The mechanisms of regenerating damaged tissues

We all do it: Regenerating damaged tissues. It might be the more obvious case of closing a wound after cutting your finger while chopping vegetables or maybe the process of regenerating your intestinal epithelium constantly without you even noticing. However, the ability to regenerate damaged tissue varies greatly in the animal kingdom. While adult humans close larger wounds via the formation of less functional scar tissue and are unable to regrow whole appendages, other animals regenerate lost tissues more efficiently. The axolotl for example can regrow whole limbs after losing its limb or zebrafish can regenerate their spinal cords after traumatic injury. The question of how those differences in regenerative potential can be explained keeps many scientists in the field of developmental biology and regenerative medicine busy.

Humans only have limited abilities to regenerate after traumatic injury. Therefore, understanding the mechanism underlying successful regeneration in species like the axolotl might allow us to target the used pathways also in humans to subsequently improve the quality of life in affected patients. In recent years, a lot of research has been conducted in investigating the cell types contributing to regeneration and the underlying genes that might play a role in controlling the regenerative potential of different tissues and species1. However, while it is known that the local repair of damaged tissue increases the amount of needed energy, it is less known how an organism regulates this increased need in resources on a global level2. What happens if the amount of local resources at the site of injury is not sufficient, and how can an animal adapt its metabolism to compensate for the increased need in energy?

Figure 1: Lipids and their importance for Tissue Regeneration in Axolotl and Fruit Fly - Copyright K.Zanaty

Changes in the systemic lipid metabolism - a response to injury to ensure efficient regeneration  

In our study, we are using two model organisms to study the systemic metabolic adaptations in two types of regeneration. We induce chronic intestinal inflammation in fruit flies, resulting in increased regeneration of the intestinal epithelium, and compare the metabolic response to the injury of the juvenile axolotl undergoing tissue repair after whole limb amputation. This approach allowed us to investigate potential conserved mechanisms in the metabolic response upon regeneration. We show that both organisms feed normally, ensuring a continuous uptake of macronutrients after injury. Animals maintain normal blood sugar and protein levels, indicating that these nutrients are consistently available in regenerating tissues. In contrast, regenerating fruit flies and axolotl adapt their systemic lipid transport and hepatic lipid storage. Animals increase their storage of fatty acids and the amount of transported sterols in circulation. Furthermore, we discovered that the regenerative response can trigger the levelling of usual sex-specific metabolic differences in axolotl (Figure 2 A). We also show that insulin signalling – most commonly known as a regulator of blood sugar levels -  is a key player in allowing the hepatic adaptation of lipid transport as a result of tissue damage (Figure 2 B). In cases when the lipid metabolism cannot be adjusted, for example, as a result of perturbation in the hepatic insulin signalling pathway, the regenerative response is negatively affected, resulting in less efficient regeneration due to lower activity of stem cells. Taken together, we uncover a conserved mechanism in adapting the systemic lipid metabolism to fulfil the increased need of resources at the side of injury and to allow efficient regeneration

Figure 2: Effects of Regeneration on the Systemic Lipid Metabolism. (A) Healthy, non-injured axolotl show differences in the amount of transported Triacylglycerols (TAGs) in circulation, whereas males transport significantly less lipids (a’). These differences are not present anymore during regeneration (a’’), and female and male axolotl display similar levels of transported TAG in circulation. (B) Perturbation of insulin signalling in the lipid storage site (fat body) in fruit flies results in reduced stem cell activity at the site of regeneration and less efficient tissue repair. 

The potential of tweaking the metabolism for enhancing wound healing and regeneration

We found that animals respond to injury with dynamic, systemic lipid adjustments, favouring a sustained sterol homeostasis in the injured tissue. By comparing fruit fly and axolotl, we were able to show that this response to injury and regeneration is conserved across different species and different types of regeneration. Further research is needed to investigate if similar mechanisms can also be observed in other species, like humans. The fact that metabolic insulin dependent control far away from the site of injury can influence regenerative capabilities brings up the question if general changes of diets and metabolism have the potential to enhance the regenerative potential of tissues. It is known that the efficiency of wound healing can be influenced by nutrition3,4. Although the dietary caloric value is one undeniable factor potentially fostering regenerative capacity, our study provides first evidence on how this might be regulated on the level of lipid metabolism. 

Thus, specific targeting of the insulin dependent lipid metabolism might therefore be a promising avenue to explore for enhancing wound healing and regenerative capacities.

References

1. Aires, R., Keeley, S. D. & Sandoval-Guzmán, T. Basics of Self-Regeneration. in 691–734 (Springer International Publishing, Cham, 2020). doi:10.1007/978-3-319-08831-0_66.

2. Kübler, I. C., Kretzschmar, J., Brankatschk, M. & Sandoval‐Guzmán, T. Local problems need global solutions: The metabolic needs of regenerating organisms. Wound Repair Regen. 30, 652–664 (2022).

3. Quain, A. M. & Khardori, N. M. Nutrition in Wound Care Management: A Comprehensive Overview. 27, 327–335 (2015).

4. Shields, B. Diet in Wound Care: Can Nutrition Impact Healing? Cutis 108, 325–328 (2021).