Researchers Identify Lysosomal Pathway for Converting Fibroblasts into Endothelial Cells
Researchers have identified a molecular axis — involving MEK2, V-ATPase, and the transcription factor TFEB — that can reprogram fibroblasts into endothelial-like cells by activating lysosomal activity. The study, posted as a preprint on bioRxiv, demonstrates that pharmacologically stimulating this pathway can replicate key features of endothelial reprogramming without requiring transcription factor overexpression. The findings suggest the lysosome may serve as a central organelle hub for directing cell fate transitions, with potential implications for regenerative medicine.
A new preprint study describes a signaling pathway through which fibroblasts — common connective tissue cells — can be converted into endothelial-like cells, which line blood vessels. The researchers found that constitutively active MEK2 drives sustained MAPK/ERK signaling, which in turn enhances vacuolar ATPase (V-ATPase) activity, lysosomal acidification, and extracellular matrix degradation, ultimately inducing an endothelial gene expression program and angiogenic behavior. Critically, inhibiting V-ATPase blocked these effects, while pharmacologic activation using the compound EN6 was sufficient to recapitulate key reprogramming features and promote nuclear translocation of TFEB, a master regulator of lysosomal biogenesis. Overexpression of TFEB — especially a phospho-deficient, constitutively active mutant — further boosted lysosomal function and endothelial gene expression, reinforcing the centrality of this axis. The study frames the lysosome as an organelle-level control point for cell identity, offering a potentially more stable and pharmacologically tractable alternative to conventional transcription factor-based reprogramming strategies.
What's missing
As a preprint, this study has not yet undergone peer review. Key open questions include whether the reprogrammed cells are functionally equivalent to primary endothelial cells in vivo, whether the approach is reproducible across different fibroblast sources or species, and whether pharmacologic V-ATPase activation carries off-target effects given the lysosome's broad role in cellular homeostasis.
What different sources said
- bioRxivCenter
V-ATPase-Driven Lysosomal Activation Orchestrates MEK2-Induced Endothelial Reprogramming
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