Are ‘zombie’ skin cells harmful or helpful? The answer may be in their shapes

Senescent skin cells, often referred to as zombie cells because they have outlived their usefulness without ever quite dying, have existed in the human body as a seeming paradox, causing inflammation and promoting diseases while also helping the immune system to heal wounds. 

New findings may explain why: Not all senescent skin cells are the same.

Researchers from Johns Hopkins University have identified three subtypes of senescent skin cells with distinct shapes, biomarkers, and functions—an advance that could equip scientists with the ability to target and kill the harmful types while leaving the helpful ones intact. 

The findings were published today in the journal Science Advances.

“We’ve known that senescent skin cells are different from senescent immune cells or senescent muscle cells. But within a cell type, senescent cells are often considered the same—in essence, skin cells are either senescent or not, for example,” said Jude Phillip, an assistant professor of biomedical engineering at Johns Hopkins University. “But we’re finding that when a skin cell goes into senescence, or a zombie-like state, the cell could go down one of three different paths, each leading to a slightly different subtype.”

Leveraging new advances in machine learning and imaging technology, the researchers compared skin cell samples from 50 healthy donors between the ages of 20 and 90 who participated in the Baltimore Longitudinal Study, an NIH-funded project that is the longest ongoing study of aging in the United States.

Researchers extracted fibroblasts—cells that produce the scaffolding to give tissues their structure— associated with skin tissue and pushed them toward senescence by damaging their DNA, something that happens with aging. Because senescent cells build up naturally as people grow older, the aged samples contained a mix of healthy/nonsenescent and senescent fibroblasts. 

Using specialized dyes, the researchers were able to capture images of the cells’ shapes and stained elements that are known to indicate senescent cells. Algorithms developed for this study analyzed the images, measured 87 different physical characteristics for each cell, and sorted the fibroblasts into groups.

Fibroblasts come in 11 different shapes and sizes, three of which are distinct to senescent skin cells, the researchers found. Only one subtype of senescent fibroblast, which the researchers named C10, was more prevalent in older donors. 

In the petri dishes, each subtype responded differently when exposed to existing drug regimens designed to target and kill zombie cells. Dasatinib + Quercetin, a drug being tested in clinical trials, for example, most effectively killed C7 senescent fibroblasts but was limited in killing the age-associated C10 senescent fibroblasts. 

Though further research is needed to verify which fibroblast subtype is harmful and which is helpful, the findings show that drugs can target one subtype and not the others.

“With our new findings, we have the tools ready to develop new drugs or therapies that preferentially target the senescence subtype that drives inflammation and disease as soon as it is identified,” Phillip said. 

More precise targeting of senescence could benefit cancer treatments, the researchers said. 

Certain therapies are being designed to trigger senescence in cancer cells, converting uncontrollably replicating cancer cells into dead-in-the-water zombie cells. While these therapies could stop tumor growth, they leave senescent cells in their wake. Conventional chemotherapies also push cells like fibroblasts toward senescence as a side effect. The buildup of senescent cells during treatment can be problematic as those cells may promote inflammation at a time when a patient’s immune system is at its most vulnerable. 

Patients may benefit from a drug administered after chemotherapy that can sweep up the mess, removing harmful senescent cells while leaving behind the helpful senescent cells. These types of drugs are called senotherapies.

Next, the researchers plan to look at senescence subtypes in tissue samples, not just in flasks and petri dishes, to see how those subtypes might be associated with various skin diseases and age-associated diseases.

“We hope, with some more development, our technology will be used to help predict which drugs might work well for targeting senescent cells that contribute to specific diseases,” Phillip said. “Eventually, the dream is to be able to provide more information in a clinical setting to help with individual diagnoses and boost health outcomes.”

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