Using systems biology approaches to identify signalling pathways activated during chronic wound initiation

Area of Science:

• Biomedical Science
• Systems Biology
• Wound Healing Research

Background:

• Chronic wounds represent a significant global health burden.
• The underlying mechanisms initiating and driving chronic wound development remain largely unknown.

Purpose of the Study:

• To identify key metabolic signaling pathways involved in the initiation of chronic wound development using a diabetic mouse model.
• To elucidate the molecular events contributing to the chronicity of wounds.

Main Methods:

• Employed a Systems Biology Approach with nanoString nCounter technology and weighted gene correlation network analysis (WGCNA).
• Analyzed gene expression in diabetic mouse wound tissues at multiple time points (6, 12, 24, 48 hours post-wounding).
• Utilized Reactome database for pathway analysis and ELISA for protein validation.

Main Results:

• Identified PTEN stabilization, down-regulating PI3K/AKT1 and Nrf2, leading to reduced antioxidant production and increased oxidative stress.
• Observed upregulation of inflammation-related pathways, including arachidonic acid metabolism, IFNγ, and catecholamines.
• Found overexpression of HIF3α, potentially inhibiting Hif1α and impairing growth factor/cytokine activation, alongside decreased FGF1 and increased thrombospondin-1, reducing angiogenesis.
• Noted downregulation of glycolytic enzymes, decreasing pyruvate and ATP production, resulting in cell death and wound paralysis.

Conclusions:

• Discovered critical metabolic and signaling pathway dysregulations contributing to chronic wound chronicity.
• Findings highlight impaired antioxidant defense, heightened inflammation, reduced angiogenesis, and energy deficits as key factors.
• These insights pave the way for novel therapeutic strategies targeting early intervention in chronic wound management.