Seminal fluid extracellular vesicles restore sperm osmoregulation after CFTR inhibition

Sperm health is influenced by tiny molecular “gatekeepers” that control how water and ions move in and out of the cell. One of these gatekeepers is CFTR (cystic fibrosis transmembrane conductance regulator), a protein best known for its role in cystic fibrosis. Researchers from the University of Porto have explored how CFTR affects sperm function and discovered a promising way to restore its activity when it’s blocked.

In their experiments, the team temporarily inhibited CFTR in human sperm, which reduced the flow of chloride ions and decreased water movement across the sperm membrane. Interestingly, this did not harm sperm vitality, but it did impair the sperm’s ability to properly regulate its water content—a critical factor for successful fertilization.

Fluorescence staining of human spermatozoa interacting with SF-EVs

(A) Human spermatozoa incubated with PHK67-marked SF-EVs; nuclei is stain with Hoechst 33342 (blue), SF-EVs PHK67 green-fluorescent cell membrane intercalating labeling dye (green), and CFTR was immunolabeled with Alexa Fluor 555 (red). (B) Negative control – human spermatozoa were incubated with unstained SF-EVs, immunolabeling was performed only with the secondary antibody (Alexa Fluor 555). Scale Bar is equal to 100 μm.

To counteract this, the researchers introduced seminal fluid extracellular vesicles (SF-EVs) carrying functional CFTR. These tiny vesicles acted like molecular delivery trucks, restoring CFTR activity, normalizing chloride and water transport, and helping sperm regain their osmoregulation capacity. This suggests that CFTR-containing EVs could one day be explored as a tool to improve sperm quality, much like they are being investigated for cystic fibrosis treatments.

The findings shed light on the molecular mechanisms of sperm osmoregulation and point to new possibilities for enhancing male fertility through targeted therapies using extracellular vesicles.

Pereira S, Fomichova O, Damião I, Oliveira S, Almeida V, Monteiro MP, Sousa M, Bernardino RL. (2025) Seminal fluid extracellular vesicles restore human sperm osmoregulation after cystic fibrosis transmembrane conductance regulator inhibition. Scientific Reports 15(1): 43627. [article]

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