At the Wellcome Sanger Institute, researchers in Professor Muzlifah Haniffa’s group are growing and using the organoids to study skin development and its interaction with immune cells. Dr April Rose Foster sat down with us to talk about how the team are using skin organoids to study human skin development and her hopes for the future of their research into skin diseases.

Our skin develops in the sterile environment of the womb, maturing after first contact with the air when we are born. It provides a waterproof barrier, regulates our temperature, senses the world and can regenerate itself. At two square meters, it is the largest organ of the human body. It is also often the first visible sign of disease or emotion. But until recently, there hasn’t been a good laboratory ‘model’ of skin that encompasses the true complexity of the tissue. Researchers either relied on using biopsies, which can be impractical and difficult to obtain, or studying the skin of animals such as mice. The cell models previously available were often composed of just two different cell types and didn’t contain many of the features of human skin.

Muzlifah Haniffa’s group study the role of immune cells in skin development and disease, and were looking for a way to scale up their work when details of the skin organoid were published. Dr April Rose Foster was hired to help the team to set up, grow and study the new model. She started at the Sanger Institute in 2022, and the team work closely with the Boston group who pioneered the technique. “It’s a huge breakthrough for the field, because it’s the first time we’ve ever had a complex model of skin that doesn’t involve taking a biopsy. My PhD was in dermatology and hair-related diseases, and now, to see a skin organoid in a dish that also makes hair and glandular structures – it just blows my mind.”

“We could do with the protocol not taking so long though, and speeding up the process to grow skin organoids from stem cells,” says April. “It takes five months at the moment!” Currently, the team gets around this by setting up new organoids every month, so there are always some available at the different stages of development. The process involves careful induction of key molecules to stimulate the differentiation of the different cell types that make up the skin. This requires precise protocols including feeding the organoids every two days in the lab. Together with staff in the Cellular Operations department at the Institute, they are working to automate the process and scale up their production.

After five months, the cells have formed a spherical structure which can grow up to 2cm across. The hairs grow into a fluid-filled cavity in the middle. “In the future, we are going to work to open the organoids up, so the epidermal layer can be in contact with the air as natural skin is,” says April.

Skin development

The focus of the Haniffa lab is using the organoids to help them decipher how human skin forms at the very earliest stages of development. They use single-cell RNA sequencing, spatial transcriptomics and imaging to study the features of the cells in the organoids at different stages. These methods provide detailed information about the organoid cells’ characteristics, interactions and functions.

To see how faithfully the organoids recapitulate real life skin as they grow, the team has benchmarked them against prenatal skin data contributing to the Human Developmental Cell Atlas. The Atlas is a comprehensive profile of cell types and states present during development. Much of the data have been generated by researchers in Muzz Haniffa’s team at the Sanger Institute. “To see those first developmental stages, especially the hair follicles, is incredibly insightful. All of our hair follicles form before birth, so there is enormous interest in being able to understand how this happens for clinical applications,” April says.

The wider team is also focused on immunity, and the role that immune cells play in the skin and skin development. “With any organoid model, it is difficult have all immune cells present and also to get good vasculature”, says April. “This is a limitation of the model, but we are working to understand how the vasculature forms, and the intersections between immune cells and the development of blood vessels. We hope to improve the model using the knowledge we gain².”

They are also working with the Gene Editing group at the Sanger Institute to generate reporter cell lines – cells where a fluorescent marker has been added to a gene, for example. This enables the team to follow specific cell types in the organoids in real time. “I’m excited to see where this goes, as it will help us truly understand the skin organoid model and map the fate of different cell lineages through development” says April.