NEW YORK – By putting together a multiomics-based atlas for prenatal skin samples, researchers in the UK have flagged immune- and non-immune cell communities involved in processes ranging from hair follicle formation or wound healing to blood vessel formation. The data also helped them garner biological clues for developing increasingly representative skin organoid models.
"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," co-senior and co-corresponding author Muzlifah Haniffa, a researcher affiliated with Newcastle University, Newcastle Hospitals NHS Foundation Trust, and the Wellcome Sanger Institute, said in a statement.
As part of the Human Cell Atlas, Haniffa and colleagues from the UK, US, Switzerland, and Germany performed a series of multiomic analyses that included 10x Chromium single-cell RNA sequencing, 10x Visium spatial transcriptomics, and multiplex RNA in situ hybridization on prenatal skin samples from aborted or miscarried fetuses seven to 17 weeks post-conception — work they outlined in a paper appearing in Nature on Wednesday.
"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," co-first author Elena Winheim, a researcher with the Wellcome Sanger Institute, said in a statement. "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."
Based on single-cell gene expression profiles for nearly 434,000 individual cells, together with spatial data from the microenvironment, the team found a key role for macrophages and macrophage-derived growth factors during the skin development process.
"Our atlas indicated that macrophages contribute to scarless skin repair, fibroblast homeostasis, and neurovascular development," the authors reported, adding that "[f]urther studies that align human fibroblast subsets across the lifespan are required to investigate the dynamics of scarless healing and the mechanical forces, microbiota, and environmental exposure on fibroblast functions."
Those results were further backed up by analyses of a "hair-bearing" skin organoid model, which the investigators developed using human embryonic stem cells and adult induced pluripotent stem cells.
Results from their subsequent imaging analyses suggested that new blood vessel formation was less pronounced in the skin organoid setting than in the prenatal skin atlas, though the researchers were able to somewhat reverse that effect with the introduction of blood vessel-promoting macrophage cells into the organoid.
"[W]e uncovered a new, important role of immune cells in promoting the growth of blood vessels in developing skin tissue," co-first author Hudaa Gopee, an investigator at Newcastle University, said in a statement, "which could help improve other organoid models."
Along with findings from the skin organoid analyses, the prenatal skin atlas offered a look at gene expression shifts in innate immune cells and non-immune cell types that took place over the course of skin development, wound healing, scar formation, neurovascular development, and other processes.
"Collectively, our findings suggest that prenatal skin fibroblasts in early gestation downregulate genes involved in extracellular matrix formation, collagen deposition, and inflammation, which may favor tissue regeneration over scarring," the authors wrote.
Consequently, the researchers suggested that the findings may offer clues to hair follicle formation for potential applications in hair regeneration, along with insights into congenital skin disorders, wound healing, skin transplantation, and therapeutic skin engineering efforts.
"Our prenatal human skin atlas represents a valuable resource to explore genes that cause congenital hair and skin disorders," the authors reported, adding that their comparison of prenatal skin and skin organoids "provides a blueprint to guide more faithful in vitro [skin organoid] generation."