High Pyrimidine and Fatty Acid Metabolism Associated with High Regenerative Capacity

Researchers here report on an interesting work of comparative biology, looking for common metabolic factors in cells, tissues, and species that are capable of proficient regeneration such as regrowth of limbs and organs. Are there commonalities between the metabolism of deer antler regrowth and salamander limb regrowth, and can one follow those commonalities into the differences between stem cells and somatic cells? Perhaps. This work is a starting point, and it will be interesting to see where it leads.

From lower animals to humans, every species is endowed with a certain degree of regeneration. For example, axolotl, the Mexican salamander, is evolutionarily primitive vertebrate known to possess a higher regenerative capacity than mammals. Another example is the deer antler, which is the only organ capable of complete regeneration in mammals. In most mammals, the limited anatomical and functional recovery capabilities reside in young tissue and decline with age, leading to compromised tissue repair after injury. Compared to stem cells from regenerative tissues of the axolotl limb and the deer antler, human stem cells, such as human mesenchymal stem cells (hMSCs), possess a relatively limited capacity for regenerative repair of damages to vital tissues and organs, but gradually lose such capacity with age. Whether molecular characteristics between these naturally occurring regeneration processes are evolutionarily conserved across species is unknown.

Using comparative methods to describe the similarities and differences between species is a powerful strategy to discover the regulatory mechanisms that underline vital life events, such as regeneration. Here, we sought to understand how metabolic regulation intersects with inherent regenerative capacity using comparative approaches. Samples for this study included i) species that are more primitive on the evolutionary scale but can renew entire organs, and ii) higher species in evolution that have lost full organ regenerative capacity but retain a limited capacity for tissue repair. We systematically depicted metabolic profiles in various regeneration-related contexts, and we discovered that high pyrimidine and fatty acid metabolism was shared across species, tissues, and cells with high regenerative capacity. We identified uridine as a pro-regenerative metabolite that promoted human stem cell activity and enhanced regeneration in multiple tissues in mammals. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

Link: https://doi.org/10.1038/s41421-021-00361-3

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