Apoptotic cell clearance triggers epithelial fate reprogramming during prostate regression.

Area of Science:

• Cell Biology
• Molecular Biology
• Urology

Background:

• Androgen deprivation triggers significant prostate tissue remodeling.
• The mechanisms behind differentiated prostate epithelial cells adopting a progenitor state are not fully understood.

Purpose of the Study:

• To investigate the role of efferocytosis in prostate regression and progenitor cell fate acquisition.
• To elucidate the metabolic and epigenetic changes associated with epithelial efferocytosis during tissue remodeling.

Main Methods:

• Studied prostate regression in vivo and in vitro models.
• Analyzed epithelial cell phagocytosis of apoptotic neighbors.
• Assessed metabolic reprogramming via glycolysis and lactate production.
• Investigated histone lysine-lactylation patterns.
• Utilized epithelial-specific dominant-negative MFGE8-D89E expression to block efferocytosis.

Main Results:

• Epithelial cells are the primary phagocytes during prostate regression, clearing apoptotic cells in coordinated waves.
• Efferocytosis promotes the acquisition of a progenitor-like state in residual luminal epithelial cells.
• Metabolic reprogramming, including increased aerobic glycolysis and lactate production, accompanies efferocytosis.
• Histone lysine-lactylation was enhanced at key gene promoters.
• Blocking efferocytosis impaired prostate regression and progenitor marker induction.

Conclusions:

• Epithelial efferocytosis is a critical mechanism linking apoptotic cell clearance to epithelial plasticity during prostate remodeling.
• Efferocytosis acts as a determinant of cell state transitions in the prostate.
• These findings have implications for castration-resistant prostate cancer and regenerative processes.