Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Area of Science:

• Comparative biology
• Regenerative medicine
• Cell signaling

Background:

• Mammals have limited regenerative capacity compared to newts.
• Signaling pathways in newt regeneration are not fully understood.
• Coordination of cell signaling factors and their conservation are key questions.

Purpose of the Study:

• Investigate the protective effects of newt cell-conditioned media on mammalian cardiomyocytes.
• Characterize extracellular vesicles (EVs) secreted by newt cells.
• Determine the molecular cargo and functional impact of newt EVs on mammalian cells.

Main Methods:

• Culturing newt limb explant cells (A1 cells) and collecting conditioned media.
• Treating mammalian cardiomyocytes with A1-conditioned media and A1-EVs.
• Analyzing A1-EVs using nanoparticle tracking analysis, electron microscopy, and proteomic/RNA sequencing.
• Assessing cardiomyocyte apoptosis and gene expression (PI3K/AKT pathway).

Main Results:

• Newt A1-conditioned media protected mammalian cardiomyocytes from oxidative stress-induced apoptosis.
• This protective effect was dependent on extracellular vesicles (EVs).
• Newt EVs (A1-EVs) are similar in size and structure to mammalian exosomes but contain higher RNA and protein levels, with unique cargo including mRNAs for nuclear receptors and transcription factors.
• Treatment with A1-EVs increased gene expression in the PI3K/AKT survival pathway in mammalian cardiomyocytes.

Conclusions:

• Newt cells secrete EVs with distinct and diverse RNA and protein contents.
• Newt EVs confer cytoprotective effects on mammalian cardiomyocytes, despite significant evolutionary divergence.
• These findings highlight the potential of newt EVs in understanding and promoting mammalian cell survival and regeneration.