Functional recovery following incomplete spinal cord injury (SCI) depends on the rewiring of motor circuits during which supraspinal connections form new contacts onto spinal relay neurons. We have recently identified a critical role of the presynaptic organizer FGF22 for the formation of new synapses in the remodeling spinal cord. Here, we now explore whether and how targeted overexpression of FGF22 can be used to mitigate the severe functional consequences of SCI. By targeting FGF22 expression to either long propriospinal neurons, excitatory interneurons, or a broader population of interneurons, we establish that FGF22 can enhance neuronal rewiring both in a circuit‐specific and comprehensive way. We can further demonstrate that the latter approach can restore functional recovery when applied either on the day of the lesion or within 24 h. Our study thus establishes viral gene transfer of FGF22 as a new synaptogenic treatment for SCI and defines a critical therapeutic window for its application.

Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

COPYRIGHT © 2023 Zeng and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Neuronal regeneration after injury: a new perspective on gene therapy

https://www.frontiersin.org/articles/10.3389/fnins.2023.1181816/pdf

Neuronal regeneration after injury: a new perspective on gene therapy

Exosomes are nanoscale-sized membrane vesicles released by cells into their extracellular milieu. Within these nanovesicles reside a multitude of bioactive molecules, which orchestrate essential biological processes, including cell differentiation, proliferation, and survival, in the recipient cells. These bioactive properties of exosomes render them a promising choice for therapeutic use in the realm of tissue regeneration and repair. Exosomes possess notable positive attributes, including a high bioavailability, inherent safety, and stability, as well as the capacity to be functionalized so that drugs or biological agents can be encapsulated within them or to have their surface modified with ligands and receptors to imbue them with selective cell or tissue targeting. Remarkably, their small size and capacity for receptor-mediated transcytosis enable exosomes to cross the blood–brain barrier (BBB) and access the central nervous system (CNS). Unlike cell-based therapies, exosomes present fewer ethical constraints in their collection and direct use as a therapeutic approach in the human body. These advantageous qualities underscore the vast potential of exosomes as a treatment option for neurological injuries and diseases, setting them apart from other cell-based biological agents. Considering the therapeutic potential of exosomes, the current review seeks to specifically examine an area of investigation that encompasses the development of Schwann cell (SC)-derived exosomal vesicles (SCEVs) as an approach to spinal cord injury (SCI) protection and repair. SCs, the myelinating glia of the peripheral nervous system, have a long history of demonstrated benefit in repair of the injured spinal cord and peripheral nerves when transplanted, including their recent advancement to clinical investigations for feasibility and safety in humans. This review delves into the potential of utilizing SCEVs as a therapy for SCI, explores promising engineering strategies to customize SCEVs for specific actions, and examines how SCEVs may offer unique clinical advantages over SC transplantation for repair of the injured spinal cord.

Schwann Cell-Derived Exosomal Vesicles: A Promising Therapy for the Injured Spinal Cord

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Inflammatory bowel disease (IBD) is a term encompassing a few chronic inflammatory disorders that leads to damage of the intestinal tract. Although much progress has been made in understanding the pathology of IBD, the precise pathogenesis is not completely understood. Circular RNAs (circRNAs) are single-stranded, covalently closed, endogenous molecules in eukaryotes with a variety of biological functions. CircRNAs have been shown to have regulatory effects in many diseases, such as cancer, cardiovascular disease, and neurological disorders. CircRNAs have also been found to play important roles in IBD, and although they are not sufficiently investigated in the context of IBD, a few circRNAs have been identified as potential biomarkers for the diagnosis and prognosis of IBD and as potential therapeutic targets for IBD. Herein, we survey recent progress in understanding the functions and roles of circRNAs in IBD and discuss their potential clinical applications.

Circular RNAs in inflammatory bowel disease

To achieve longevity, IgA plasma cells require a sophisticated anatomical microenvironment that provides cytokines, cell-cell contacts, and nutrients as well as metabolites. The intestinal epithelium harbors cells with distinct functions and represents an important defense line. Anti-microbial peptide-producing paneth cells, mucus-secreting goblet cells and antigen-transporting microfold (M) cells cooperate to build a protective barrier against pathogens. In addition, intestinal epithelial cells are instrumental in the transcytosis of IgA to the gut lumen, and support plasma cell survival by producing the cytokines APRIL and BAFF. Moreover, nutrients are sensed through specialized receptors such as the aryl hydrocarbon receptor (AhR) by both, intestinal epithelial cells and immune cells. However, the intestinal epithelium is highly dynamic with a high cellular turn-over rate and exposure to changing microbiota and nutritional factors. In this review, we discuss the spatial interplay of the intestinal epithelium with plasma cells and its potential contribution to IgA plasma cell generation, homing, and longevity. Moreover, we describe the impact of nutritional AhR ligands on intestinal epithelial cell-IgA plasma cell interaction. Finally, we introduce spatial transcriptomics as a new technology to address open questions in intestinal IgA plasma cell biology.

/pdf/the-intestine-a-highly-dynamic-microenvironment-for-iga-2vk0lg5c.pdf

The intestine: A highly dynamic microenvironment for IgA plasma cells

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Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

The intestine: A highly dynamic microenvironment for IgA plasma cells