Scientists at Israel’s Weizmann Institute of Science have uncovered a cellular mechanism that could deepen understanding of tissue regeneration while offering clues to why some cancers return after treatment.
Published in Nature Communications, the study identified a population of cells that begins the process of programmed cell death but survives to help rebuild severely damaged tissue.
Named DARE cells, they multiplied rapidly and replenished nearly half of the damaged tissue within 48 hours in experiments involving fruit fly larvae.
The discovery sheds light on compensatory proliferation, a biological process in which surviving cells multiply to replace those lost through injury.
However, the same survival mechanism could potentially enable cancer cells to withstand treatment.
Apoptosis, commonly known as programmed cell death, helps the body eliminate damaged, ageing and unwanted cells. Caspases, a group of enzymes, initiate and execute the process.
Research led by Prof. Eli Arama of the Weizmann Institute’s Department of Molecular Genetics has shown that caspases can also perform functions beyond cell destruction.
His team suspected they might contribute to tissue regeneration.
Led by Dr. Tslil Braun, the researchers recreated a classic 1970s experiment in which radiation-damaged fly larvae regenerated functional wings. Using modern genetic tools, they tracked cells that activated the early stages of apoptosis but survived.
“We set out to identify cells that push the self-destruct button but survive anyway,” Braun explained.
The researchers discovered DARE cells, which not only survived radiation but multiplied and repaired nearly half of the damaged tissue within 48 hours.
They also identified a second population, called NARE cells. Unlike DARE cells, NARE cells had not activated their initiator caspase, although they survived and contributed to regeneration.
The distinction was crucial. When DARE cells were removed, compensatory proliferation disappeared. The researchers also found that signals from dying cells activated DARE cells, triggering rapid tissue repair.
The study found that apoptosis begins normally in DARE cells. However, the process stops before the effector caspases can complete cellular destruction.
The researchers linked this interruption to a molecular motor protein that appears to tether the initiator caspase to the cell membrane, preventing activation of the enzymes responsible for completing cell death.
When the team silenced the motor protein, DARE cells died and tissue regeneration was impaired.
Arama noted that overactivation of the same protein had previously been associated with cancerous tumour growth, raising the possibility that cancer cells could exploit a similar mechanism to evade apoptosis.
The finding does not establish that this process causes cancer recurrence in humans, but it provides a pathway for further investigation.
The scientists next examined whether DARE cells could pass their resistance to death to their descendants. After exposing the tissue to radiation a second time, they found that cell deaths during the initial hours were half those recorded after the first exposure. Most of the cells that died belonged to the NARE population. Descendants of DARE cells were reportedly seven times more resistant to cell death than cells in the original tissue.
“We wanted to understand whether resistance to death is inherited by the descendants of death-resistant cells that survived the initial irradiation,” Arama said.
The finding may help explain how surviving cells acquire characteristics that allow them to withstand subsequent injury. In cancer, however, similar resistance could potentially enable tumour cells to survive treatment and contribute to recurrence.
The researchers stressed that their experiments were conducted in fruit flies, and the relevance to human cancers remains to be established.
The study also revealed a feedback system that appears to prevent excessive regeneration.
DARE cells release growth signals that promote the multiplication of nearby NARE cells. In return, NARE cells release signals that inhibit DARE cell growth. This negative feedback loop allows tissue repair to proceed while helping prevent uncontrolled proliferation.
According to Arama, understanding these mechanisms could eventually support efforts to accelerate healthy tissue regeneration and improve cancer treatment strategies.
“Many cancers originate in epithelial cells that have lost normal growth control, and many traditional cancer treatments aim to cause them to self-destruct through apoptosis,” he said.
“Our findings pave the way for understanding why such treatments sometimes fail and how they could be improved.”
The discovery offers a new perspective on the body’s response to injury. A mechanism that helps healthy tissue recover could, under different circumstances, provide dangerous cells with a means of survival.
The next challenge for researchers is to understand how to harness the regenerative benefits without enabling cancer cells to escape treatment.
