Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy
Diana Tavares-Ferreira, Breanna Q. Shen, Juliet M. Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B. Kotamarti, Nikhil N. Inturi, Khadijah Mazhar, Eroboghene E. Ubogu, Geneva L. Thomas, Trapper Lalli, Shai M. Rozen, Dane K. Wukich, Theodore J. Price
Diana Tavares-Ferreira, Breanna Q. Shen, Juliet M. Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B. Kotamarti, Nikhil N. Inturi, Khadijah Mazhar, Eroboghene E. Ubogu, Geneva L. Thomas, Trapper Lalli, Shai M. Rozen, Dane K. Wukich, Theodore J. Price
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Research Article Inflammation Neuroscience

Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease using transcriptomics on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population and control sural nerves from cross-facial nerve graft surgery. First, comparing DPN versus control sural nerves revealed inflammatory activation and sensory changes in DPN. Second, when comparing mixed sensory and motor tibial and purely sensory sural nerves, we identified key pathway differences in affected DPN nerves, with distinct immunological features observed in sural nerves. Third, spatial transcriptomics of sural nerves revealed shifts in immune cell types associated with axonal loss progression. We also found clear evidence of neuronal transcript changes, like PRPH, in nerves with axonal loss, suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons, generating evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work provides insight into altered cellular and transcriptomic profiles in human nerves in DPN and highlights sensory axon mRNA transport as a potential contributor to nerve degeneration.

Authors

Diana Tavares-Ferreira, Breanna Q. Shen, Juliet M. Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B. Kotamarti, Nikhil N. Inturi, Khadijah Mazhar, Eroboghene E. Ubogu, Geneva L. Thomas, Trapper Lalli, Shai M. Rozen, Dane K. Wukich, Theodore J. Price

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Figure 5

Comparative analysis in sural nerves with moderate versus severe axonal loss.

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Comparative analysis in sural nerves with moderate versus severe axonal ...
(A) Overview of spatial transcriptomic samples used for cell-cell interaction analysis. (B) Venn diagram showing the number of signaling pathways shared between each severe sample and the moderate axonal loss sample. (C) Heatmap of communication probabilities for top shared signaling pathways across severe-versus-moderate comparisons. Red indicates pathways enriched in severe samples; blue indicates pathways enriched in moderate axonal loss sample. (D) Dot plot of ligand-receptor pairs and associated sender-receiver cell type pairs that are uniquely present in the moderate sample (S8). (E) Cell type–level communication roles for the SEMA7 and ANGPT signaling pathways in the moderate sample, showing sender, receiver, mediator, and influencer roles across cell types. (F) Dot plot of ligand-receptor pairs uniquely shared across severe samples. (G) Cell type–level communication roles in the TGF-β signaling network in a representative severe sample (S11). (H) Overview of moderate and severe axonal loss samples used for bulk RNA sequencing analysis. (I) Differential gene expression between sural nerves with severe versus moderate axonal loss (fold change > 1.5, adjusted P value < 0.05). (J) Top genes differentially expressed. (K) Gene enrichment analysis shows the top pathways affected by the differentially expressed genes. Q = adjusted P value.