First map of human limb development reveals unexpected growth processes and explains syndromes found at birth

Human fingers and toes do not grow outward; instead, they form from within a larger foundational bud, as intervening cells recede to reveal the digits beneath. This is among many processes captured for the first time as scientists unveil a spatial cell atlas of the entire developing human limb, resolved in space and time.

Researchers at the Wellcome Sanger Institute, Sun Yat-sen University, EMBL's European Bioinformatics Institute and collaborators applied cutting-edge single-cell and spatial technologies to create an atlas characterising the cellular landscape of the early human limb, pinpointing the exact location of cells.

This study is part of the international Human Cell Atlas initiative to map every cell type in the human body, to transform understanding of health and disease.

The atlas, published today (6 December) in Nature, provides an openly available resource that captures the intricate processes governing the limbs' rapid development during the early stages of limb formation.

The atlas also uncovers new links between developmental cells and some congenital limb syndromes, such as short fingers and extra digits.

Limbs are known to initially emerge as undifferentiated cell pouches on the sides of the body, without a specific shape or function.

However after 8 weeks of development, they are well differentiated, anatomically complex and immediately recognisable as limbs, complete with fingers and toes.

This requires a very rapid and precise orchestration of cells.

Any small disturbances to this process can have a downstream effect, which is why variations in the limbs are among the most frequently reported syndromes at birth, affecting approximately one in 500 births globally.

While limb development has been extensively studied in mouse and chick models, the extent to which they mirror the human situation remained unclear.

However, advances in technology now enable researchers to explore the early stages of human limb formation.

In this new study, scientists from the Wellcome Sanger Institute, Sun Yat-sen University, and their collaborators analysed tissues between 5 and 9 weeks of development.

This allowed them to trace specific gene expression programs, activated at certain times and in specific areas, which shape the forming limbs.

Special staining of the tissue revealed clearly how cell populations differentially arrange themselves into patterns of the forming digits.

As part of the study, researchers demonstrated that certain gene patterns have implications for how the hands and feet form, identifying certain genes, which when disrupted, are associated with specific limb syndromes like brachydactyly -- short fingers -- and polysyndactyly -- extra fingers or toes.

The team were also able to confirm that many aspects of limb development are shared between humans and mice.

Overall, these findings not only provide an in-depth characterisation of limb development in humans but also critical insights that could impact the diagnosis and treatment of congenital limb syndromes.

Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, said: "Decades of studying model organisms established the basis for our understanding of vertebrate limb development. However, characterising this in humans has been elusive until now, and we couldn't assume the relevance of mouse models for human development. What we reveal is a highly complex and precisely regulated process. It is like watching a sculptor at work, chiselling away at a block of marble to reveal a masterpiece. In this case, nature is the sculptor, and the result is the incredible complexity of our fingers and toes."

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: "For the first time, we have been able to capture the remarkable process of limb development down to single cell resolution in space and time. Our work in the Human Cell Atlas is deepening our understanding of how anatomically complex structures form, helping us uncover the genetic and cellular processes behind healthy human development, with many implications for research and healthcare. For instance, we discovered novel roles of key genes MSC and PITX1 that may regulate muscle stem cells. This could offer potential for treating muscle-related disorders or injuries."

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The Viking disease can be due to gene variants inherited from Neanderthals

Many men in northern Europe over the age of 60 suffer from the so-called Viking disease, which means that the fingers lock in a bent position. Now researchers at Karolinska Institutet, together with colleagues, have used data from over 7,000 affected individuals to look for genetic risk factors for the disease. The findings, which have been published in Molecular Biology and Evolution, show that three of the strongest risk factors are inherited from Neanderthals.

Up to 30 percent of men in northern Europe over 60 suffer from a condition called Dupuytren's contracture. The condition is sometimes called the Viking disease because it mainly affects individuals with northern European ancestry. The disease is significantly more common in men than women and usually begins as a lump in the palm of the hand that grows and causes one or more fingers to lock in a bent position. The condition is usually not painful, but the nodules may sometimes be tender to pressure.

The researchers in the study, led by Hugo Zeberg from Karolinska Institutet and Svante Pääbo from Max Planck Institute for Evolutionary Anthropology, set out to investigate whether genetic variants inherited from Neanderthals are involved in the disease.

Neanderthals lived in Europe and western Asia until about 40,000 years ago, when they were replaced by modern humans. However before Neanderthals disappeared, they mixed with modern humans. As a result, between one and two percent of the genomes of people with roots outside of Africa come from Neanderthals.

"Since Dupuytren's contracture is rarely seen in individuals of African descent, we wondered whether gene variants from Neanderthals can partly explain why people outside of Africa are affected," says Hugo Zeberg, assistant professor at the department of Physiology and Pharmacology, Karolinska Institutet.

The researchers used data from three large clinical cohorts in the US, UK, and Finland, which allowed them to compare the genomes of 7,871 sufferers and 645,880 healthy controls. They identified 61 genetic risk factors for Dupuytren's contracture. The researchers found that three of these were inherited from Neanderthals, and these included the second and third most important risk factors.

The study is further evidence that the intermingling between Neanderthals and our ancestors has important consequences for the prevalence of some diseases, particularly among certain groups.

"This is a case where the meeting with Neanderthals has affected who suffers from illness, although we should not exaggerate the connection between Neanderthals and Vikings," says Hugo Zeberg.

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