Secrets of killifish regeneration may help us heal humans

It’s a fact as solid as gravity. Lose a limb or sustain damage to the spinal cord, and our human bodies can’t self-repair. However, some members of the animal kingdom, like the African killifish, boast an extraordinary capacity to regenerate after injury.

Sequencing a precise chain of cellular events, they can restore missing body parts in a way our species can only marvel at.

Recently, researchers at the Stowers Institute for Medical Research have made strides in understanding one aspect of this regeneration process – the timing of cellular response to injury in killifish.

Killifish tail regeneration

The study was led by Dr. Augusto Ortega Granillo, in collaboration with Dr. Alejandro Sánchez Alvarado, President and Chief Scientific Officer at Stowers.

The team investigated how the African killifish can regrow its tail fin after an injury, focusing on what influences the duration and frequency of cellular engagement in the repair process.

“One of the greatest unsolved mysteries of regeneration is how an organism knows what has been lost after injury,” noted Dr. Sánchez Alvarado.

“Essentially, the study points to a new variable in the equation of regeneration. If we can modulate the rate and the length of time that a tissue can launch a regenerative response, this could help us devise therapies that may activate and perhaps prolong the regenerative response of tissues that normally would not do so.”

Repair response after injury

What happens when the tail of a killifish gets injured? The remaining tissue has to gauge the extent of the damage.

Then, the right number of repair cells must be mobilized to the injury site for the appropriate duration of time. This entire process rests on the coordination of damage sensing, repair cell recruitment, and timing.

The team studied different injury locations in the killifish tail fin. They discovered that skin cells – not just at the injury site, but also at distant, uninjured regions – initiated a genetic program to prepare the entire organism for the repair response.

The extracellular matrix

These skin cells then sustained this response, temporarily altering their state to modify the surrounding material, also known as the extracellular matrix.

“We very clearly defined when and where – at 24 hours post-injury and in the extracellular matrix – the transient cell state is acting in the fin tissue,” explained Dr. Ortega Granillo.

“Knowing when and where to look allowed us to make genetic disruptions and gain a better understanding of the function of these cell states during regeneration.”

To comprehend how the unique cellular states convey information to the extracellular matrix during the repair process, the team turned to the CRISPR-Cas9 gene editing technique.

Profiling a gene known to modify the extracellular matrix, the experts found that disrupting the function of this gene led to a deficient speed in tissue growth.

“This is telling us that by changing the extracellular space, skin cells inform the tissue how much was lost and how fast it should grow,” said Dr. Ortega Granillo.

Evolutionary aspects of killifish regeneration

The team demonstrated that controlling the state of the cells that modify the extracellular matrix could potentially amplify regenerative regrowth. This could lead to more robust regeneration responses, opening up exciting possibilities for regenerative medicine.

“Our goal is to understand how to shape and grow tissues. For people who sustain injuries or organ failure, regenerative therapies could restore function that was compromised during illness or following injury,” noted Dr. Ortega Granillo.

However, the matter isn’t closed. Understanding why certain organisms are prodigious regenerators, while others like humans have limited regenerative abilities, is still a driving force in the field of regenerative biology.

By dissecting the principles observed in organisms with high regenerative capacity, researchers aim to apply these insights to enhance regeneration in humans. This could not only unveil the evolutionary aspects of regeneration but also instigate the development of innovative therapeutic strategies.

Regenerative medicine in humans

The findings hint at the tantalizing possibility of deploying regenerative medicine in humans, bringing us one step closer to bridging the gap.

The African killifish, in its seemingly mundane existence, unlocks a world of potential therapeutic strategies that could one day revolutionize the way humans heal.

Until then, the scientific community remains relentlessly committed to exploring the enigma of regeneration, inching closer to answers one experiment at a time.

The research was supported by the Stowers Institute for Medical Research and the Howard Hughes Medical Institute (HHMI).

The study is published in the journal iScience.

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