Researchers Identify Lysosomal Pathway for Converting Fibroblasts into Endothelial Cells
A new study describes a method to reprogram fibroblasts into endothelial-like cells by activating lysosomes through a MAPK-V-ATPase-TFEB signaling axis. The approach relies on sustained MAPK/ERK signaling rather than transcription factor overexpression alone, potentially offering more stable cell conversions. This discovery could advance regenerative medicine by providing a new framework for cell reprogramming based on organellar function.
Researchers have identified a novel mechanism for direct lineage reprogramming that converts fibroblasts into endothelial-like cells by activating lysosomal function. The study found that constitutively active MEK2 triggers an endothelial gene program through sustained MAPK/ERK signaling, which enhances vacuolar ATPase (V-ATPase) activity and lysosomal acidification. This leads to extracellular matrix degradation and angiogenic behavior. The researchers demonstrated that V-ATPase inhibition blocks these effects, while pharmacologic activation with EN6 reproduces key reprogramming features and promotes nuclear translocation of TFEB, a master regulator of lysosomal function. TFEB overexpression, particularly a phospho-deficient mutant, further enhanced lysosomal function and endothelial gene expression. The findings establish a MAPK-V-ATPase-TFEB axis as central to endothelial reprogramming and position the lysosome as a critical hub for cell fate transitions.
Limitations & open questions
The study does not discuss potential limitations such as the stability and longevity of reprogrammed cells in vivo, off-target effects of pharmacologic V-ATPase activation, or comparative efficacy versus existing endothelial differentiation protocols. Timeline for clinical translation and scalability for therapeutic applications are not addressed.
What different sources said
- bioRxivCenter
V-ATPase-Driven Lysosomal Activation Orchestrates MEK2-Induced Endothelial Reprogramming
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