Then and Now: Valerie Horsley Unlocks the Secrets of Skin Healing

For more than 20 years, Yale University cell and molecular biologist Valerie Horsley has gone under the skin to understand how the cells and molecules there regulate its maintenance and healing.

In 2017, The Scientist featured Horsley’s work, which focused on skin adipocytes. She showed how these fat storage cells control hair growth by activating hair stem cells.¹ In celebration of The Scientist’s 40^th anniversary, we spoke with Horsley again about her research, which has delved even deeper under the skin as her team explores how adipocytes and other epidermal cells regulate skin repair.

Skin Adipocytes: Master Remodelers of Tissue Healing

When Horsley started her own lab at Yale University, she was interested in understanding the functions of adipocytes in the skin. Adipose tissue is known for its roles in thermal insulation, energy storage, and mechanical support.² Horsley’s team expanded that list when they showed how these fatty cells modulate hair growth.¹

While discussing these findings with other researchers at conferences, Horsley became intrigued by a fact that plastic surgeons shared with her: They use patients’ fat tissue to speed up the healing process after surgical procedures.

To explore the role of adipocytes in skin healing, Horsley’s team made small skin wounds on the backs of mice genetically engineered to lack white adipose tissue throughout their bodies. They then compared the wounds of these fatless mice with those of wild type animals.³ “What we found in those mice was that [their skin] didn't repair normally,” Horsley explained. “The epithelium repaired, but the fibroblasts did not come back into the dermis, and the wound reopened after injury. That was our first suggestion that fat cells might be involved in tissue repair.”

A few years later, Horsley’s team built upon those findings, showing that a subset of skin adipocytes modulates the macrophage-mediated inflammatory response through lipolysis. This is a process in which the enzyme adipose triglyceride lipase breaks down triglycerides into free fatty acids and forms of diacylglycerol. What’s more, these lipolysis-engaged adipocytes dedifferentiate to produce myofibroblasts within the wound bed, which contribute to skin healing after injury.⁴

Immune Cells and More Play a Role in Tissue Repair

After identifying that adipocytes in the skin regulate inflammation, Horsley and her team turned their attention to immune cells in the skin and their roles in wound repair. They focused on a specialized population of skin-resident phagocytic immune cells called Langerhans cells. In these cells, skin injury upregulated the expression of genes involved in angiogenesis, the process by which new blood vessels form from existing ones. Using mice lacking Langerhans cells, the team found that these immune cells promoted the proliferation of endothelial cells, which are responsible for forming the new blood vessels during angiogenesis.⁵ “We were surprised by this angiogenesis phenotype in the wounds. [Langerhans cells] are normally thought to migrate from the epidermis into the dermis and go to the lymph nodes to activate T cells. No one had really linked T cells or these Langerhans cells to angiogenesis before,” Horsley said.

She emphasized that recent technical advances have been instrumental to her team’s work in understanding the roles of the many cellular players in the skin during tissue repair. In the Langerhans cell study, for instance, she explained that using live imaging of 3D cleared whole-mounted skin samples allowed her team to visualize the interaction of these cells during wound healing. She also stressed the key role that sequencing techniques, such as single-cell and spatial transcriptomics, play in her skin research. “We can understand what [skin cells] are making, but understanding how they're organized is really going to give us a lot of insights into how these cells are functioning,” Horsley added.

Besides exploring the roles of immune cells in skin repair, Horsley’s team is currently investigating other players in that process, including lymphatic vessels and neurons, painting an even more comprehensive picture of how skin heals after tissue damage. Horsley is also expanding her research to include skin fibrosis, a process involving excessive collagen and increased proliferation of fibroblasts that harden the skin.⁶ Recent work by her team showed that skin adipocyte lipolysis prevents the remodeling of the extracellular matrix induced by pro-fibrogenic fibroblasts, suggesting that these fatty cells may delay the formation of fibrotic tissue.⁷

Like a sailor navigating uncharted waters, Horsley’s curiosity and the questions that arise from each scientific project have swept her in unpredictable directions over these almost 20 years as a principal investigator. “To be honest, I feel that every project takes you in new ways that you never dreamed you would go,” she said. “So, it's better not to try to predict and just follow where the science is leading because every time I've tried to predict what I thought was going to happen, it never really goes in that direction.”