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Somatic Mutations Help to Map out Human Development

Review of “Lineage tracing of human development through somatic mutations” Nature from by Stuart P. Atkinson

The little that we currently understand about the development of the human fetal hematopoietic system derives mainly from microscopic observations [1]. In the hope of gaining additional insight into human prenatal development and the origins of primitive and definitive hematopoiesis, researchers led by Peter J. Campbell and Ana Cvejic (Wellcome Trust Sanger Institute, Hinxton/University of Cambridge, Cambridge, UK) reconstructed a phylogenetic tree of blood development using whole-genome sequencing of single-cell-derived hematopoietic colonies from human fetuses between eight and eighteen weeks after conception and coupled this data with deep targeted sequencing of embryonic tissues [2].

Excitingly, Chapman et al. [3] now report on their findings and describe how their analyses of somatic mutations in fetal hematopoietic stem and progenitor cells (HSPCs) [4, 5] help to show that the extra-embryonic mesoderm and primitive blood in humans derive from the hypoblast [6, 7], one of the distinct layers arising from the inner cell mass in the mammalian blastocyst.

Here are all the highlights from this exciting new study:

  • The first three cell divisions after fertilization associated with a high acquisition of somatic mutations due to extensive chromatin accessibility or the dilution of maternally produced DNA repair factors
    • Mutation acquisition then drops at the time of the maternal-to-zygotic transition
  • Reconstructed phylogenetic trees reveal an unequal contribution of each blastomere to blood, which agrees with the stochastic nature of early cell-fate decisions
  • Targeted sequencing of non-hematopoietic tissues for HSPC-associated somatic mutations determined the timing of mutation acquisition relative to developmental events
    • Results suggested that many lineages contributed to gut epithelium and blood HSPCs
    • Several lineages from at least the sixth round of cell division from the zygote give rise to around 8% of gut epithelial cells (which predates gastrulation, when the endoderm and mesoderm split from one another)
  • A similar analysis in embryonic and extra-embryonic tissues revealed the separation of the trophoblast and inner cell mass occurs at the four-to-sixteen cell stage (like in the mouse) and directly inferred five independent lineages newly committed to an inner cell mass fate
    • The number of blood antecedent lineages increased to twenty by epiblast specification
    • Further mutational analysis then suggested that human extra-embryonic mesoderm and primitive blood emerge from the hypoblast
  • The observed pattern of shared mutations in ectodermal tissues differed from mesodermal and endodermal tissues
    • Epiblast cells contribute to mesoderm and endoderm development and made broadly similar but individually small contributions
    • Fewer epiblast cells contribute to ectodermal tissues than to endoderm or non-hematopoietic mesoderm

For more on how somatic mutations and single-cell analysis can help describe the unknowns of human development, stay tuned to the Stem Cells Portal!

References

  1. Ivanovs A, Rybtsov S, Ng ES, et al., Human haematopoietic stem cell development: from the embryo to the dish. Development 2017;144:2323-2337.
  2. Lee-Six H, Øbro NF, Shepherd MS, et al., Population dynamics of normal human blood inferred from somatic mutations. Nature 2018;561:473-478.
  3. Spencer Chapman M, Ranzoni AM, Myers B, et al., Lineage tracing of human development through somatic mutations. Nature 2021;595:85-90.
  4. Blokzijl F, de Ligt J, Jager M, et al., Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538:260-264.
  5. Baron CS and van Oudenaarden A, Unravelling cellular relationships during development and regeneration using genetic lineage tracing. Nature Reviews Molecular Cell Biology 2019;20:753-765.
  6. Rossant J and Tam PPL, New Insights into Early Human Development: Lessons for Stem Cell Derivation and Differentiation. Cell Stem Cell 2017;20:18-28.
  7. Enders AC and King BF, Formation and differentiation of extraembryonic mesoderm in the rhesus monkey. American Journal of Anatomy 1988;181:327-340.