Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications.

Area of Science:

• Hematology
• Cell Biology
• Physiology

Background:

• Sickle cell disease (SCD) is characterized by abnormal phosphatidylserine (PS) exposure on red blood cells (RBCs).
• This PS exposure contributes to anemia, thrombosis, and vaso-occlusive crises (VOC) in SCD.
• The precise mechanisms driving excessive PS exposure in sickle RBCs are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying phosphatidylserine exposure in sickle RBCs.
• To identify key mediators involved in the mechanotransduction pathway leading to PS exposure.
• To explore potential therapeutic strategies targeting this pathway for SCD management.

Main Methods:

• Utilized electrophysiology, live-cell imaging, and flow cytometry.
• Investigated the role of the mechanosensitive channel PIEZO1 and the lipid scramblase TMEM16F in sickle RBCs.
• Assessed the impact of PIEZO1 inhibition using benzbromarone on cellular events.

Main Results:

• Deoxygenation-induced sickling activates PIEZO1, leading to calcium influx and TMEM16F activation.
• This cascade results in increased phosphatidylserine exposure and microparticle release.
• Activated PIEZO1 enhances thrombin generation and RBC adhesion to endothelial cells.
• Partial inhibition of PIEZO1 with benzbromarone mitigated these SCD-associated changes.

Conclusions:

• Identified a novel mechanotransduction pathway involving PIEZO1 and TMEM16F in sickle RBCs.
• This pathway is a critical driver of phosphatidylserine exposure and subsequent SCD complications.
• Targeting the PIEZO1-TMEM16F axis presents a promising therapeutic strategy for SCD.