Human toes and fingers do not grow outward, instead, they are created within a larger initial bud, as intervening cells regress to reveal the digits beneath. This is amid many developments captured for the first time as researchers reveal a spatial cell atlas of the complete developing human limb, determined in space and time.
Scientists at the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute and collaborators practical cutting-edge single-cell and spatial skills to produce an atlas describing the cellular landscape of the primary human limb, pinpointing the precise location of cells.
This study is part of the international Human Cell Atlas creativity to map every cell category in the human body to alter our understanding of health and disease.
The atlas, published in Nature, delivers an openly accessible resource that captures the complicated processes governing the limbs’ quick development during the initial stages of limb formation.
The atlas also reveals new associations between developmental cells and some congenital limb syndromes, such as short and extra fingers.
Limbs are identified to primarily appear as undifferentiated cell pouches on the sides of the body, with no specific shape or function. However, after 8 weeks of growth, they are well distinguished, structurally complex and immediately identifiable as limbs, complete with fingers and toes. This necessitates a very fast and precise orchestration of cells. Any small instabilities to this course can have a downstream effect, which is why disparities in the limbs are among the most regularly reported syndromes at birth, affecting around one in 500 births globally.
While limb development has been widely studied in mouse and chick models, the degree to which they reflect the human condition remained unclear. However, progress in technology now permit scientists to explore the early phases of human limb development.
In this new study, researchers from the Wellcome Sanger Institute and their collaborators examined tissues between 5 and 9 weeks of growth. This allowed them to follow detailed gene expression programs, triggered at certain times and in specific areas, which shape the developing limbs.
Special staining of the tissue shows clearly how cell populations differentially position themselves into shapes of the forming digits.
As part of the study, scientists established that certain gene patterns have implications for how the hands and feet develop, recognizing certain genes, which when disrupted, are related with specific limb conditions like brachydactyly – short fingers – and polysyndactyly – additional fingers or toes.
The team were also able to authorize that many features of limb development are common between humans and mice.
General, these results not only offer an in-depth characterization of limb development in humans but similarly critical understandings that could influence the diagnosis and treatment of congenital limb syndromes.
Professor Hongbo Zhang, lead author of the study from said, decades of perusing model organisms established the foundation for our understanding of vertebrate limb growth. However, illustrating this in humans has been intangible until now, and we couldn’t assume the significance of mouse models for human development. What was revealed is a extremely complex and precisely controlled process. It is like watching a sculptor at work, shaping a block of marble to reveal a masterpiece. In this case, nature is the sculptor, and the outcome is the incredible complexity of our fingers and toes.
Dr Sarah Teichmann co-founder of the Human Cell Atlas and senior author of the study from the Wellcome Sanger Institute said, for the first time, we have been able to witness the extraordinary process of limb development down to single cell resolution in space and time. The study in the Human Cell Atlas is expanding our understanding of how anatomically complex structures form, helping us unearth the genetic and cellular processes behind healthy human growth, with many implications for research and healthcare. For example, we revealed novel roles of key genes MSC and PITX1 that may control muscle stem cells. This could offer the probability for treating muscle-related disorders or injuries.
