First ‘blueprint’ of human skeletal development offers new insights into bone formation

The first ‘blueprint’ of human skeletal development reveals how the skeleton is formed, shedding light on the arthritis process and highlighting the cells involved in conditions that affect skull and bone development.

Researchers from the Wellcome Sanger Institute and colleagues have used cutting-edge genomic techniques to identify all the cells and pathways involved in the early stages of skeletal development. Part of the wider Human Cell Atlas (HCA) project, this resource could be used to investigate whether current or future therapeutic drugs could disrupt skeletal development if used during pregnancy.

The study, published today (November 20) in Natureshows a clear picture of how cartilage acts as a scaffold for bone growth throughout the skeleton, except for the top of the skull. The team mapped all the cells critical to skull formation and investigated how genetic mutations can cause the soft spots in newborns’ skulls to fuse together too early, limiting the growth of the developing brain. In the future, these cells could be used as potential diagnostic and therapeutic targets to identify and treat congenital diseases.

They also found certain genes activated in early bone cells that may be linked to an increased risk of developing hip arthritis as an adult. By comparison, they suggest that other genes in early cartilage cells are associated with an increased risk of knee arthritis, possibly because of their role in cartilage repair. In the future, further study of these different cells could help develop new treatments for these conditions.

Overall, the developing skeletal atlas is a freely available resource that can be used to understand more about bone development and how it affects conditions affecting these tissues that occur in children and adults.

This paper is one of a collection of more than 40 HCA publications in Nature Portfolio journals that represent a milestone in our understanding of the human body. These highly complementary studies have shed light on central aspects of human development and the biology of health and disease, and have led to the development of vital analytical tools and technologies, which will contribute to the creation of the Human Cell Atlas¹.

Children’s skulls fully harden and fuse when they are between one and two years old. Before this developmental process, there are soft spots in the skull that allow the brain to continue developing after the child is born. In some cases, these soft spots fuse too early, causing a condition known as craniosynostosis, which prevents the brain from expanding.

In the UK, this is usually treated quickly through an operation, but if left untreated, it can cause pressure to build up in the skull, leading to learning difficulties, vision problems and hearing loss. While craniosynostosis has been linked to genetic mutations, until now it has not been possible to identify which cells in humans are disrupted by these mutations.

Osteoarthritis (OA) is the most common form of arthritis in the UK and causes painful and stiff joints such as the hip and knees over time. This is because the protective layer, known as cartilage, around these joints has broken down or worn away. Eventually, in most cases, it is necessary to replace the joint through major surgery, as adults cannot grow new cells to repair the damaged cartilage.

Using new cutting-edge technology, researchers from the Sanger Institute and colleagues mapped skeletal development in the first trimester of pregnancy, from 5 to 11 weeks after conception, at the spatial and single-cell level. This allowed them to describe all the cells, gene networks and interactions involved with bone development during early development, including the location of the cells in the rapidly growing tissue.

The single-cell map revealed how cartilage cells develop first, acting as a scaffold for bone cells to develop next. The team highlighted how this happens everywhere in the skeleton, except for the top of the skull, called the calvarium. Inside the calvarium, they discovered new types of early bone cells involved in skull development. The team investigated how genetic mutations linked to craniosynostosis disrupt these early bone cells, causing them to fuse too early.

The researchers also found that genetic variants associated with a higher risk of hip OA are involved in the early development of bone cells and their downstream regulators, while variants that affect the risk of knee arthritis are involved in cartilage formation.

In addition, the team used the atlas to investigate the effect of medication on skeletal development. They compiled a list of 65 clinically approved drugs, currently not recommended during pregnancy, and pointed out where they may disrupt skeletal development. By including this information in the atlas, it highlights the impact drugs can have on the developing human and could be informative when considering whether the therapies are safe for use during pregnancy.

There are countless processes that act in concert during the development of the human skeleton and joints, and our research has characterized cell types and mechanisms involved in bone formation and skull fusion. By studying these, we were able to give context to DNA variants linked to congenital conditions such as craniosynostosis, predicting how genetic changes affect the developing skeleton. Ultimately, using this atlas could help us better understand the conditions of both the young and the aged skeleton. “Having this ‘design’ of bone formation may also help us develop efficient ways to grow bone and cartilage cells in a dish, which has huge therapeutic potential.”

Dr. Ken To, co-first author from the Wellcome Sanger Institute

Dr Jan Patrick Pett, co-first author from the Wellcome Sanger Institute, said: “We are excited to have created the first multi-omic map of the developing human skeleton, which has enormous potential for understanding how children grow. our bones. and addressing the conditions that may affect this Our time- and space-resolved multilayer atlas enabled new computational analyses, which we used to build a comprehensive view of how it was developmental. The processes are regulated by a clearer picture of what happens as our skeleton forms, and how this affects conditions such as osteoarthritis, could help unlock new treatments in the future.”

Professor Sarah Teichmann, co-founder of the Human Cell Atlas and former senior author at the Wellcome Sanger Institute, now based at the Cambridge Stem Cell Institute at the University of Cambridge, said: “Our only freely available skeletal atlas sheds new light on cartilage. , bone and joint development during the first trimester, detailing the cells and pathways involved together for the first time state-of-the-art spatial technology with genetic analysis and can be used by the research community worldwide This detailed atlas of the development of of bone in space and time is coordinated with other studies that bring the entire Human Cell Atlas initiative one step closer to fully understanding what happens in the. the human body throughout development, health and disease’.