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Wellcome - MRC Cambridge Stem Cell Institute

 
A human embryo at the blastocyst stage, about six days after fertilization, viewed under a light microscope. The embryo is in the process of "hatching" out of the zona pellucida - the tough outer membrane - just before implanting in the wall of the uterus

New insights into how our bodies come into being from a single cell have been generated by researchers at the Wellcome - MRC Cambridge Stem Cell Institute working with collaborators at the Wellcome Sanger Institute and across the University of Cambridge.

It is the first study of its kind to describe fetal development in humans by retracing how and when mutations are acquired during pregnancy. The team found higher rates of mutation in early cell divisions, with the ‘decision’ for whether cells become the fetus or become protective tissues like the placenta occurring much earlier than previously thought.

The study, published in Nature, highlights subtle differences between human biology and that of mice, which have previously been relied upon as models for such research. It provides an important reference of mutation under normal conditions for researchers seeking to understand the causes of diseases such as childhood cancers and rare developmental disorders, which often begin in utero.

Studying development is motivated in large part by the desire to understand how our bodies, with their incredible complexity, come into being from a single cell. Understanding how this is coordinated and which cells give rise to others under normal circumstances may help us to identify how and why development can sometimes go wrong.

Tracking development forward through time can be achieved through lineage tracing, which involves ‘marking’ cells in a way that this is passed on to the offspring of a cell. This allows you to map how cells are related to each other and create a ‘family tree’.

This technique requires manipulation of the developing embryo, however, so is not ethical or feasible in humans. Study of human development has therefore been limited primarily to careful microscopy, with much of our knowledge of development based on model organisms such as zebra fish and mice.

For this study, researchers at the Wellcome Sanger Institute and Wellcome - MRC Cambridge Stem Cell Institute collected eight week and eighteen week-old haematopoietic stem and progenitor cells (HSPCs) from human fetal tissue1 and grew them into 511 single-cell-derived colonies.

DNA from hundreds of these colonies underwent whole genome sequencing to identify somatic mutations that could be used to trace the lineage of blood cells back to the first division of the embryo. Looking for these ‘marker’ mutations in tiny biopsies from other tissues then allowed the researchers to see when these tissues diverged from the blood cell population.

The team found that by week eight of development, cells had acquired 25 mutations and 42 by week 18, indicating a higher rate of mutation in early cell divisions. They also timed the ‘decision’ for which cells would become the fetus and which would become extra-embryonic tissue, which includes the placenta and yolk-sac, occurred between four and 16 cells.

Dr Anna Ranzoni, a first author of the study from the Wellcome - MRC Cambridge Stem Cell Institute and Department of Haematology at the University of Cambridge, said: “The findings of this study have challenged some of our previous understanding about how the fetus grows from one cell during the earliest stages of life, such as when the embryonic and extra-embryonic tissues diverge. This kind of resolution will be essential if we are to try to pinpoint the origin of diseases that have their roots in development.”

There was also evidence that the extra-embryonic mesoderm and the blood cells that deliver oxygen to the fetus in the first trimester of pregnancy arise from the hypoblast, which is generally considered an extra-embryonic tissue – a clear difference between human and mouse biology.

Dr Michael Spencer Chapman, a first author of the study from the Wellcome Sanger Institute, said: “Mice have been an excellent model for studying human development, but there was always the question of whether mouse biology was the same as our biology or merely similar. We found evidence that primitive human blood cells arise from the hypoblast, which is different to mice, settling a question that has been debated for decades.”

These insights into the precise biological processes involved in human development provide an essential reference of developmental dynamics under normal circumstances for those studying childhood cancers, which often begin in utero, as well as rare developmental disorders.

Dr Ana Cvejic, a senior author of the study and Group Leader at the Wellcome - MRC Cambridge Stem Cell Institute and Department of Haematology at the University of Cambridge, said: “Our study provides important insights into the incredibly complex biological processes at work in the earliest weeks of life, which have simply not been possible until now. This resource will be an invaluable reference for what happens under normal circumstances, so that we can start to unravel what happens when development goes wrong.”

Publication

Spencer Chapman, M., Ranzoni, A.M., Myers, B. et al. (2021)

Lineage tracing of human development through somatic mutations. Nature.

DOI: https://doi.org/10.1038/s41586-021-03548-6

Funding

This work was supported by the European Research Council, EMBO, the Medical Research Council and Wellcome.

Credit

Lead image: Human blastocyst hatching. K. Hardy. Attribution 4.0 International (CC BY 4.0)

This news article was adapted from a press release by the Wellcome Sanger Institute.