Researchers create 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 from the Wellcome Sanger Institute, Newcastle University and their collaborators used single cell sequencing and other genomics techniques to create the atlas and uncover how human skin, including hair follicles, is formed. These insights could be used to create new hair follicles in regenerative medicine and skin transplants for burn victims.

In the study, published today (16 October) in Nature, the team also created a ‘mini organ’ of skin in a dish with the ability to grow hair. Using the organoid, they showed how immune cells play an important role in scarless skin repair, which could lead to clinical applications to prevent scarring after surgery, or scarless healing after wounding.

As part of the Human Cell Atlas, which is mapping all cell types in the human body to transform understanding of health and disease, the researchers provide a molecular ‘recipe’ to build skin and a new organoid model to study congenital skin diseases.

Skin is the largest organ of the human body, measuring on average two square meters. It provides a protective barrier, regulates our body temperature and can regenerate itself. Skin develops in the sterile environment of the womb, with all hair follicles formed before birth – there is follicle cycling after birth, but no new follicles are made. Before birth, skin has the unique ability to heal without scarring.

It has been very difficult to study how the human skin develops, as animal models have key differences. As part of the Human Cell Atlas, a team of researchers is focused on studying how human skin is built. Understanding how skin develops, where cells are in space and time, and the role of genetics will help reveal how specific mutations cause congenital skin disorders, such as blistering disorders and scaly skin.

In this new study, researchers at the Wellcome Sanger Institute, Newcastle University 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 look at individual cells in suspension, as well as cells in place within the tissue. Scientists used cutting-edge single-cell sequencing and spatial transcriptomics to analyze individual cells in space and time, and the cellular changes that regulate skin and hair follicle development. They described the steps that outline how human hair follicles are formed and identified differences from mouse hair follicles.

Using adult stem cells, the researchers also created a ‘mini organ’ of skin in a dish, known as an organoid, with the ability to grow hair. They compared the molecular characteristics of skin organoids with prenatal skin and found the skin organoid model more closely resembled prenatal skin than adult skin.

The team found that blood vessels did not form in the skin organoid as well as prenatal skin. By adding immune cells known as macrophages to the organoid, they discovered the macrophages promoted the formation of blood vessels, and the team undertook 3D imaging to assess blood vessel formation within the tissue.

It’s known that these immune cells protect the skin from infection. However, this is the first time that macrophages have been shown to play a key role in the formation of human skin during early development by supporting the growth of blood vessels. This offers an option to improve vascularization of other tissue organoids.

The team also analyzed differences in cell types between prenatal skin and adult skin. They show how macrophages play an important role in scarless skin repair in prenatal skin, which could lead to clinical applications to avoid scarring after surgery or wounding.

As a result of this study, the team provides a molecular ‘recipe’ for how human skin is built and how hair follicles form. These insights could be used in the creation of new hair follicles for regenerative medicine, such as for skin transplants for burn victims, or those with scarring alopecia.

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

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

We’re excited to have made a skin organoid model that grows hair. In this process, we uncovered a new, important role of immune cells in promoting the growth of blood vessels in developing skin tissue, which could help improve other organoid models. These immune cells, called macrophages, also appear to play a key part in scarless skin repair in prenatal skin. Our findings could inform clinical advances to avoid scarring after surgery.”

Dr Hudaa Gopee, co-first author, Newcastle University

Professor Muzlifah Haniffa, co-lead author and Interim Head of Cellular 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 regenerative medicine possibilities. We are making exciting strides towards creating the Human Cell Atlas, understanding the biological steps of how humans are built, and investigating what goes wrong in disease.”