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Developmental Biology - Cell Differentiation

Cell Identity

Cells face multiple competing choices on the way to a single identity...

From light-sensing cones in our retinas, blood-pumping muscle cells in our heart and our waste filtering kidneys — our body is made up of hundreds of cell types exquisitely specialized for unique jobs with great precision. This complexity belies the fact that each of our trillions of highly specialized cells began as a single cell — a primordial cell. How do primitive, undifferentiated cells ultimately choose one destiny? It's a question that has tantalized biologists for centuries.

Now, scientists from Harvard Medical School, the Karolinska Institute and the Medical University of Vienna and other institutions, have uncovered new clues about how molecular logic decides cell fate. Their findings, published June 7 in Science are based on the formation of mouse neural crest tissue.
Researchers found cells face multiple competing choices on the way to a final identity, performing a series of binary decisions before reaching their final destination.

"A progenitor cell could become anything, but how is that choice realized?" asks co-senior investigator Peter Kharchenko PhD, associate professor of biomedical informatics at Blavatnik Institute, Harvard Medical School. "Our study represents an attempt to define the molecular logic behind cell choice. We believe our findings can help us understand how cells orient themselves toward a particular fate and what might go wrong in the process of cell differentiation."
Research reveals neural crest cells occur in three phases: (1) competition between genetic programs vying for attention, (2) gradual bias toward one of these programs and (3) an ultimate decision.

Researchers caution that at this point their findings solely pertain to neural crest cells, but this same approach could be used to understand cell differentiation in other tissues as it remains unclear whether other tissues, even organisms, follow a similar mechanism in cell differentiation.
"We hope our findings can provide a new window into the diversity of neural crest cells and help explain both normal development of cells giving rise to craniofacial, heart and sensory tissues — but also some pathologic 'detours' that lead to abnormalities of cell differentiation."

Igor Adameyko PhD, senior researcher, Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Austria and study co-senior author.

A Cell's Dilemma

Researchers traced trajectories of primitive cells from mouse neural crest tissue - cells that arise from the ectoderm, a primary germ-cell layer formed in embryo development. Progenitor cells give rise to various cell types including: brain nerve cells in the spinal cord and elsewhere; pigment-producing cells; cells of the bones and cartilage; and smooth muscles on the skull and face.

To retrace each 'decision' made in primitive cells as they become specialized, investigators used a single-cell sequencing technique allowing observation of genetic change within individual cells. This allowed for plotting a cell's trajectory in the form of trees, marked by a series of forks on the road. A cell's decision to commits to a given fate was tracked by the rate of RNA changes in individual cells. RNA changes were measured by shifts in the rate of gene expression and protein production which occur when a cell is starting to transform. As genetic programs get activated or silenced, the rate of RNA production changes accordingly.

Much to researchers' surprise,the analysis revealed how competing groups of genes - genetic programs that regulate various cellular functions - nudge cells simultaneously toward different developmental paths. As cells decide on a path, one genetic program becomes stronger, while the competing one gets weaker, allowing the cell to move toward a chosen path.
Analysis shows that cells face a series of binary choices, with each subsequent decision narrowing choice of specialization. For example, the first bifurcation occurs when a neural crest cell must choose whether it will become a sensory nerve cell or some other type. At the next fork on the road, the nerve cell must decide between becoming a glial cell that supports and shields neurons — or a neuron, and so forth until a final state is reached.

The next question is how is a cell steered toward a particular gateway decision. "Does the cell slowly start to activate the molecular machinery that pushes it on the right path or is there something else going on?" asks Peter Kharchenko, departments of Biomedical Informatics and the Stem Cell Institute, at Harvard University.
Findings reveal individual genes do not bias a cell's choice. Instead, clusters of genes associated with distinct fates activate all at once. The closer a cell is to a decision fork, the greater co-activation of both genetic programs, beckoning a decision such as becoming a cell in the jaw or a nerve cell.

This observation suggests a cell makes a choice only after both programs are partly activated, priming the cell for either alternative before commitment. Once a choice is made, the losing genetic program is silenced.

"That was rather surprising," Kharchenko adds. "We expected to see something simpler like the cell showing early preference for one option over another. Instead, we observed that the cell prepares for both options, considers both options and only then commits to a decision." And according to Adameyko, these findings suggest "a complex, long history of conflicting signals gradually preparing a cell for a range of possible outcomes..."

Researchers caution that the findings reveal internal decision making of a cell and how a decision is executed, not factors that actually guide the ultimate choice. Those factors are likely external signals from cell surroundings, rather than signals arising from within. However, the cell must be primed in order to respond to relevant external signals.

Kharchenko: "What we see is how the cell prepares for that decision and gears up to respond to one call or another. Something pushes the cell in one direction, but we still do not know what that catalyst is."

Veering off the right path

Understanding how cells mature and perform is important to understanding how and when they may veer off course and begin dividing uncontrollably, a cardinal feature of cancer. Several types of cancer originate from neural crest cells, including tumors of the peripheral nervous system, some endocrine tumors and melanoma. Although cell specialization is a tightly controlled process, errors in differentiation can occur and give rise to malignancies.
"There has been some indication that neural crest tumors arise from a cell's inability to overcome differentiation forks on the road and get stuck. Moving forward, we want to find out at what point a cell breaks away from its intended path and starts to overproliferate."

Peter V. Kharchenko PhD, Department of Biomedical Informatics, and Harvard Stem Cell Institute, Harvard Medical School, Cambridge, Massachusetts, USA.

In the future, researchers want to conduct a similar analysis on human neural crest tissue and detail the precise molecular events as they occur at the same critical junctures. How human cells resolve or fail to resolve these events is important in understanding changes in genetic programming that accompanies normal and abnormal differentiation.

Structured Abstract
Multipotent progenitors must choose among multiple downstream fates. In developing embryos, progenitor cells exhibit transcriptional or epigenetic heterogeneity that is related to early biases in cell fate choices, and can be externally induced or stochastic in nature. Molecular assessment of the transient states assumed by cells during these developmental progressions has the potential to illuminate how such fate-specific biases emerge and unfold to ensure fate commitment. With this aim, we examine multipotent neural crest cells—transient embryonic progenitors unique to vertebrates that build the head, teeth, neuroendocrine tissue, and autonomic and sensory nervous systems. Cranial neural crest preferentially gives rise to a multitude of mesenchymal types of facial cartilage and bones, in addition to neuronal, glial, and pigment cell–type progeny. By contrast, trunk neural crest does not form bone or cartilage derivatives in vivo. The logic and molecular mechanisms that allow neural crest to resolve multiple potential cell fates at each axial level remain poorly understood.

Here we used single-cell and spatial transcriptomics with statistical analysis of branching trajectories to investigate lineage relationships in mouse neural crest. Combined with lineage tracing and functional perturbations, we addressed spatiotemporal dynamics associated with early cell fate decisions in mouse trunk and cranial neural crest cells with different fate potential.

We find that up to early migration, neural crest cells progress through a sequence of common transcriptional states, followed by fate bifurcations during migration that can be formalized as a series of sequential binary decisions. The first decision separates sensory neuro-glial fate from all other fates, whereas the second decision occurs between autonomic and mesenchymal lineages and reveals a bipotent Phox2b+/Prrx1+ subpopulation. Decision points uncover distinct roles of neural crest regulators: Neurog2 is involved in early repression of melanocytes and activation of sensory fate at later steps. Each decision consists of initial coactivation, gradual biasing, and commitment phases. Early genes of competing cell fate programs coactivate in the same cells, starting from premigratory stage. As cells approach cell fate bifurcation points, increased synchronization of fate-specific programs and repulsion of competing fate programs lead to gradual appearance of cell fate bias, which becomes pronounced upon neural crest migration. Cell fate commitment culminates with activation of mutually exclusive, fate-specific gene expression programs. Early transcriptional patterns reveal that fate biasing of neural crest is already detectable when neural crest cells delaminate from the neural tube. In particular, the neuronal bias of trunk and mesenchymal bias of cranial neural crest emerge during delamination, indicating that this might be the time when the mesenchymal potential, distinct between cranial and trunk neural crest, is installed. In support to this hypothesis, we find that sustained overexpression of a single gene, Twist1, normally activated upon delamination only in the cranial compartment, is sufficient to reverse the trunk crest developmental program to a mesenchymal route.

Our analysis resolved a branching transcriptional trajectory of the differentiating neural crest, illustrating transcriptional implementation of major cell fate decisions and pinpointing the key differences defining cranial versus trunk neural crest potential. Our results show that neural crest cells differentiate through a series of stereotypical lineage-restriction events that involve coexpression and competition of genes driving alternative fate programs.

Co-investigators included Ruslan Soldatov, Marketa Kaucka, Maria Eleni Kastriti, Julian Petersen, Tatiana Chontorotzea, Lukas Englmaier, Natalia Akkuratova, Yunshi Yang, Martin Häring, Viacheslav Dyachuk, Christoph Bock, Matthias Farlik, Michael Piacentino, Franck Boismoreau, Markus Hilscher, Chika Yokota, Xiaoyan Qian, Mats Nilsson, Marianne Bronner, Laura Croci, Wen-Yu Hsiao, David Guertin, Jean-Francois Brunet, Gian Giacomo Consalez, Patrik Ernfors, and Kaj Fried.

The research was supported by Swedish Research Council grant ERC Consolidator grant "STEMMING-FROM-NERVE" N647844 and grants 2015-03387 and 2016-03645; by the Paradifference Foundation and Bertil Hallsten Research Foundation, by National Science Foundation grant NSF-14-532 CAREER award and by a National Institutes of Health grant R01HL131768. Additional support was provided by Knut and Alice Wallenberg Foundation and Familjen Erling Perssons stiftelse, and by a Russian Science Foundation grant 18-75-10005.

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Jun 19 2019   Fetal Timeline   Maternal Timeline   News  

Structure of mouse cell fate decisions. CREDIT The authors

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