Blocking immune cell signals reduces scar tissue formation in wounds

Researchers at the University of Arizona uncovered a previously unknown population of circulating immune cells that play a critical role in fibrosis, the buildup of scar tissue that can lead to organ failure and disfigurement. The findings, published in Nature Biomedical Engineering, add to the understanding of the healing process and could lead to new strategies for preventing or treating fibrosis.

Fibrosis contributes to nearly half of all deaths in developed countries, including conditions such as pulmonary fibrosis, renal fibrosis, organ transplant rejection, nonalcoholic steatohepatitis and some forms of heart disease. Yet no U.S. Food and Drug Administration-approved therapies exist to treat or prevent it. 

"Following injury in any organ system, the body builds scar tissue through a complex wound healing process," said co-lead author Kellen Chen, associate professor of surgery in the U of A College of Medicine - Tucson. "The resultant fibrosis causes tissue dysfunction and serves as one of the leading causes of death in the United States. In our study, we identify a specific immune cell type that circulates in the blood and acts as one of the primary drivers of fibrosis across the body."

In experiments both in mouse models and human cells in the laboratory dish, they found that blocking signals from the immune cells during wound healing could reduce scar tissue formation. They also observed that these cells were upregulated in human fibrotic skin and human fibrotic liver tissue. 

Wound healing involves several steps in an orchestrated repair process. As blood clotting halts a wound from bleeding, inflammatory cells flock to the wound site to clean up dead cells and debris. This is followed by new cell growth, and then tissue remodeling.

When the process fails to work properly, scar tissue can result. Inflammatory and immune cells play important parts in the early healing process, but their roles in its later stages are poorly understood.

Dr. Geoffrey Gurtner, chair of the Department of Surgery in the College of Medicine – Tucson, and Chen found that myeloid cells, which include immune and inflammatory cells, started a signaling cascade of cellular activity that promoted scar development. At the same time, they found less anti-inflammatory cell activity.

When they disrupted this signaling activity, the cells changed tactics from building scar tissue to promoting normal healing. Blocking the cells' signaling also restored anti-inflammatory cell activity.

As a result,researchers saw less evidence of fibrosis development. Instead, the healed wound contained thinner tissue with collagen, which resembled normal skin. 

The findings suggest a crosstalk between mechanical cues in healing and immune cell regulation that could be used as a potential therapeutic strategy against the development of fibrosis in skin and other tissues.

"This study offers a paradigm shift in how we think about fibrosis," Gurtner said. "By targeting the immune cells that feel mechanical forces, circulate throughout the body, and drive pathological repair, we may be able to prevent or even reverse fibrosis across multiple organ systems – from the skin and lungs to the heart and liver."

Other current University of Arizona scientists who contributed to this work include Dr. William Hahn, Dr. Mohammad Khreiss, Dr. Maria Gracia Mora Pinos, Dr. Katharina Berryman, Dr. Andrew Hostler, and students Adbdelrahman Alsharif, Maisam Jafri, Dharshan Sivaraj, Hudson Kussie, Fidel Saenz, Nicholas Matthews and Amelia Knochel.