but only detectable at low levels in Schwann cells in both zebrafish and mice. We find SARM1 protein is readily detectable in murine oligodendrocytes in vitro and in vivo and activation of endogenous SARM1 in oligodendrocytes induces cell death. In contrast, SARM1 protein is not detectable in Schwann cells and satellite glia in the adult murine nervous system. Cultured Schwann cells contain negligible functional SARM1 and are insensitive to specific SARM1 activators. Using zebrafish and mouse Sarm1 mutants, we show that SARM1 is not required for initiation of myelination nor myelin sheath maintenance by oligodendrocytes and Schwann cells. Thus, strategies to inhibit SARM1 function in the nervous system to treat neurological disease are unlikely to perturb myelination in humans. Main PointsO_LISARM1 protein is detectable in oligodendrocytes but not in Schwann cells C_LIO_LIOligodendrocytes but not Schwann cells die in response to endogenous SARM1 activation C_LIO_LICNS nor PNS myelination, in zebrafish and mice, is hindered by loss of sarm1/Sarm1 C_LI

neuroscience↗

bioRxiv2022

Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration after peripheral nerve injury

After peripheral nerve injuries, successful axonal growth and functional recovery requires the reprogramming of Schwann cells into a reparative phenotype, a process dependent on the activation of the transcription factor c-Jun. Nevertheless, axonal regeneration is greatly impaired in aged organisms or after chronic denervation leading to important clinical problems. This regenerative failure has been associated to a diminished c-Jun expression by Schwann cells, but whether the inability of these cells to maintain a repair state is associated to the transition into a phenotype inhibitory for axonal growth, has not been evaluated so far. We find that repair Schwann cells transitions into a senescent phenotype, characterized by diminished c-Jun expression and secretion of factor inhibitory for axonal regeneration in both aging and chronic denervation. In both conditions, elimination of senescent Schwann cells by systemic senolytic drug treatment or genetic targeting improves nerve regeneration and functional recovery in aging and chronic denervation, associated with an upregulation of c-Jun expression and a decrease in nerve inflammation. This work provides the first characterization of senescent Schwann cells and their impact over axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration, and functional recovery after peripheral nerve injuries.

neuroscience↗

bioRxiv2021

A genetic compensatory mechanism regulated by c-Jun and Mef2d modulates the expression of distinct class IIa HDACs to ensure peripheral nerve myelination and repair

The class IIa histone-deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express HDAC4, 5 and 7 but not HDCA9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when HDAC4 and 5 are knocked-out from Schwann cells, a c-Jun dependent mechanism induces the compensatory overexpression of HDAC7 permitting, although with a delay, the formation of a myelin sheath. When HDAC4,5 and 7 are simultaneously removed, the Myocyte- specific enhancer-factor d (Mef2d) binds to the promoter and induces the de novo expression of HDAC9, and although several melanocytic- lineage genes are mis- expressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa HDAC family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.

cell biology↗

bioRxiv2020

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

neuroscience↗