University of Arizona surgery researchers discover strategy to prevent fibrosis

TUCSON, Ariz. — A study led by Geoffrey Gurtner, MD, FACS, department chair of surgery, and co-lead author Kellen Chen, PhD, associate professor of surgery, at the University of Arizona College of Medicine – Tucson Department of Surgery has been published in Nature Biomedical Engineering.

The research uncovers 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. “Following injury in any organ system, the body builds scar tissue through a complex wound healing process,” Chen said. “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.”

How mechanical stress drives scarring

Wound healing involves hemostasis, inflammation, proliferation and remodeling. This response is essential for tissue repair, but dysregulated healing often results in fibrosis and loss of normal tissue structure. While inflammatory and immune cells begin the process during hemostasis and inflammation, their role in later stages of healing is less understood.

To study this, the Gurtner and Chen Lab used an animal model equipped with a device that applied uniform mechanical strain across wounds. The strain mimics the stress naturally present in human and porcine skin, where wounds are exposed to 5 to 20 percent strain. Under these conditions, mice developed hypertrophic scars, allowing researchers to examine how immune cells respond to stress.

Mechanoresponsive immune cells identified

The team found that myeloid cells — particularly monocytes and macrophages — are mechanoresponsive. When exposed to strain, these cells expressed signaling molecules such as FAK, RAC2 and PIEZO1, along with pro-fibrotic proteins like thrombospondin-1, while showing reduced levels of the anti-inflammatory marker EGR1.

Targeting these signaling pathways shifted the cells from pro-fibrotic to pro-healing profiles. Blocking mechanical signaling restored anti-inflammatory activity and reduced fibrosis markers. The result was thinner tissue with collagen that resembled unwounded skin. Fibroblasts, long thought to be the main scar-forming cells, also showed significant changes when immune cell signaling was disrupted.

Implications for multiple diseases

These findings were supported by studies of human scars, fibrotic liver samples and immune cells exposed to strain. Healthy skin and non-fibrotic liver tissue showed less inflammation and higher EGR1 expression, while fibrotic skin and fibrotic liver demonstrated increased presence of Thrombospondin 1-expressing mechanoresponsive macrophages. When human immune cells were treated with a FAK inhibitor, fibrosis-related activity dropped and regenerative pathways increased.

“This study offers a paradigm shift in how we think about fibrosis,” Gurtner said. “By targeting the cells that feel mechanical forces 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.”

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 FDA-approved therapies exist to treat or prevent it. The discovery of mechanoresponsive immune cells as regulators of fibrosis points to new systemic therapies, such as FAK inhibitors or immune-targeted treatments.

Dr. Chen and Dr. Gurtner’s work bridges mechanobiology, immunology and tissue engineering, reflecting the University of Arizona’s commitment to cross-disciplinary innovation that addresses urgent clinical needs. Other current University of Arizona scientists who contributed to this work are Maria Gracia Mora Pinos, MD, Katharina Berryman, MD, Adbdelrahman Alsharif, Maisam Jafri, Dharshan Sivaraj, Hudson Kussie, Fidel Saenz, Nicholas Matthews, Amelia Knochel, Andrew Hostler, MD, William Hahn, MD, and Mohammad Khreiss, MD.

About the Gurtner Laboratory

The Gurtner Lab focuses on developing translational research projects in the lab that can become commercialized to improve patient care. The lab is located at the University of Arizona College of Medicine – Tucson campus, which serves as a unique, collaborative hub that connects both clinical and basic science researchers to tackle ongoing clinical issues. The lab has multiple collaborations across the hospital, College of Medicine – Tucson, College of Engineering and the rest of the university, as well as partnerships with industry to facilitate an interdisciplinary approach to our projects. Major funding support is provided by the NIH (e.g., NIDDK, NIA), Department of Defense, clinical trials, and industry contracts.

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