University of Miami Miller School of Medicine Researchers Uncover Key Driver of Nonhealing Venous Leg Ulcers
A Miller School-led study published in Science Translational Medicine identifies PTEN as a master regulator of nonhealing venous leg ulcers, revealing a potential therapeutic strategy to restart stalled wound repair.
For millions of patients living with chronic venous leg ulcers (VLUs), healing remains a major challenge. Despite standard treatments that include compression therapy and wound care, fewer than half of VLUs heal successfully. These chronic wounds can persist for years, causing pain, loss of mobility, social isolation and substantial health care costs.
A study led by researchers at the University of Miami Miller School of Medicine has uncovered a key molecular driver of these nonhealing wounds and identified a potential therapeutic strategy that could help restart the healing process.
What the Study Found
- PTEN activity is elevated in chronic venous leg ulcers.
- Elevated PTEN suppresses immune, vascular and lymphatic repair processes.
- Blocking PTEN restored healing pathways in preclinical models.
- PTEN may represent a future therapeutic target for chronic wounds.
Published in Science Translational Medicine, researchers from the Wound Healing and Regenerative Medicine Research Program at the Miller School found that the signaling molecule PTEN acts as a master regulator of several biological processes that fail in chronic, nonhealing venous leg ulcers. The study was led by Jelena Marjanovic, Ph.D., a research assistant professor in the Dr. Phillip Frost Deparment of Dermatology and Cutaneous Surgery who recently completed her postdoctoral training in the Wound Healing and Regenerative Medicine Research Program, with Marjana Tomic-Canic, Ph.D., the William H. Eaglstein, M.D., Chair in Wound Healing and director of the program.
Elevated PTEN activity suppresses immune responses, blood vessel formation and lymphatic vessel development, effectively trapping wounds in a persistent, nonhealing state. In preclinical models, inhibiting PTEN reversed many of these defects and accelerated wound closure, highlighting new potential therapeutic approach.
Looking Beneath the Surface: Why Some Wounds Heal and Others Don’t
Venous leg ulcers account for approximately 70% of all leg ulcers and affect up to 3% of the general population. Despite representing a major clinical and public health burden, the molecular mechanisms that distinguish wounds that heal from those that do not are poorly understood.
To address that gap, the research team combined advanced genomic technologies with a prospective clinical study of patients with VLUs. The study began with single-cell RNA sequencing of tissue from chronic VLUs and healthy skin to build a detailed map of the cellular landscape of nonhealing VLUs. Investigators followed patients with VLUs undergoing standard treatment to determine which wounds were healing and which remained stalled. Wound samples collected at enrollment were analyzed using bulk RNA sequencing and linked to healing outcomes measured over four weeks. Ulcers that decreased in size by more than 50% were classified as healing, while those that failed to reach that threshold were considered nonhealing.
“Venous leg ulcers are what I consider an ‘invisible epidemic.’ Although they are so common, debilitating and costly, they remain underrecognized by the public,” said Dr. Tomic-Canic. “We wanted to understand why some wounds heal while others remain biologically stalled, despite receiving appropriate clinical care. By integrating advanced molecular analyses with studying human wounds over time, we were able to identify the molecular programs that distinguish healing from nonhealing wounds.”
A Failure of Coordinated Repair
The analyses revealed fundamental differences between healing and nonhealing ulcers. Chronic nonhealing wounds showed widespread suppression of immune activity, including impaired recruitment and movement of immune cells into injured tissue. Key inflammatory pathways that are normally activated during healthy wound repair were largely absent. By contrast, healing VLUs displayed gene-expression patterns that closely resembled those observed in normal acute wound healing.
The team also found significant defects in angiogenesis, the formation of new blood vessels that deliver oxygen, nutrients and immune cells to damaged tissue. Nonhealing ulcers had fewer blood vessels and reduced expression of genes associated with vascular growth.
A third hallmark of nonhealing wounds involved lymphangiogenesis, the formation of lymphatic vessels that help regulate inflammation and remove fluid and cellular debris. Nonhealing ulcers exhibited fewer lymphatic vessels and reduced trafficking of immune cells through the lymphatic system, suggesting that both immune recruitment and immune clearance were compromised.
“Wound healing is like a symphony, with many different cell types and biological processes orchestrated to work together to close a wound,” said Dr. Tomic-Canic. “We wanted to understand what happens when that harmony is lost and why some wounds fail to progress through the normal healing process despite appropriate care.”
Together, the findings revealed a breakdown of multiple interconnected healing processes, highlighting simultaneous defects in immune, vascular and lymphatic systems that fail in concert, rather than a single underlying mechanism.
PTEN Emerges as a Master Regulator
Using bioinformatic analyses to identify upstream regulators of these defects, the investigators repeatedly arrived at the same candidate. PTEN is a well-known tumor suppressor protein that regulates multiple cellular signaling pathways. PTEN activity was elevated in nonhealing ulcers and was associated with suppression of key signaling pathways involved in cell migration, inflammation, angiogenesis and tissue repair.
Further analyses confirmed increased PTEN signaling in immune cells and lymphatic endothelial cells within chronic wounds. The researchers concluded that PTEN serves as a master regulator capable of simultaneously influencing many of the biological processes disrupted in nonhealing VLUs.
“What makes this discovery particularly intriguing is that PTEN emerges as a central control capable of influencing multiple healing processes at once,” said Dr. Marjanovic. “PTEN is a well-known tumor suppressor. Together with our previous work in diabetic foot ulcers, these findings point to an unexpected connection between pathways that suppress cell growth and those required for effective healing.”
PTEN Inhibition in Preclinical Models
To determine whether targeting PTEN could improve healing, the researchers treated wounds with a pharmacologic PTEN inhibitor. PTEN inhibition increased immune-cell recruitment, enhanced inflammatory signaling, stimulated angiogenesis and lymphangiogenesis and accelerated wound closure. Investigators also observed greater granulation tissue formation and faster re-epithelialization, two hallmarks of successful wound repair. Similar regenerative effects were observed in a human ex vivo skin-wound model. These findings suggest that PTEN inhibition may help restore multiple healing processes that are impaired in nonhealing wounds.
“What makes this finding especially exciting is that targeting a single molecule was able to restore multiple processes required for healing,” said Dr Tomic-Canic. “The ability to influence so many impaired pathways at once points to a promising new direction for chronic wound research and therapy.”
Although additional studies will be needed to evaluate safety and determine whether the approach can be translated to patients, the findings suggest that temporary, localized PTEN inhibition may help convert a chronically stalled wound into an actively healing one. For clinicians and patients facing the persistent challenge of venous leg ulcers, the discovery offers a new framework for understanding chronic wound biology and a potential pathway toward more effective treatments.
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Tags: chronic venous leg ulcers, dermatology, Dr. Marjana Tomic-Canic, Dr. Philip Frost Department of Dermatology and Cutaneous Surgery, leg and foot ulcers, venous leg ulcers, wound healing, Wound Healing and Regenerative Medicine Research Program