Peripheral nerve regeneration relies critically upon the remarkable plasticity of Schwann cells (SCs), which undergo profound phenotypic reprogramming after injury to execute myelin clearance, neurotrophic support, axonal guidance, and target reinnervation. This reprogramming is governed by a dynamic interplay of signaling networks—including c-Jun, Notch, neuregulin 1 (NRG1)/ErbB receptor tyrosine kinase, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR), transforming growth factor-β (TGF-β)/Smad, Wnt/β-catenin, integrin–focal adhesion kinase (FAK) and Hippo–Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)—that collectively regulate SC dedifferentiation, migration, proliferation, and remyelination. Here, we summarize how these pathways integrate biochemical and mechanical cues from the injury microenvironment to determine SC fate and function. Building on the mechanistic foundation, we highlight emerging biomaterial-based strategies, particularly advanced nerve guidance conduits and functionalized scaffolds, that are being explored to modulate these signaling networks and thereby influence SC reprogramming and neural regeneration. Although such approaches have been shown promise in preclinical models, current evidence remains largely experimental; whether biomaterials can steer SC behavior in spatiotemporally defined manner and overcome the limitations of current clinical approaches has yet to be established. We propose that therapeutic strategies centered on multi-signal, biomaterial-mediated regulations of SC plasticity represent a promising direction for peripheral nerve repair. Finally, we discuss key challenges and future opportunities in translating these findings into clinical practice, emphasizing the need for microenvironment-responsive platforms that recapitulate the natural dynamics of successful nerve regeneration.
Neural stem cell-derived extracellular vesicles (NSC-EVs) are being studied as cell-free interventions after cerebral ischemia-reperfusion injury (CIRI), but the evidence that a specific non-coding RNA (ncRNA) is the active therapeutic component is uneven. This critical narrative review separates vesicle-associated RNA detection, experimental RNA delivery, target engagement, and cargo-specific causal necessity. An explicitly context-sensitive three-tier framework is applied alongside a domain-by-domain evidence matrix that distinguishes direct ischemia evidence from lineage-adjacent, hypoxia-only, transplantation-associated, and cross-disease observations. Among the studies reviewed, engineered human NSC-EVs enriched with miR-125a-5p provide comparatively direct evidence for IKBKG/NF-κB pathway modulation in a rat transient middle cerebral artery occlusion model; however, effectiveness of engineered loading does not establish that endogenous EV miR-125a-5p is required for unmodified-product activity. The miR-150-3p/CASP2 study supports a neuronal survival mechanism in oxygen-glucose deprivation and an MCAO-associated brain-injury model, without establishing direct microglial reprogramming. miR-362-3p/MCAM/Wnt-β-catenin, miR-9/Hes1, and hNPC-EV miR-100-5p/NOX4 extend the experimental picture toward endogenous repair and vascular responses but retain important limitations in cargo necessity, model match, or cell lineage. hNSC transplantation-associated miR-204-5p/EFNB3 cannot be assumed to represent purified NSC-EV action. Spinal cord injury, miR-124, lncRNA, and circRNA observations are explicitly considered indirect for a CIRI-specific NSC-EV claim. This review identifies experimental design and reporting gaps, distinguishes observed dosing from proposed intervention windows, and outlines falsifiable, rather than clinically established, translational priorities. The updated PubMed and Web of Science export audit identified 150 distinct title/abstract records from 224 primary-database records and additionally highlighted an NSC-EV miR-128-3p/oligodendrocyte progenitor cell repair axis, while preserving a clear distinction between title/abstract screening and definitive full-text causal appraisal.
Neurons preserve functional activity despite continual changes in synaptic drive, morphology, and membrane protein turnover. This stability is commonly attributed to homeostatic regulation. There is converging evidence that neurodevelopmental disorders (NDDs) may arise from failure of this regulation. Here, we formulate neuronal homeostasis as a negative-feedback control problem comprising a regulated variable, set point, sensor, controller, and effectors. This formulation converts broad claims of impaired homeostasis into mechanistically distinct hypotheses. Dysfunction may arise from sensor miscalibration, a displaced set point, defective controller transduction, incorrect gain, or saturation or loss of an effector’s adjustability. We use this framework to reinterpret evidence from NDDs in which diverse genetic lesions converge on altered excitability, excitatory-inhibitory balance, and circuit stability. The framework yields two central conclusions. First, homeostatic dysfunction should often be direction-specific rather than uniformly deficient, because upward and downward compensation rely on partially separable molecular and physiological mechanisms. Second, electrophysiological measurements are insufficient to identify the governing regulatory rule as degeneracy permits distinct ion-channel configurations to support similar activity, whereas integral feedback allows the same electrophysiological measurements to arise from different regulatory dynamics. Consequently, localizing dysfunction within the loop requires bidirectional perturbations, longitudinal measurement, and computational models that represent a population of models rather than a unique set of parameters. A control-theoretic framework therefore provides both a mechanistic taxonomy and an experimental strategy for determining how neuronal regulation fails in disease.
Prenatal oxycodone (Oxy) exposure has been associated with several neurodevelopmental outcomes in newborns. However, the molecular mechanisms involved in Oxy-induced placental and fetal brain damage during gestation remain unknown. Endoplasmic reticulum (ER) stress is a cellular stress response triggered by the accumulation of unfolded proteins, which activates the unfolded protein response. Here, we hypothesized that Oxy exposure induces ER stress in the fetal brain-placental axis. To test this hypothesis, we used three model systems: in vitro primary neurons, primary mixed neuroglial cells, and an in vivo model of maternal Oxy exposure. Quantitative Reverse Transcription PCR (qRT-PCR) was employed to detect mRNA expression of ER stress mediators, such as Binding Immunoglobulin Protein (Bip), activating transcription factor 4 (ATF4), spliced X-box binding protein 1 (sXBP1), and C/EBP homologous protein (CHOP). Immunoblot analysis was also used to detect protein expression of ER stress mediators, such as Bip; phosphorylated and total forms of inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α and t-IRE1α) and protein kinase R-like endoplasmic reticulum kinase α (p-PERKα and t-PERKα); phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α); and sXBP1. Further, we detected pro-apoptotic markers such as Bcl-2 interacting mediator of cell death (Bim), p53 upregulated modulator of apoptosis (PUMA), and cleaved poly (ADP-ribose) polymerase (PARP). Exposure of Oxy to rat primary fetal neuronal cells increased mRNA expression of Bip and ATF4. sXBP1 and CHOP mRNA levels were upregulated in both rat primary fetal neuronal cells and mixed neuroglial cells. Prenatal Oxy exposure resulted in increased mRNA expression of all ER stress markers tested in both the placenta and fetal brain. We also observed that Oxy exposure increased protein levels of ER stress markers (Bip, p-IRE1α, t-IRE1α, p-PERKα, t-PERKα, p-eIF2α, and sXBP1), as well as pro-apoptotic and apoptotic markers (Bim, PUMA, and cleaved PARP). In conclusion, Oxy exposure increases ER stress mediators in both the placental and fetal brain compartments, which could further lead to apoptosis.
Social stress is a key risk factor for disorders of increased aversion responsiveness, and changes in cortico-limbic oligodendrocyte lineage and myelination may contribute to this pathological process. In adult male mice, we demonstrated previously that social stress-induced aversion hyper-responsiveness co-occurs with altered oligodendrocyte proliferation-maturation dynamics and myelin content. Overall, however, findings on these inter-relationships are inconsistent across studies using various stress paradigms, suggesting that there is not a simple relationship between social stress and the extent and direction (i.e., loss vs. gain) of changes in the oligodendrocyte lineage and myelin. Under physiological conditions, the immune cells of the CNS, microglia, monitor the CNS microenvironment and contribute to oligodendrocyte lineage and myelin homeostasis. Also, recent reports suggest that microglia state might influence oligodendrocyte lineage changes in response to certain social stress paradigms. Here, we begin to address the hypothesis that social stress induced changes in microglia and oligodendrocyte lineage are inter-related in mice. We employed histological and semi-automated image analyses to characterize a subset of microglia and OPC histological properties in medial prefrontal cortex (mPFC) and basal amygdala (BA) following aversive social experiences, including chronic social stress (CSS), CSS followed by aversion learning (excessive aversive stimulation), and social isolation (as the absence of sociopositive stimulation). Specifically, we assessed: (1) the density and proliferation rate of microglia and OPCs; (2) the spatial relationship between microglia and OPCs; and (3) microglia morphological complexity as a proxy for their activity/state. The preliminary integrative histological evidence is for subtle stress paradigm-associated alterations in microglia- and OPC-related features, and limited correlative histological associations between these cell populations.
