From the photosensitive cones of the retina to the blood-pumping muscle of the heart or the waste-filtering cells of the kidneys, the human body is made up of hundreds of cell types, each highly specialised to perform its particular function with maximum precision. These billions of complex cells all originate from a single type of primordial germ cell. Scientists from the Medical University of Vienna, Harvard Medical School, Karolinska Institute in Sweden and other institutions have now discovered new clues that cast light upon the molecular logic that cells use to determine their destiny.
The researchers studied the development of primitive cells from the neural crest (embryonal tissue structure) of mice – these are cells that appear during early development and are the basis for formation of extraordinarily diverse cell types within the body. In humans, the neural crest is responsible for creating the face, teeth, sensory neurons, pigmentation, neuroendocrine cells and glial cells, as well as many other cell types in the body. The researchers used the technique of single-cell sequencing to observe the genetic changes in individual cells, one cell at a time.
Numerous bifurcations with choice-points
The study group plotted a cell's trajectory in the form of a decision-tree comprising a series of bifurcations. In order to determine the sequence of a cell's decisions and how it commits to a given purpose, the scientists tracked the rate of RNA (ribonucleic acid) changes. RNA changes occur when a cell starts to implement its start commands from the genes and to transform itself. Since genetic programs can be activated or silenced, the rate of RNA production changes accordingly.
The results show that, on their path to maturity, cells are faced by multiple competing options and make a series of binary choices until they arrive at their final destination. In the case of crest cells, for example, this is a three-phase process: activation of competing genetic programs vying for the cell's attention, gradual biasing towards one of the alternatives and the cell's final commitment. The first fork on a cell's journey occurs at an intersection where a neural crest cell must choose whether it will become a sensory nerve cell or another type of cell. At the next fork in the road, the nerve cell must decide between becoming a glial cell or a neuron – and so on until its final state is reached.
Competitors vie for the cell
Competing groups of genes – genetic programs that regulate various cellular functions – simultaneously nudge the cells towards different developmental paths. The closer the cell comes to its choice-point, the greater the co-activation of the two genetic programs, each of which wants to entice the cell in a different direction – for example to decide whether to be a jawbone cell or a nerve cell. Once a cell has chosen a path, the successful genetic program becomes stronger, while the competing programme gets weaker and shuts down.
Observations indicate that the cell only makes its decision once both programs have been partially activated, so that it prepares for both alternatives before committing. The researchers were surprised by this, as they had expected cells to display an early preference for one option or the other. On this point, Igor Adameyko, joint Principal Investigator from MedUni Vienna and Karolinska Institute says: "This might imply that a complex and long sequence of conflicting signals prepares the cell for a range of possible outcomes and it is only at the very end that the situation is resolved and reduced to a single viable option."
It is not yet clear what factors actually lead to the final decision. The team believes that it is more likely to be external signals from a cell's surroundings than signals that arise within the cell itself. The cell prepares to respond to one signal or the other but it is still not understood exactly what drives the cell in a particular direction. Although the findings initially only pertain to neural crest cells, the same approach could also be used to help understand cell differentiation in other tissues.
Taking a wrong turn
The observations of the study can help scientists understand how cells mature to perform their roles and, just as importantly, how they might "take a wrong turn" and start to divide uncontrollably – the key feature of cancer, for example. Although cell specialisation is a tightly controlled process, errors can occur in differentiation, leading to malignancy. Says Adameyko: "Cancer-initiating events are still a mystery and our research suggests that they may result from miscalculations that, in the same way as when a computer program crashes, leave the cell hanging in a corrupted state, even though the underlying hardware is still working." However, understanding the underlying biology of how cells make these decisions could also help to grow artificial tissues for medical treatments.
“Spatio-temporal structure of cell fate decisions in murine neural crest”
Ruslan Soldatov, Marketa Kaucka, Maria Eleni Kastriti, Julian Petersen, Tatiana Chontorotzea, Lukas Englmaier, Natalia Akkuratova, Yunshi Yang, Martin Haring, Viacheslav Dyachuk, Christoph Bock, Matthias Farlik, Michael L. Piacentino, Franck Boismoreau, Markus M. Hilscher, Chika Yokota, Xiaoyan Qian, Mats Nilsson, Marianne E. Bronner, Laura Croci, Wen-Yu Hsiao, David A. Guertin, Jean-Francois Brunet, Gian Giacomo Consalez, Patrik Ernfors, Kaj Fried, Peter V. Kharchenko, Igor Adameyko; Science 07 Jun 2019: Vol. 364, Issue 6444, eaas9536 – DOI: 10.1126/science.aas9536