Revolutionary Human Skin Map Offers Blueprint for Skin Regeneration and Scar Prevention

A team from the Wellcome Sanger Institute, Newcastle University, and other partners utilized single cell sequencing alongside various genomic methods to construct the atlas, revealing how human skin and hair follicles are created. This knowledge could pave the way for new techniques in regenerative medicine, including creating hair follicles for skin transplants in burn victims.

In a study published today (16 October) in Nature, the researchers also engineered a ‘mini organ’ of skin in a lab setting that has the capability to grow hair. Through this organoid, they demonstrated the significant role of immune cells in promoting scarless skin repair, which may lead to treatments to prevent scarring after surgeries or injuries.

As part of the Human Cell Atlas¹, an initiative aiming to map all human cell types to enhance our understanding of health and disease, the researchers offered a molecular blueprint for constructing skin and introduced a novel organoid model for investigating congenital skin disorders.

Skin is the body’s largest organ, averaging two square meters in surface area. It acts as a protective shield, maintains body temperature, and possesses self-regenerative capabilities. Skin develops within the sterile womb environment, where all hair follicles are formed before birth; while hair follicle cycling occurs post-birth, no new follicles are generated. Notably, fetal skin can heal without leaving scars.

Researching human skin development has been challenging due to significant differences with animal models. A segment of the Human Cell Atlas project is dedicated to examining the construction of human skin. By understanding skin development, spatial and temporal cell positioning, and genetic influences, researchers hope to decipher how specific genetic mutations lead to congenital skin diseases, such as blistering disorders and scaly skin.

In this latest research, scientists from the Wellcome Sanger Institute, Newcastle University, and partners created the first single cell and spatial atlas of human prenatal skin.

The team analyzed samples of prenatal skin tissue², isolating individual cells in suspension as well as examining their positions within the tissue. Using advanced single-cell sequencing and spatial transcriptomics³, they investigated how cells change over time and the regulatory mechanisms behind skin and hair follicle development, detailing the formation process of human hair follicles and noting the differences compared to mouse follicles.

Employing adult stem cells⁴, the researchers also produced a skin organoid in the lab that could grow hair. When they compared the molecular traits of these skin organoids with those of prenatal skin, they observed that the organoid model closely mirrored prenatal skin characteristics rather than those of adult skin.

It was found that blood vessels did not develop as effectively in the skin organoid compared to prenatal skin. However, by introducing immune cells called macrophages, they observed an enhancement in blood vessel formation, confirmed through 3D imaging of the tissue.

While it’s established that these immune cells shield the skin from infections, this study marks the first indication of macrophages being integral to human skin development by facilitating blood vessel growth. This could provide pathways to enhance vascularization in other organoid models.

The team further explored the differences in cell types between prenatal and adult skin. They illustrated the crucial role macrophages play in achieving scarless skin repair in prenatal skin, which may lead to practical applications for preventing scarring after injuries or surgeries.

This research culminated in sharing a molecular ‘recipe’ for constructing human skin and understanding the formation of hair follicles. This knowledge could contribute to generating new hair follicles for regenerative medicine applications, such as skin grafts for burn patients or those suffering from scarring alopecia.

The prenatal human skin atlas will aid in pinpointing where the genes linked to congenital hair and skin disorders—like blistering and scaling skin—are active or expressed. The researchers identified that these disorder-related genes are found in prenatal skin, indicating their origin during fetal development. The skin organoids created from this research present a precise model for studying these conditions.

Dr. Elena Winheim, co-first author from the Wellcome Sanger Institute, stated: “Our work on the prenatal human skin atlas has resulted in the first comprehensive molecular ‘recipe’ for making human skin and clarified how hair follicles are formed before birth. These discoveries have tremendous potential in clinical applications, especially in regenerative medicine, for skin and hair transplants, benefitting burn victims or those with scarring alopecia.”

Dr. Hudaa Gopee, co-first author from Newcastle University, expressed excitement about the development of a hair-growing skin organoid model. During this process, they identified a new and crucial function of immune cells in promoting blood vessel growth in the developing skin tissue, which could enhance other organoid models. These macrophages also seem vital for achieving scarless skin repair in prenatal conditions, leading to possible clinical advancements for minimizing scars after surgical procedures.

Professor Muzlifah Haniffa, co-lead author and Interim Head of Cellular Genetics at the Wellcome Sanger Institute, emphasized: “Our prenatal human skin atlas and organoid model give researchers valuable tools to investigate congenital skin disorders and the prospects for regenerative medicine. We are making significant progress towards completing the Human Cell Atlas, deciphering the biological processes that contribute to human formation, and identifying the mechanisms that lead to diseases.”