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Axis formation and gastrulation initiate embryo development.
Click on GREEN embryo to see the Cambridge University video of a growing cultured "embryo".
Click on INSET to see Gastrula stage beginning in human embryo.
Constructing embryos from stem cells
Researchers at the University of Cambridge have reconstructed the earliest stages of mammalian development using embryonic stem cells. Their work reveals how a critical mass of cells is needed before self-organization can begin and an embryo form.
All organisms develop from embryos, from one cell dividing over and over to generate many cells. In the early stages of this process, the aggregate of cells looks like a featureless structure, most often a ball. Then the ball begins to ‘specialise’ into different types of cells and spread asymmetrically, forming a central axis — the structure along which an embryo develops.
Animal embryos follow this stage with a process known as gastrulation: the movement of the cells around the central axis to position a head and tail, the front and back of the animal. During gastrulation, cells form into three layers: endoderm, mesoderm and ectoderm, determining what tissues or organs will develop next.
“Gastrulation was described by biologist Professor Lewis Wolpert as being ‘truly the most important event in your life’ because it creates the blueprint of an organism.
"Axis formation and gastrulation are the two central processes that initiate the development of an organism and are inextricably associated with the embryo. We have managed to recreate this for the first time in the lab.”
Alfonso Martinez-Arias PhD, professor, department of genetics, University of Cambridge, and lead researcher.
Professor Martinez-Arias and colleagues have reconstructed these early stages of development using mouse embryonic stem cells. Their research was supported by the European Research Council and the Wellcome Trust in the United Kingdom,
Embryonic stem cells, discovered by Sir Martin Evans in the Department of Genetics in the 1980s (for which he was awarded the Nobel Prize in Physiology or Medicine in 2007) have become an important tool for developmental biologists to understand disease and useful in regenerative medicine for their ability to give rise to all cell types.
Over the last few years, mouse embryonic stem cells have been used to ‘grow’ organs including the eye and the cerebral cortex; both structures develop without an axis.
The research published in the journal Development reports how to coax cells into creating an axis, then undergo movement and organisation mimicking gastrulation. Over the years, researchers have been making aggregates of embryonic stem cells to obtain specific cell types, such as red blood cells. However, these cell aggregates lack structure and the cell types emerge in a disorganised fashion.
This research is the first to culture cells with an established axis, spatial organisation and gastrulation-like movement from aggregates of embryonic stem cells.
The researchers found that if the number of cells in an aggregate is similar to that found in a mouse embryo, the cells will generate a single axis. This axis serves as a template for a sequence of events mimicking early embryo formation. By introducing cell signals at unique intervals, they were also able to influence what type of cell was generated as well as its' future organisation.
In one experiment, activation of a particular signal at the correct time elicited the appearance of the mesoderm, endoderm and ectoderm – the precursors of all tissue types – with a spatial organization pattern similar to that of an embryo.
Using this system to begin the process of gastrulation, researchers were able to generate the early stages of a spinal cord. This finding complements previous research from the University of Edinburgh and the National Institute for Medical Research, showing that embryonic stem cells can be coaxed into spinal cord cells. However, the Cambridge embryo-like aggregates have more robust structural organization which may allow for the continued polarised growth of tissue.
“It is early, but this laboratory cultured cell growth promises insight into how early stages of human embryos develop and what determines the specialization of each different cell type. This discovery will allow for more robust protocols to determine which differentiation cues cells are subject to within embryo growth.
“Most significantly, this new system will provide a means to test, experimentally, how a homogeneous group of cells organizes itself within 3D space — a central process for development of any organism.”
Mouse embryonic stem cells (mESCs) are clonal populations derived from preimplantation mouse embryos that can be propagated in vitro and, when placed into blastocysts, contribute to all tissues of the embryo and integrate into the normal morphogenetic processes, i.e. they are pluripotent. However, although they can be steered to differentiate in vitro into all cell types of the organism, they cannot organise themselves into structures that resemble embryos. When aggregated into embryoid bodies they develop disorganised masses of different cell types with little spatial coherence. An exception to this rule is the emergence of retinas and anterior cortex-like structures under minimal culture conditions. These structures emerge from the cultures without any axial organisation. Here, we report that small aggregates of mESCs, of about 300 cells, self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation. The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. We discuss the meaning and implications of these observations and the potential uses of these structures which, because of their behaviour, we suggest to call ‘gastruloids’.
Van den Brink, SC et al. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse ES cells. Development; 4 Nov 2104
Turner, DA, et al. Wnt/β-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse ES cells. Development; 4 Nov 2104
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