Highlights

  • A set of regeneration-related metabolite modulators is conserved across species, including the metabolite uridine.
  • Uridine can rejuvenate aged human stem cells and promote regeneration of various tissues in mice. 
  • These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

Many of our body parts are capable of regeneration — a rejuvenating process that replaces damaged, diseased, or aged tissues. If we fall and scrape our skin or break a bone, the damage will eventually heal either on its own or guided by medical treatment. On the other hand, if we lose a limb or have a heart attack, we can’t just regrow or replace these damaged parts. However, this limited healing capacity isn’t the case for the entire animal kingdom. The antlers of deer and limbs of the Axolotl can completely grow back.

In an article published in Cell Discovery, Liu and colleagues from the Institute for Stem Cell and Regeneration, and the University of Chinese Academy of Sciences in Beijing reveal previously unknown links between metabolism and regeneration across different species. By comparing animal stem cells with differential regenerative capacities — including axolotl regeneration-competent limb progenitor cells and deer antler stem cells — with young and aged human stem cells, the research team uncovered a set of regeneration-related metabolites conserved across species. One such metabolite, uridine, rejuvenated aged human stem cells and promoted regeneration of various tissues in animals. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.


(Liu et al., 2022 | Cell Discovery) Uridine is a key metabolite reinforcing regeneration in multiple mouse tissues. 

What underlies regenerative capability across species?

From lower animals to humans, every species is endowed with a certain degree of regeneration, but regenerative capacity declines throughout evolution and with age. In many animals, tissue regeneration is impaired by aging due to cellular senescence, organ degeneration, and other age-associated processes.

While the structure of proteins can vary between species, the structures of metabolites are more often similar, making them ideal for researching the similarities between species across evolutionary time. In other words, perhaps there are metabolic pathways shared across species that promote tissue repair.

Studying the metabolites of cells and tissues with high regenerative capacity enables researchers to discover new youth factors associated with regeneration enhancement shared across species. A metabolomic atlas was assembled to allow the researchers to identify metabolites associated with high and low regenerative capabilities target the ones that promote tissue regeneration. 

(Liu et al., 2022 | Cell Discovery) The cross-species metabolomic analysis identifies potent regeneration promoting factors. The researchers investigated data from samples with different regenerative capacities. The samples examined were from axolotl blastema before and afteramputation (DPA), deer antler stem cells (dASCs), tissues from young and aged non-human primates (NHPs), and young and aged human mesenchymal stem cells (hMSCs).

Uridine is a potent regeneration promoting factor

Through the cross-species metabolic screening, the research team identified the metabolite uridine as a potent regeneration promoting factor. In other words, uridine was more abundant in tissues or cells with higher regenerative potential. In addition, the concentration of uridine decreased in the blood plasma of aged individuals, suggesting uridine may navigate a delicate balance between aging and regeneration.

This study also identified that a single-dose injection of uridine in mice is sufficient to make the blood uridine concentration reach the concentration required to rejuvenate stem cells from aged adults in cell culture. This result suggests that uridine treatment may result in systemic exposure to uridine to enhance regeneration of different tissues.

Furthermore, the researchers found that uridine supplementation rejuvenated senescent stem cells, promoted the regeneration and repair of multiple tissues, and improved the fitness of aged mice. For example, when the researchers evaluated the effect of orally administered uridine (20 mg/kg/day) daily for two months in aged mice (22 months old), they found improved physical performance, as indicated by their enhanced grip strength and exercise endurance.

(Liu et al., 2022 | Cell Discovery) Uridine supplementation in physiologically aged mice improved physical performance. The aged mice (22 months old) with oral administration of uridine for two months had enhanced grip strength and exercise endurance compared to their non-treated litter-mates. The left bar chart shows the grip strength evaluation of the forelimbs and hind limbs of mice not given uridine  (vehicle) or given uridine. The right bar chart shows the times of electric shock for mice orally administered vehicle or uridine on the treadmill within 30 min at day 63 post-treatment.

Liu and colleagues also observed that uridine treatment promoted tissue repair in both muscle and heart injury models. Uridine treatment facilitated muscle tissue regeneration, reduced scarred or eroded areas, and improved grip strength and running distance. Additionally, the uridine treatment improved the heart’s function in mice that had induced heart attacks (myocardial infarction).

In addition to muscle and heart injury models, uridine treatment also facilitated the regeneration of the liver after injury, as evidenced by increased liver weight and decreased liver fibrosis. In another tissue injury model, uridine treatment facilitated the regeneration of injured cartilage and further reduced functional deterioration, as shown by improved grip strength and athletic ability compared to those of the untreated group.

New avenues for metabolic intervention in tissue repair and regeneration

Given the beneficial roles of uridine in promoting tissue repair and improving physiological function, these findings may also have broad relevance for healthy aging treatments. As a test for safety, the data from this study showed that long-term uridine treatment by injection (up to 5 months) or oral administration (up to 7 months) did not cause cancer. In fact, other studies have reported the beneficial roles of uridine metabolism in cancer treatment. Even though the regeneration study was conducted in rodents, these results also provide helpful information for the design of future primate-based preclinical studies and clinical trials on uridine.