TSG-6-Mediated Extracellular Matrix Modifications Regulate Hypoxic-Ischemic Brain Injury

Area of Science:

• Neuroscience
• Extracellular Matrix Biology
• Developmental Biology

Background:

• Proteoglycans regulate extracellular matrix (ECM) homeostasis and tissue response to injury.
• Hypoxic-ischemic (H-I) injury disrupts brain homeostasis.
• The role of hyaluronic acid (HA) modifications in the brain's response to H-I injury is unknown.

Purpose of the Study:

• To investigate the role of TNFα-stimulated gene-6 (TSG-6) in modifying brain ECM hyaluronic acid (HA).
• To determine if TSG-6-mediated ECM modifications regulate the Hippo-YAP1 pathway during neurodevelopment and in response to H-I injury.
• To examine the age- and sex-dependent effects of TSG-6 deficiency on H-I injury outcomes.

Main Methods:

• Utilized male and female mice lacking TSG-6 expression (TSG-6-/-).
• Analyzed ECM HA modifications by TSG-6 during neurodevelopmental windows.
• Assessed Hippo-YAP1 pathway activity and expression of YAP1 targets (EAAT1, EAAT2).
• Evaluated brain response to H-I injury in TSG-6-/- mice at different ages and sexes.

Main Results:

• TSG-6 is active in the brain from birth, differentially modifying ECM HA during development.
• TSG-6-dependent ECM HA modifications regulate Hippo-YAP1 pathway activity.
• TSG-6-/- mice exhibit dysregulated YAP1 target expression (EAAT1, EAAT2).
• TSG-6 deficiency leads to age- and sex-dependent sensitization to H-I injury, with neonates showing anti-inflammatory and adult males showing pro-inflammatory responses.

Conclusions:

• TSG-6-dependent ECM HA modifications act as a developmental switch regulating the Hippo-YAP1 pathway in the brain.
• The Hippo-YAP1 pathway, modulated by TSG-6 and ECM, is a key regulator of age- and sex-dependent brain injury responses.
• Findings highlight TSG-6 as a critical factor in brain homeostasis and injury resilience.