Skin and the epithelial layers that cover or line many organs can rebuild themselves after extensive injury. Scientists have known about this response, called compensatory proliferation, for about half a century. However, the cellular mechanisms that drive such dramatic tissue regeneration have remained unclear.

The phenomenon was first documented in the 1970s, when researchers exposed fly larvae to high doses of radiation. Despite severe damage to their epithelial tissue, the larvae regenerated fully functional wings. Similar regenerative responses have since been observed in many species, including humans.

Researchers at the Weizmann Institute of Science have now identified a molecular mechanism that may help explain how this process works. Their research, published in Nature Communications, reveals a surprising role for caspases—enzymes best known for helping destroy cells.

Instead of simply causing cell death, caspases can help some cells become resistant to it. These surviving cells can contribute to tissue repair and may become better equipped to withstand future injuries. The same survival mechanism, however, could also be exploited by cancer cells, allowing tumors to return in more aggressive and treatment-resistant forms.

The findings could eventually help researchers develop treatments that support healthy tissue regeneration while reducing the risk of cancer recurrence.

When cell-death machinery promotes survival

One of the body’s main ways of eliminating unwanted cells is apoptosis, a tightly controlled form of cellular “suicide.” Cells can enter apoptosis when they become damaged, grow old, or receive molecular signals instructing them to die.

Several caspase enzymes coordinate this process. Initiator caspases activate the death pathway, while effector caspases then break down proteins inside cells that are destined for destruction.

Over the past two decades, researchers have discovered that apoptotic caspases can also perform functions that do not kill cells. Scientists around the world, including researchers in the laboratory of Professor Eli Allama in the Weizmann Department of Molecular Genetics, have shown that these enzymes can participate in biological processes essential to life.

Allama, an early researcher of these non-lethal caspase functions, suspected that they might also help trigger compensatory tissue growth.

Researchers identify cells that survive radiation-induced cell death

To investigate this possibility, a team led by Dr. Turil Brown in the Allama laboratory recreated the classic radiation experiment that revealed compensatory proliferation. The researchers exposed fruit-fly larvae to ionizing radiation and used modern genetic tools to track epithelial regeneration in greater detail.

“We decided to identify cells that would survive even if we pressed the self-destruct button,” Brown explains. “To do this, we used a delayed sensor that reports cells that survived radiation despite activation of the initiator caspases.”

This approach revealed a population of cells the researchers named DARE cells. These cells survived radiation, multiplied, repaired damaged tissue, and replenished nearly half of their population within 48 hours.

The discovery raised an important question: If DARE cells contributed almost half of the repaired tissue, where did the remaining cells come from?

The researchers identified a second population of cells that was also resistant to cell death. They named these cells NARE cells. Unlike DARE cells, NARE cells did not activate initiator caspases.

“We identified another population of death-resistant cells, but unlike DARE cells, they did not show activation of initiator caspases. We called them NARE cells,” Brown says. “NARE cells ultimately contribute to tissue regeneration, but they cannot do it alone.”

When the researchers removed DARE cells from the system, compensatory proliferation disappeared completely. They also found that dying cells within the tissue helped trigger the regeneration burst: signals released by dying neighboring cells activated DARE cells.

How DARE cells escape apoptosis

The team next examined why DARE cells could withstand radiation levels that caused nearby cells to undergo apoptosis.

The researchers found that the death process initially began normally in DARE cells. Initiator caspases became active, but the pathway stopped before effector caspases could complete the destruction of the cell.

“We observed that although initiator caspases were activated in these cells, the cell death process stalled and did not proceed to the next step,” Allama explains.

The researchers suspected that a protein known as a molecular motor was involved. Molecular motors can tether initiator caspases to the cell membrane, preventing the activation of effector caspases.

When the researchers inhibited this motor protein, DARE cells died and tissue regeneration was impaired. Previous research has also linked overactivation of the same motor protein to cancerous tumor growth. This suggests that the mechanism may help cancer cells evade apoptosis.

Radiation-resistant cells may pass survival traits to their descendants

The finding is particularly significant because cancer treatments such as radiation therapy often damage tumor cells enough to trigger apoptosis.

Tumors that return after radiation treatment are frequently more aggressive and more difficult to treat. The researchers therefore investigated whether cells that survived an initial radiation exposure could pass their resistance to future generations of cells.

“We wanted to know whether resistance to death was passed on to the descendants of death-resistant cells that survived the initial irradiation,” Allama says.

When the researchers irradiated the same tissue a second time, they found that the number of cells dying during the first few hours was half the number observed after the initial exposure. Most of the cells that died belonged to the NARE population.

By contrast, descendants of DARE cells were highly resistant to cell death—seven times more resistant than cells from the original tissue. This may help explain why tumors that recur after radiation can become more resistant to treatment.

The results suggest that surviving an initial attack can leave a lasting biological legacy. DARE cell descendants were much harder to kill than cells in tissue that had not previously experienced radiation.

This survival advantage can help healthy tissue recover after severe injury. In cancer, however, the same mechanism may allow dangerous cells to persist despite treatment.

A feedback loop keeps tissue regeneration under control

Rapid tissue repair creates another challenge. Cells must multiply enough to replace damaged tissue, but their growth must eventually stop. If proliferation continues unchecked, the repair process could lead to excessive or uncontrolled growth.

In the final stage of the study, the researchers discovered a signaling system between DARE and NARE cells that appears to maintain this balance.

“DARE cells promote the growth of nearby NARE cells, apparently by secreting growth signals,” Allama says. “The NARE cells then secrete a signal that inhibits the proliferation of the DARE cells.”

The researchers identified a negative feedback loop between the two cell populations. DARE and NARE cells support tissue regeneration while helping prevent excessive proliferation.

What the findings could mean for tissue repair and cancer treatment

The experiments were conducted in fruit flies, so further research will be needed to determine how closely the mechanism operates in humans. However, the Drosophila model has repeatedly helped scientists uncover fundamental biological processes that later proved relevant to human biology.

“As is common in fly models, we hope that the knowledge gained here will lead to an understanding of the mechanisms that balance human tissue growth and confer resistance to cell death,” Allama concluded.

Many cancers originate in epithelial cells that have lost normal growth control. In addition, many conventional cancer treatments work by prompting tumor cells to self-destruct through apoptosis. Understanding how cells escape that process could help explain why some treatments fail and how they might be improved.

The findings may also point to new ways of promoting healthy tissue regeneration after injury. The same biological system that helps damaged tissue recover could, however, give cancer cells a survival advantage and contribute to treatment resistance.

Dr. Nama Afgin, Dr. Lena Sapozhnikov, and Dr. Keren Jacobi-Sharon from the Department of Molecular Genetics at Weizmann University also participated in the study. Additional contributors included Dr. Ehud Sivan of Weizmann’s Life Sciences Core Facilities Department; Professor Andreas Bergmann of Massachusetts Chan College of Medicine in Worcester, Massachusetts; and Professor Luis Alberto Baena López of the Severo Ochoa Center for Molecular Biology in Spain.

Professor Eli Allama is the incumbent of the Harry Kaye Cancer Research Professorship and director of the Crown Human Genome Center.