Piezo1 identified as key trigger for tension driven skin expansion

Investigators at Johns Hopkins Medicine report new evidence that the protein Piezo1 controls skin growth by detecting when skin is stretched and then coordinating the metabolic and immune changes necessary for growth. Experts say the findings could ultimately help doctors develop noninvasive therapeutic approaches to create new skin for treating burns and other injuries that require a skin graft. 

Scientists have long understood that too much physical stress, defined as the internal and external tension experienced by cells and structures within the body, causes skin to tear, but moderate levels promote growth, such as the body changes seen during child development and pregnancy. 

Tension-based skin growth involves the epidermis (outermost layer of skin) and dermis (middlemost layer of skin), but how it’s controlled molecularly has remained unclear. In contrast, researchers know that wound healing, another body process that involves skin growth, is controlled by the Hippo signaling pathway and requires coordination among blood, fat, immune, nerve and skin cells. 

Previous research found Piezo1, a so-called mechanotransducer protein that turns physical force into actionable biological signals, was present at high levels in the skin, suggesting a potential role for it in in skin growth. 

In a set of NIH-funded experiments published July 25 in Nature Communications, the JHM-led research team set out to explore how Piezo1 might sense and respond to mechanical stretching first by identifying the molecular signals triggered when skin is stretched in mice, and then by examining how these signals can contribute to growth when Piezo1 is manipulated. 

According to Yingchao Xue, Ph.D., first author of the study and research associate in the Garza Laboratory at the Johns Hopkins University School of Medicine, the team used an analytic method known as spatial transcriptomics to compare the levels of gene expression and the physical locations of where genes were being activated across skin samples collected 14, 32 and 70 days post-expansion. 

In expanded samples, the team found the stretch, angiogenesis and stress granule gene signature scores they created based on existing literature increased 2.1 times, 1.4 times and 1.4 times, respectively. The elevated scores plus increased immune cell activity present throughout the samples indicated a systemic, coordinated response to the increased skin tension. 

“Existing literature showed that the pathways we identified were closely correlated with Piezo1 expression,” says Xue. One of the pathways, the TGF-beta signaling pathway, regulates immune system function and cell growth. 

Delving deeper to explore Piezo1’s role, the team sought to uncover how increasing or decreasing Piezo1 activity would alter tension-based skin growth. 

To do this, the investigators first treated a group of mice with a Piezo1 activator, Yoda1. They observed that Yoda1 treatment increased the expression of tension-related inflammation and metabolism pathways in less time than initially observed in the expanded versus nonexpanded mice, resulting in a 130% increase in skin surface area, 120% increase in skin weight and 130% increase in epidermis thickness versus nontreated control mice. 

Because increasing Piezo1 expression further amplified pathway expression, we were able to show it is a key skin growth trigger.”

Yingchao Xue, Ph.D., first author of the study and research associate in the Garza Laboratory at the Johns Hopkins University School of Medicine

Next, the group created a Piezo1 “knockout” mouse line in which the Piezo1 protein was selectively removed from the skin upon being treated with tamoxifen. In the knockout mice, an average 0.9 times decrease in skin surface area, 0.84 times decrease in skin weight and 0.80 times decrease in epidermis thickness was seen in comparison to the control, demonstrating that Piezo1’s absence negatively affects the body’s ability to adapt and grow under physical tension. 

Together, says Xue, the findings are believed to be the first to demonstrate Piezo1 plays a key role in regulating molecular changes necessary for the skin’s ability to grow in response to mechanical stress. 

The investigators say the study could advance the search for safe and effective ways to grow skin, which would help patients undergoing reconstructive surgery for burns, trauma or congenital defects. Current methods, such as silicone expanders, are time-consuming and can cause complications, including skin infections. 

In the future, the research team plans to explore how their findings translate to humans.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR074846, R56AR082660), the National Institute on Aging (P30AG021334), the Daniel Nathans Scholar fund, the Maryland Stem Cell Research Fund (2022-MSCRFD-5917) and the Dermatology Foundation Research Career Development Award. 

Luis A. Garza, M.D., Ph.D., has received grant support and royalty payments from Sun Pharma Advanced Research Company (SPARC) as a part of a licensing agreement with the group, which are not related to the study. The other authors report no conflicts of interest. 

Other Johns Hopkins researchers involved in the study are Elizabeth Winnicki, Zhaoxu Zhang, Ines Lopez, Saifeng Wang, Charles Kirby, Sam Lee, Ang Li, Chaewon Lee, Hana Minsky, Kaitlin Williams, Kevin Yueh-Hsun Yang, Sashank K. Reddy and Luis A. Garza.