Dataset Information

Multi-omics analysis of the bladder and its sensitivity to inosine in a rat model of spinal cord injury

ABSTRACT: This study investigates the molecular changes in the bladder following spinal cord injury (SCI) in rats and the impact of inosine treatment using a multi-omics approach. We discovered the activation of PARP (Poly(ADP-ribose) polymerase) in response to SCI, a previously unrecognized phenomenon, and its attenuation with inosine treatment. SCI triggered significant DNA damage and oxidative stress pathways, whereas inosine treatment prevents DNA damage and inhibits PARP activation, offering a potential therapeutic avenue. The integrated analysis of transcriptomics and proteomics data revealed concordant regulation of multiple pathways following SCI, including EIF2 signaling and NRF2-mediated oxidative stress response, which are ameliorated by inosine treatment. These findings have relevance to human neurogenic bladder pathobiology. Pathway inhibition by inosine in the setting of SCI suggests its potential for neuroprotection in the bladder. Despite limitations, such as the focus on male rats and a lack of proteomics data from separated detrusor and mucosa, this study provides valuable insights into the molecular mechanisms underlying bladder dysfunction following SCI. It also suggests the repurposing of FDA-approved PARP inhibitors for the treatment of bladder dysfunction following spinal injury.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Urinary Bladder

SUBMITTER: Wei Yang

LAB HEAD: Wei Yang

PROVIDER: PXD046096 | Pride | 2025-07-14

REPOSITORIES: Pride

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Multiomics analysis unveils an inosine-sensitive DNA damage response in neurogenic bladder after spinal cord injury.

Hashemi Gheinani Ali A Sack Bryan S BS Bigger-Allen Alexander A Thaker Hatim H Atta Hussein H Lambrinos George G Costa Kyle K Doyle Claire C Gharaee-Kermani Mehrnaz M Patalano Susan S Piper Mary M Cotellessa Justin F JF Vitko Dijana D Li Haiying H Kadayil Prabhakaran Manubhai M Cristofaro Vivian V Froehlich John J Lee Richard S RS Yang Wei W Sullivan Maryrose P MP Macoska Jill A JA Adam Rosalyn M RM

JCI insight 20250508 12

Spinal cord injury (SCI) evokes profound dysfunction in hollow organs such as the urinary bladder and gut. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed that systemic treatment with the neuroprotective agent inosine improved bladder function following SCI in rats. Here, we applied integrated multi-omics analysis to explore molecular alterations in the bladder over time and their sensitivity to inosine following SCI. Canonica ...[more]

PMID: 40338665

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Project description:T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T-cell deficient athymic nude (AN) rats recover better than immunocompetent Sprague-Dawley (SD) rats following spinal cord transection. In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery. AN rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for Th2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue. 2x2 model with 4 groups and 12 total samples. 2 rat strains (athymic nude [AN] and Sprague-Dawley [SD]) and 2 time points (1 week post-injury [acute] and 8 weeks post-injury [chronic]). 3 samples per group, for a total of 12 samples. No technical replicates were performed. Acute SD group = rats 618, 619, and 620. Chronic SD group = rats 605, 606, and 608. Acute AN group = rats 714, 715, and 717. Chronic AN group = rats 707, 712, and 713.

Project description:Background: Traumatic spinal cord injury (SCI) triggers local and systemic inflammation cascades, limiting neuroregeneration and impeding functional recovery. We investigated the systemic effect of immunomodulation with Interleukin-4 (IL-4) on the local immune reaction and regeneration in injured spinal cord tissue, in addition to the systemic cytokine landscape after SCI in rats. Methodology: After performing a T10 laminectomy, 120 female Wistar rats were randomized to either thoracic clip compression/contusion SCI or sham. SCI animals received intraperitoneal (i.p.) IL-4 or vehicle injections twice daily for up to 7 days post-injury (dpi). Rats underwent a battery of neurobehavioral tests and were sacrificed at 1, 3, 7, 14, and 28 dpi. Transcriptomcis, proteomics and immunohistochemistry (IHC) was used to assess macrophage polarization, cellular neurodegeneration, and astrogliosis of explanted spinal cords. High throughput seromics was applied to measure levels of 18 cytokines in rat serum, which were also compared to SCI patient serum data. Results: IL-4-treated rats showed a significantly better recovery in the Basso, Beattie, Bresnahan locomotor rating scale score and several Catwalk XT gait analysis parameters at 14 dpi. RNA-Seq and proteomics analyses revealed a significant upregulation in gene ontologies pertaining to improved axonogenisis and tissue repair along with reduced neuronal death and the pro-inflammatory TNFa signaling. This was verified via IHC, showing a higher abundance of IBA1+/ARG1+ and IBA1+/CD206+ M2-macrophages with a lower abundance of IBA1+/iNOS+ M1-macrophages compared to vehicle-treated rats at 3 dpi. Furthermore, post-traumatic cyst size was significantly reduced with IL-4 treatment at 28 dpi. While APC+ oligodendrocytes showed a significantly higher cell count in the IL-4 group, no significant difference was noted in NeuN+ neurons compared to the vehicle-treated group at 28 dpi. Seromics revealed significantly higher levels of pro-inflammatory serum cytokines in vehicle-treated rats compared to sham rats in the acute to subacute post-injury phase (1, 3 and 7 dpi), which were effectively suppressed by IL-4 treatment. Consistent with our rat model, data analysis of SCI patients revealed improved outcome of patients with low serum levels of pro-inflammatory cytokines reduced by IL-4. Conclusions: Intraperitoneal IL-4 treatment modulated local and systemic inflammation after SCI and improved functional recovery. Transcriptomic and proteomic profiling revealed activation of regenerative and neuroprotective pathways and suppression of pro-inflammatory signaling, supporting the histological and behavioral findings. These results provide mechanistic insight into IL-4’s effects and support its further preclinical evaluation in SCI.

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