'Zombie' cells may not be that harmful, healing damaged tissues

A new study conducted by researchers from the University of California, San Francisco, has demonstrated that not all senescent (or 'zombie') cells are damaging, according to a press release published on Eurekalert.

The research indicates that some of the senescent cells are present in young, healthy tissues and help repair damaged tissues. It highlights not all of these cells should be wiped out for the prevention of age-related disease.

After observing the function of zombie cells in organs that serve as barriers in the body, such as lung tissues, small intestine, colon, and skin, the researchers used medicines called senolytics, which eradicate zombie cells, and found that it took longer for damaged tissues to recover.

Activating stem cell repair from 'privileged' positions

“Senescent cells can occupy niches with privileged positions as ‘sentinels’ that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair,” said Tien Peng, MD, the senior author of the study and associate professor of pulmonary, critical care, allergy and sleep medicine.

Zombie cells accumulate during aging and are often associated with aging-related illnesses, including Alzheimer's and arthritis.

Previous research would typically used senolytics to kill "zombie cells" due to the discovery that eradicating these cells from animals prevented or reduced age-related illness and increased the animals' longevity. This also promoted the research on finding and developing more potent versions of drugs that carry out this function.

However, Peng asserts that eradicating these senescent cells may not be as beneficial as thought since they also enable healing by activating stem cell repair.

“Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behavior,” said Peng.

Zombie cells 'secrete' specific growth factors to encourage tissue development

Researchers developed a technique that coalesces the relevant p16 gene with the green fluorescent protein (GFP) to detect the exact location of the cells under green light. Afterward, postdoctoral scholar Nabora Reyes de Barboza, Ph.D. significantly amplified the fluorescent signal in these senescent cells by increasing the amount and stability of green fluorescent protein, allowing the researchers to see senescent cells in living tissues- their natural habitat.

Researchers used this powerful tool and discovered that senescent cells are present in young and healthy tissues more than previously thought and start to appear shortly after birth. They also detected some particular growth factors that "zombie cells" secrete in order to activate stem cells and encourage tissue development.

A potentially beneficial insight for making people live longer and healthier lives

Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.

Leanne Jones, Ph.D., director of the UCSF Bakar Aging Research Institute and Stuart Lindsay Endowed Professor in Experimental Pathology, stated that Peng's study could provide beneficial insight for aging research, which aims to make people live longer and healthier lives

“The studies suggest that senolytics research should focus on recognizing and precisely targeting harmful senescent cells, perhaps at the earliest signs of disease, while leaving helpful ones intact,” she said. “These findings emphasize the need to develop better drugs and small molecules that will target specific subsets of senescent cells that are implicated in disease rather than in regeneration.”

The study was published in Science on October 13, 2022.

Abstract:

We engineered an ultrasensitive reporter of p16INK4a, a biomarker of cellular senescence. Our reporter detected p16INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these p16INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, p16INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.