Transcriptomic Evidence Of Sympathetic Modulation Of Cells Involved In Peripheral Nerve Injury

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PURPOSE: Peripheral nerve injury initiates complex regenerative programs involving Schwann cells, macrophages, fibroblasts, and endothelial cells. Sympathetic activity rises markedly after injury, yet its direct influence on the local repair microenvironment remains poorly defined. We hypothesized that nerve injury induces upregulation of adrenergic receptors across key cell types, enabling direct sympathetic modulation of immune and regenerative processes via catecholaminergic signaling. METHODS: We performed single-cell RNA sequencing (scRNA-seq) meta-analysis of two public datasets: (1) longitudinal mouse sciatic nerve crush injury (GEO: GSE198582) and (2) sympathetic/sensory ganglia transcriptomes (GSE175421). Using single-cell analysis, we profiled adrenergic receptor expression (α: ADRA1A/B/D, ADRA2A/B/C; Β: ADRB1/2/3) across cell types and timepoints (Days 0-14). Intercellular communication between sympathetic neurons and injury-site cells was inferred using NicheNet and CellPhoneDB v5. RESULTS: Adrenergic receptor expression was markedly increased following injury. ADRB2 (β₂-adrenergic receptor) exhibited a 3-5-fold rise, with receptor-positive Schwann cells and macrophages increasing from 15-20% at baseline to 60-75% at Day 3 post-injury. Temporal profiling revealed biphasic activation: early receptor induction in macrophages (Days 1-3) corresponding to inflammatory influx, followed by sustained Schwann cell expression (Days 7-14) during remyelination. Fibroblasts preferentially upregulated ADRA1B, while endothelial cells showed mixed α/β receptor expression. Ligand-receptor mapping identified sympathetic neuron catecholamine synthesis genes (TH, DBH, DDC) as key senders driving downstream injury-site transcriptional responses. CONCLUSION: Peripheral nerve injury elicits robust, time-dependent adrenergic receptor upregulation in multiple cell types, establishing a molecular framework for sympathetic regulation of both inflammatory and reparative phases. These findings reveal adrenergic signaling as a previously unrecognized determinant of nerve regeneration. Ongoing validation studies using denervation and pharmacologic blockade models aim to define optimal intervention windows for clinical translation.