Findings published in The American Journal of Pathology shows organoids can form complex self-organizing microvascular networks similar to those in native human skin

April 28, 2026 – New research has shown that single blood vessel cells that appear in the earliest stages of lab-grown skin organoids have the ability to form complex microvascular networks that grow and mature over time. These self-organizing structures function similarly to those in native human skin, as they can appropriately respond to compounds our bodies release during inflammation and can re-grow after injury. The study in The American Journal of Pathology, published by Elsevier, is the first to show microvascular responses to inflammatory stimuli and injury using this system, which has major implications for understanding the critical role of skin blood vessels in inflammation, repair, regeneration, and aging.

The skin is a highly complex organ, as witnessed by its unique microscopic anatomy that includes a plethora of cell types that collaborate to achieve its protective functions. Millions of people worldwide live with skin conditions driven by inflammation, such as psoriasis, as well as disorders that hinder their ability to heal skin wounds, such as cardiovascular disease and diabetes.

“A few years ago, investigators at Boston Children’s Hospital developed a highly innovative procedure using stem cells to generate hair-forming human skin in a dish, which was a major advance in the fields of skin biology and regenerative medicine,” says senior investigator of the current study, George F. Murphy, MD, from the Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Boston. “As skin pathologists and stem cell biologists, we wanted to use these skin ‘organoids’—the name given to such small, self-organizing multicellular systems that replicate many of the anatomic features and biological functions of an organ growing inside the body—in our lab to study skin development and disease.”

The researchers found that vascular endothelial cells develop as early as six days into the organoid differentiation process and persist for months. They discovered that skin organoids produce several molecules important for initiating and maintaining small blood vessel growth, and as the organoids continue to grow in size and complexity, their vessels also mature and become progressively surrounded by mural cells that support and stabilize them, much like in native human skin.

Molecular triggers of inflammation caused skin organoids to activate their blood vessels and surrounding tissues to express proteins necessary for immune cell homing (guiding immune cells to the site of infection) and function in inflamed tissues. These triggers also led to the release of additional inflammatory mediators from the organoids themselves. Finally, the investigators demonstrated that skin organoid blood vessels could re-grow after traumatic injuries induced by sharp objects.

“We were intrigued to see that the skin organoid vessels showed a molecular signature of small arteries but not veins or lymphatic vessels. So, while this system strongly resembles native human skin in many ways, it remains imperfect. That said, microvasculopathy involving small arterioles, as occurs in diabetes, is a potentially fertile future application for our model. Our findings present exciting opportunities to explore additional factors that control vascular development in skin while further refining the system,” notes first author Anthony R. Sheets, MD, PhD, from the Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Boston.

The NIH and the FDA have recently announced initiatives to support the creation of sophisticated models that more accurately reflect human disease. This work contributes to the shift away from animal models, demonstrating the functional similarities between stem cell—derived skin organoids and native human skin.

Overall, the study’s findings suggest the skin organoid system can be used to further study the pathways that control the growth and function of skin blood vessels in health and disease. Therapeutic modulation of these signals will have future potential to resolve inflammatory skin conditions and restore healing capacity in patients with chronic wounds.

Dr. Murphy concludes, "Our work provides a novel model for studying blood vessel pathology in vitro within a spatially intact three-dimensional microenvironment. The ability to now interrogate ex vivo the formation, physiology, and pathology of critically important cutaneous blood vessels in the environs of an intact tissue microenvironment is potentially transformative for understanding the pathobiology of our largest and most important protective organ."