Researchers Identify ‘DARE’ Cells That Survive Death Triggers to Repair Tissue

Researchers at the Weizmann Institute of Science have uncovered a cellular survival mechanism that enables severely damaged tissue to regenerate, while also revealing why certain cancers return with increased aggression after treatment. The study, published in Nature Communications, identifies a surprising role for caspases—enzymes typically associated with executing cell death—in promoting tissue repair and resistance to apoptosis.

Compensatory proliferation, the process by which surviving cells replace damaged ones, has been recognized for approximately 50 years. First observed in the 1970s when fruit fly larvae regenerated fully functional wings despite radiation-induced epithelial damage, the phenomenon has since been documented across various species, including humans. However, the specific molecular signals triggering this dramatic regrowth remained unclear until now.

Prof. Eli Arama’s laboratory in the Molecular Genetics Department led the investigation into whether apoptotic caspases, previously known only for their lethal functions, might also drive regeneration. The team recreated the classic radiation experiment but utilized modern genetic tools to track epithelial tissue recovery in high detail.

“We set out to identify cells that push the self-destruct button but survive anyway,” explained lead researcher Dr. Tslil Braun. Using a delayed sensor to detect cells where the initiator caspase had activated yet survived irradiation, the researchers discovered a population they named “DARE” cells—cells that Defy Apoptosis in Regeneration. These DARE cells not only survived the radiation but multiplied rapidly, repairing damaged tissue and replenishing nearly half of it within 48 hours.

The study further identified a second population, termed “NARE” cells, which also resisted death but had never activated their initiator caspase. While NARE cells contribute to regeneration, they rely on DARE cells; removing DARE cells caused compensatory proliferation to cease entirely. The data indicates that dying neighbors send signals that activate DARE cells, initiating the repair process.

Investigating how DARE cells escape their death sentence, the team found that while the initiator caspase switches on normally, the death pathway stalls before executioner caspases can destroy the cell. This blockage appears to be caused by a molecular motor protein that tethers the initiator caspase to the cell membrane. When researchers silenced this motor protein, DARE cells proceeded to die, and tissue regeneration was impaired. Notably, overactivation of this same motor protein has previously been linked to tumor growth, suggesting a potential mechanism for cancer cells to evade apoptosis.

The implications for oncology are significant. Because many cancer therapies, including radiation, work by triggering cell self-destruction, the ability of surviving cells to pass on resistance is concerning. The researchers found that descendants of DARE cells are exceptionally resistant to subsequent insults—seven times more resistant to cell death than cells in untreated tissue. When tissue was irradiated a second time, half as many cells died compared to the first exposure, and most of those that did die belonged to the NARE population.

“Descendants of DARE cells were found to be exceptionally resistant… This may help explain why recurrent tumors become more resistant after radiation,” Arama noted.

Despite this potential danger in cancer, the mechanism offers promise for healing healthy tissue. The study also revealed a negative-feedback loop between DARE and NARE cells that prevents overgrowth: DARE cells secrete growth signals to stimulate NARE cells, while NARE cells secrete signals that inhibit DARE cell growth, ensuring regeneration remains balanced.

Although the experiments were conducted in fruit flies, such models have historically provided insights into fundamental biological processes relevant to humans. The researchers hope these findings will lead to new strategies for accelerating tissue repair after injury while preventing cancer cells from exploiting survival pathways to resist treatment.