Tag Archives: #epidermis

MSU Research Is Revealing How Immune Cells Organize Themselves in the Epidermis (Biology)

It can be easy to forget that the human skin is an organ. It’s also the largest one and it’s exposed, charged with keeping our inner biology safe from the perils of the outside world.

But Michigan State University’s Sangbum Park is someone who never takes skin or its biological functions for granted. He’s studying skin at the cellular level to better understand it and help us support it when it’s fighting injury, infection or disease.

In the latest installment of that effort, Park, who works in IQ — MSU’s Institute for Quantitative Health Science & Engineering — has helped reveal how the skin’s immune cells organize themselves to ward off would-be intruders. Park and his colleagues published their work in the journal Nature Cell Biology.

“Immune cells are the soldiers of our body. In our skin, that army is maintained according to two factors: density and distribution,” said Park, an assistant professor in the College of Human Medicine’s Department of Medicine and Department of Pharmacology and Toxicology.

“We need enough immune cells to cover the whole area of our skin uniformly for proper protection. Otherwise, our skin would be vulnerable to damage and infection,” Park said. “As sensible as that might sound, it was unclear how, or even if, these immune cells were organized before this study. Many researchers thought the cells’ distribution was random.”

Skin’s immune cells have a history of being misunderstood. Many people don’t realize that our outermost layer of skin, the epidermis, is home to immune cells. And when the German scientist Paul Langerhans first discovered one type of these immune cells in the late 1800s — cells that are now called Langerhans cells — he mistook them for cells from our nervous system (to be fair, they do have a similar morphology).

To bring more clarity to how skin’s immune cells do their jobs, Park and his co-workers used state-of-the-art microscopy tools. The researchers illuminated how live immune cells arranged themselves in the skin of mice, a popular animal model with a skin biology similar to that of humans.

“IQ has so many advantages for a young investigator like me,” said Park, who joined MSU in January 2020. Just two months later, he had to start working from home due to the coronavirus pandemic. But thanks to IQ’s strong microscopy core, Park’s team was able to work almost immediately as restrictions lifted.

“I didn’t have to wait to set up microscopes in my own lab or train my students how to use them,” he said. “At IQ, we already have many different microscopes for a wide range of animal models.”

As a result, Park’s team is revealing the skin’s structure and function like never before. Having validated these new techniques and observing how immune cells are organized in the healthy skin of mice, Park’s team can start probing new questions about how skin heals.

“My lab is interested in how skin regenerates and recovers from injury,” he said. That injury could be a cut, an infection, an allergic reaction or an even more persistent disorder, such as psoriasis. “We can answer so many questions with our intravital imaging technique that you just can’t with conventional methods.”

Note for media: Please include a link to the original research in your online coverage: https://www.nature.com/articles/s41556-021-00670-5

Reference: Park, S., Matte-Martone, C., Gonzalez, D.G. et al. Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis. Nat Cell Biol 23, 476–484 (2021). https://doi.org/10.1038/s41556-021-00670-5

Provided by Michigan State University

Scientists Regenerate Skin With Stem Cells to see how DNA Defects in Kids Cause Cancer (Medicine)

Bioengineered models let researchers try out new treatments on human tissues before testing actual people.

Physicians and scientists at Cincinnati Children’s Hospital Medical Center used new stem cell technology to regenerate and study living patient-specific skin in the lab, giving them a precise close up view of how inherited DNA defects cause skin damage and deadly squamous cell carcinoma in children and young adults with Fanconi anemia (FA).

Shown are microscopic images of human epidermis with pluripotent stem cells derived from donated skin cells. The images on the left are epidermis from a healthy control subject, the images at right being from a person with Fanconi anemia. The colorful confocal images (bottom) offer a more superficial view that does not reveal differences between control and FA samples. The black and white electron microscopic images, with 1,000-fold greater magnification, do reveal defects in the FA epidermis. Researchers studying Fanconi anemia-related skin disease and cancer report new data in Cell Stem Cell. ©Cincinnati Children’s

Reporting their findings in the journal Cell Stem Cell, the researchers are now using the complex 3D laboratory models of FA patient epidermis – and the enhanced biological detail they provide – to screen for drugs that could slow or stop the disease progression. Study authors explain that new human stem cell-derived tissue models overcome inherent limitations when studying human disease in mice, giving researchers an innovative tool to finally solve what has been a long-standing and dangerous molecular mystery.

“Squamous cell carcinoma is a global health problem, and DNA instability in children with Fanconi anemia makes them extremely susceptible,” said Susanne Wells, PhD, the study’s principal investigator and a cancer biologist at the Cincinnati Children’s Cancer and Blood Diseases Institute. “Unlike the general population, squamous cell carcinomas that arise in the head, neck, anogenital regions, and skin of children and young adults with FA tend to be unusually aggressive and deadly.”

Treatments are available for FA, but Wells explained that they come with side effects because of how the disease works.

“We need effective treatments, but identifying the molecular and cellular consequences of FA gene mutations has been difficult because mouse models don’t fully recapitulate human disease. Fortunately, our bioengineered models of 3D human epidermis are helping us overcome this,” said Wells, who is also director of the Epithelial Carcinogenesis and Stem Cell Program.

A Pathway to DNA Instability

FA is an inherited disorder caused by loss of function mutations in over 20 genes in human reproductive (germline) cells. Usually, the FA pathway plays an important role in normal skin structure and function. And although all cells contain crosslinked DNA, defective DNA repair machinery in people with FA causes the accumulation of defective crosslinks. This makes kids with FA prone to DNA instability, bone marrow failure, and cancer.

©Susanne Wells et al.

Researchers on the current study demonstrate this important role in their most recent data. They conducted a small controlled clinical test to demonstrate that patients with FA mutations are more prone to skin damage and blistering from environmental stress. The test, approved by the Cincinnati Children’s Institutional Review Board, involved applying moderate pressure to the arms of children and young adults with FA and to a control group without FA.

Individuals with FA developed skin blisters much faster when compared to individuals in the non-FA control group, suggesting intrinsic skin fragility in this population.

Mimicking Nature’s Developmental Process

To track the biological development of epidermal vulnerabilities in children with FA, donated skin tissue was used to generate patient-derived pluripotent stem cells (PSCs). The PSCs take on embryonic-like traits and can form any kind of tissue in the body. The patient-specific stem cells in this study harbored FA gene mutations, which for the purpose of direct comparison could be corrected by researchers using an inducible system.

The PSCs were then biochemically converted into epidermal stem and progenitor cells, the developmental stage at which FA mutations usually begin to disrupt skin function. Epidermal stem and progenitor cells were then used to generate complex 3D epidermal models called organotypic skin rafts, which also harbored FA mutations when left uncorrected.

The FA patient-specific tissues had diminished cell-to-cell junctions, key biological connections important to skin formation and function, together with other molecular and structural defects. These defects translated into accelerated blistering of skin after mechanically induced stress, which sets off disease processes that can progress into cancer. Skin fragility in FA might also promote cancer via elevated exposure of the body to carcinogens in the external environment.

According to the study’s first author, Sonya Ruiz-Torres, PhD, a fellow in the Wells laboratory, the researchers are continuing their project. Because the study was limited by a small number of patients, the researchers are generating 3D human organotypic skin rafts to study a broader range of people with FA mutations. This should give scientists a more comprehensive look at different FA gene mutation disease processes, understand how these promote squamous cell carcinoma, and help advance the potential clinical impact of their work.

References: https://www.sciencedirect.com/science/article/abs/pii/S1934590920305063?via%3Dihub https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30506-3

Provided by Cincinnati Children Hospital Medical Center