Understanding the role of PPAR-γ in peripheral nerve injury: cellular and transcriptomic approach

Abstract

Although microsurgery remains the standard clinical approach for managing peripheral nerve injury (PNI), clinical outcomes are often suboptimal. Recovery following injury is often poor, particularly over long distances or significant gaps, due to the slow regeneration rate (~1–3 mm per day) and the lack of approved regenerative pharmacological therapies. Thus, researchers are exploring ways to accelerate nerve regeneration. To bridge the gap between previous animal findings and clinical translation, the effect of peroxisome proliferator-activated receptor gamma (PPAR-γ) on neurite outgrowth was investigated using a human neuroblastoma cell line (SH-SY5Y), a 3D co-culture of SH-SY5Y with Schwann cells (SCL4.1/F7), and a chemotherapeutic-induced degenerative in vitro model. Neurite outgrowth increased with 10 μM ibuprofen across all conditions examined in the study, including SH-SY5Y monocultures, 3D co-cultures, and the chemotherapeutic injury model. To better understand the role of PPAR-γ in a broad range of relevant cell types, a publicly available single-cell RNA sequencing dataset (GSE216665) of rat sciatic nerve post-chronic constriction injury was analysed at multiple time points and compared to the naïve condition. Differentially expressed genes (DEGs) were identified, followed by Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses at early stages of injury across Schwann and myeloid populations. The dynamic changes in PPAR-γ (Pparg) expression following injury in Schwann cells and myeloid cells suggest a potential role of PPAR-γ in nerve regeneration. Preliminary co-expression and protein protein interaction analyses were also performed to explore PPAR-γ-related signalling in nerve repair and immune regulation. An epidemiological study using the Clinical Practice Research Datalink (CPRD)-Aurum database was also conducted to gain insights into the demographics, common types and sites of injury, and associated comorbidities of PNI patients in the UK between 2000 and 2001. These insights are crucial for developing more effective therapeutic strategies.