Targeting the Mechanosensitive Channel Piezo2 Alleviates Intracerebral Hemorrhage-induced Brain Injury by Modulating...

Area of Science:

• Neuroscience
• Cell Biology
• Mechanobiology

Background:

• Secondary brain injury (SBI) after intracerebral hemorrhage (ICH) involves neuronal damage from mechanical forces.
• The mechanisms by which neurons sense and respond to mechanical stress are not fully understood.

Purpose of the Study:

• Investigate the role of the mechanosensitive ion channel Piezo2 in ICH-induced SBI.
• Elucidate the molecular mechanisms underlying Piezo2's involvement in neuronal damage.

Main Methods:

• Utilized a collagenase-induced ICH mouse model.
• Performed single-cell RNA sequencing to identify Piezo2 upregulation.
• Employed genetic knockdown (shRNA) and pharmacological inhibition (D-GsMTx4) of Piezo2 in vivo.

Main Results:

• Piezo2 was significantly upregulated in neurons surrounding the hematoma.
• Piezo2 inhibition alleviated acute neurological deficits, reduced brain edema, and improved long-term cognitive function.
• Inhibition of Piezo2 attenuated neuronal endoplasmic reticulum (ER) stress by downregulating the PERK/ATF4/CHOP pathway.

Conclusions:

• Piezo2 plays a critical role in mediating neuronal damage following ICH.
• Modulating Piezo2 offers a potential therapeutic strategy to mitigate secondary neurodegeneration by reducing ER stress.
• Targeting Piezo2 warrants further preclinical investigation for clinical applications in ICH treatment.