Researchers create the first single cell atlas of prenatal human skin

For the first time, researchers have created a single-cell atlas of prenatal human skin to understand how skin forms and what goes wrong in disease.

Researchers at Newcastle University’s Wellcome Sanger Institute and their collaborators used single-cell sequencing and other genomic techniques to create the atlas and discover how human skin, including hair follicles, is formed. These findings could be used to create new hair follicles in regenerative medicine and skin transplants for burn victims.

In the study published today (October 16th) in NatureThe team also created a “mini-organ” made of skin in a shell with the ability to grow hair. Using the organoid, they showed how immune cells play an important role in scar-free skin repair, which could lead to clinical applications in preventing scarring after surgery or scar-free healing after injury.

As part of the Human Cell Atlas, which maps all cell types in the human body to transform the understanding of health and disease, researchers provide a molecular “recipe” for building skin and a new organoid model for studying congenital skin diseases.

The skin is the largest organ in the human body and measures an average of two square meters. It provides a protective barrier, regulates our body temperature and can regenerate. The skin develops in the sterile environment of the uterus, with all hair follicles formed before birth – after birth, a follicular cycle occurs, but no new follicles are formed. Before birth, the skin has the unique ability to heal without scarring.

It has been very difficult to study how human skin develops because animal models have key differences. As part of the Human Cell Atlas, a team of researchers is investigating how human skin is structured. By understanding how skin develops, where cells are located in space and time, and the role genetics plays, we can figure out how certain mutations cause congenital skin conditions such as blistering and flaky skin.

In this new study, researchers at Newcastle University’s Wellcome Sanger Institute and their collaborators created the first single-cell and spatial atlas of human prenatal skin.

The team used samples of prenatal skin tissue, which they broke down to examine individual cells in suspension as well as cells in the tissue. Scientists used state-of-the-art single-cell sequencing and spatial transcriptomics to analyze individual cells in space and time and the cellular changes that regulate the development of skin and hair follicles. They described the steps that describe how human hair follicles are formed and noted differences from mouse hair follicles.

Using adult stem cells, the researchers also created a skin “mini-organ” in a shell, a so-called organoid, with the ability to grow hair. They compared the molecular properties of skin organoids with prenatal skin and found that the skin organoid model was more similar to prenatal skin than adult skin.

The team found that blood vessels did not form in the skin organoid and prenatal skin. By adding immune cells called macrophages to the organoid, they discovered that the macrophages promote blood vessel formation, and the team performed 3D imaging to assess blood vessel formation in the tissue.

These immune cells are known to protect the skin from infections. However, this is the first time that macrophages play a key role in the formation of human skin during early development by supporting the growth of blood vessels. This offers the opportunity to improve the vascularization of other tissue organoids.

The team also analyzed differences in cell types between prenatal skin and adult skin. They show that macrophages play an important role in scar-free skin repair in prenatal skin, which could lead to clinical applications to prevent scar formation after surgery or injury.

As a result of this study, the team provides a molecular “recipe” for the structure of human skin and the formation of hair follicles. These findings could be used to create new hair follicles for regenerative medicine, such as skin transplants for burn victims or people with cicatricial alopecia.

The prenatal atlas of human skin will also be used to determine in which cells the genes known to cause congenital hair and skin diseases such as blistering and flaky skin are active or expressed. The researchers found that genes involved in these diseases are expressed in prenatal skin, meaning they originate in the uterus. The skin organoids created in this study provide a new, accurate model for studying these diseases.

Dr. Elena Winheim, co-first author from the Wellcome Sanger Institute, said: “With our prenatal atlas of human skin, we have provided the first molecular ‘recipe’ for making human skin and revealed how human hair follicles are formed before birth.” These findings have amazing clinical potential and could be used in regenerative medicine when offering skin and hair transplants, for example for burn victims or people with cicatricial alopecia.”

We are pleased to have created a skin organoid model that grows hair. We discovered a new, important role for immune cells in promoting blood vessel growth in developing skin tissue, which could help improve other organoid models. These immune cells, called macrophages, also appear to play a key role in scarless skin repair in prenatal skin. Our findings could inform clinical advances to prevent scarring after surgery.”

Dr. Hudaa Gopee, co-first author, Newcastle University

Professor Muzlifah Haniffa, co-lead author and interim head of cell genetics at the Wellcome Sanger Institute, said: “Our prenatal human skin atlas and organoid model provide the research community with freely available tools to study congenital skin diseases and explore the possibilities of regenerative medicine.” We do exciting advances in creating the Human Cell Atlas, understanding the biological steps of how humans are built, and studying what goes wrong in disease.”