Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications

Area of Science:

• Biochemistry
• Cell Biology
• Hematology

Background:

• Sickle cell disease (SCD) is characterized by abnormal phosphatidylserine (PS) exposure on sickle 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 red blood cells (RBCs).
• To identify key mediators involved in the mechanotransduction pathway leading to PS exposure in SCD.
• To explore potential therapeutic strategies targeting this pathway for SCD treatment.

Main Methods:

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

Main Results:

• Identified TMEM16F as a critical mediator of PS exposure downstream of Ca2+ influx via PIEZO1 in sickle RBCs.
• Demonstrated that deoxygenation-induced sickling activates PIEZO1, leading to Ca2+ entry, TMEM16F activation, and subsequent PS exposure.
• Observed that this cascade promotes microparticle release, thrombin generation, and RBC adhesion, which are suppressed by partial PIEZO1 inhibition.

Conclusions:

• Defined a novel mechanotransduction pathway involving PIEZO1 and TMEM16F in sickle RBCs.
• Proposed a therapeutic strategy targeting PIEZO1 to mitigate hypercoagulability and vaso-occlusion in SCD.
• Highlighted the potential of targeting this pathway for developing new treatments for sickle cell disease.