Single-Cell Analysis of Prenatal Skin and Skin Organoids Offers Scarless Skin Repair Clues

Researchers at the Wellcome Sanger Institute and Newcastle University, together with a team of international collaborators, have created a single-cell atlas of prenatal human skin, and a “mini organ” of skin in a dish with the ability to grow hair.

Created using single-cell sequencing and other genomics techniques, the skin atlas could help scientists better understand how skin, including hair follicles (HFs), is formed, and potentially provide new information on what goes wrong in disease. The resulting insights may then help researchers develop approaches to creating new hair follicles in regenerative medicine, and generate skin transplants for burn victims. Using the skin organoids (SkO) the investigators also 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.

The skin atlas resource has been created as part of the Human Cell Atlas, which aims to map all cell types in the human body. Elena Winheim, PhD, at the Wellcome Sanger Institute, commented, “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.”

The human skin atlas data is freely available to explore interactively through a web portal: https://developmental.cellatlas.io/fetal-skin. Muzlifah Haniffa, PhD, interim head of cellular genetics at the Wellcome Sanger Institute, added, “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 toward creating the Human Cell Atlas, understanding the biological steps of how humans are built, and investigating what goes wrong in disease.”

Winheim  is co-first author, and Haniffa co-lead author of the team’s published paper in Nature, titled “A prenatal skin atlas reveals immune regulation of human skin morphogenesis.”

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. “Prenatal HFs start forming between 11 and 14 post-conception weeks (PCW) …” the team explained. There is follicle cycling after birth, but no new follicles are made. Before birth, skin also has the unique ability to heal without scarring. “Prenatal human skin is able to heal without scarring but loses this capacity after 24 PCW,” they further explained.

It has been difficult to study how human skin develops, as animal models have key differences. As part of the Human Cell Atlas, researchers are 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 newly reported study, teams 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. The investigators used single-cell sequencing and spatial transcriptomics—a molecular method that maps gene activity in a tissue sample and its location—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. “Our current study provides a comprehensive multi-omics cell atlas of 7–17 PCW human prenatal skin,” they wrote. “We profiled human prenatal skin using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multiplex RNA in situ hybridization to decode the dynamic cellular and molecular changes across gestation that regulate skin and HF morphogenesis.”

Using adult stem cells the researchers also created organoids—a “mini organ” of skin in a dish—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.

Through their studies, the team found that blood vessels did not form in the skin organoid as well as prenatal skin. They discovered that adding macrophage immune cells to the organoid promoted the formation of blood vessels, and undertook 3D imaging to assess blood vessel formation within the tissue. “Our data suggested that macrophages contribute to prenatal skin angiogenesis,” they noted. “… vascular network remodeling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures … Collectively, our findings demonstrate that interactions between macrophages and endothelial cells are required to support angiogenesis through blood vessel remodeling.”

While it’s known that these immune cells protect the skin from infection 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. The discovery may lead to an approach to improving the vascularisation of other tissue organoids.

The team also analyzed differences in cell types between prenatal skin and adult skin. Their results indicated 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. “Our atlas indicated that macrophages contribute to scarless skin repair, fibroblast homeostasis, and neurovascular development,” the researchers further noted.

From the collective results of their studies, the team suggested 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. “Our prenatal human skin atlas represents a valuable resource to explore genes that cause congenital hair and skin disorders,” the team stated. They found that genes involved in these disorders are expressed in prenatal skin, meaning they originate in utero. “We found that implicated genes are indeed expressed during prenatal skin development and HF differentiation, thereby supporting an in utero origin for these disorders.” The skin organoids created in the study offer a new, accurate model for studying these diseases. “Our systematic prenatal skin–SkO comparison provides a blueprint to guide more faithful in vitro SkO generation, which can facilitate future studies of interactions with the microbiota, the pathogenesis of congenital skin disorders, and hair and skin engineering for therapeutic applications, including hair regeneration and skin transplant,” they concluded.

Hudaa Gopee, MD, co-first author from Newcastle University, commented, “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.”

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