Simulation of Neural Crest Cell Migration in Embryonic Development of the Nervous System
Kevin Wong, Congzhen Shi, Sandhya Selvakumar, Leah Edelstein-Keshet (Mentor)
University of British Columbia
- Kasemeier-Kulesa, Jennifer C., et al. "TrkB/BDNF Signalling Patterns the Sympathetic Nervous System." Nature Communications, vol. 6, no. 1, 2015, pp. 8281.
- Morpheus - A computational software created by the University of Dresden
Acknowledgments: we are grateful to Dr. Paul Kulesa for suggesting this project and to URO for the REX opportunity.
- Increasing the rate of secretion of chemoattractant by the target increases chemotaxis rate up to a point
- A minimal amount of chemoattractant must be secreted by migrating cells to effectively migrate as a cluster
- Too much cell secretion masks the attraction to the target, preventing the cells from completing their journey
- Increasing cell number directly increases the amount of chemoattractant secreted by the cluster
- Adhesion does not appear to correlate strongly with time taken to reach the target
- Chemotaxis is a tightly regulated process with many parameters to optimize
- There is a range of chemoattractant concentration for tolerable/optimal chemotaxis
- Stronger source chemoattractant leads to more effective and faster arrival of the cell cluster at target site
- Intracellular chemoattractant secretion appears to be more important than adhesion, when migrating as a cluster
Cell migration plays a key role in embryo development. Neural crest cells (NCCs), migrate from their origin (neural plate border), travel throughout the embryo, and eventually differentiating into vital tissues, including the sympathetic nervous system (network that innervates internal organs) that we model. NCCs migrate both as single cells and as adherent clusters throughout their journey. It is thought that chemical concentration gradients of various chemoattractant guide migratory cells to key sites, through a process called chemotaxis. Our simulations explore this hypothesis.
We model a variety of migratory simulations in Morpheus, a modelling and simulation environment for multi-scale and multicellular systems. We explore how cell properties and interactions affect successful group chemotaxis towards a target (fixed source of attractant).
We investigate how levels of intracellular adhesion, of cell-secreted chemoattractant and the number of cells affect cell group cohesion, mean squared displacement, and time to arrive at the target. Our long-term goal is to understand the role of NCC migration in the development of the sympathetic nervous system (SNS). Data for cell migration are available from the Paul Kulesa lab in the Stower’s Institute. We plan to compare our predictions to that data set.
- NCC differentiation depends on collective cell migration and spatio-temporal chemical gradients
- NCC differentiation is responsible for forming the sympathetic nervous system, which helps innervate internal organs and regulates the “fight or flight” response
- Cellular migration often occurs via chemotaxis
- We investigate cell properties that affect chemotaxis and impact collective cell migration
Concentration gradients are established by fixed sources, secreting a chemical, that decays over time. The concentration gradient was modelled using this equation:
Results for mean squared displacement (MSD) were generated as well as pictures illustrating cell motility. MSD and images of cell clusters were used to determine whether or not the cells had reached the target site.
- We varied levels of intercellular adhesion, levels of chemoattractant, and number of cells.
- Our hypothesis is that each of the above parameters plays a crucial role in determining the effectiveness in which cells travel to the target/source.
- For instance, with high levels of intercellular adhesion, cells may become more compact and travel faster.
- Our aim is to find the relationship between the above parameters and the required travel time.
- We seek an optimal combination of these parameters for the shortest time and the most effective travel pattern of the cells.
Time to reach the target decreases as rate of chemical release at the source increases.
- Increasing rate of chemical release from the target showed bigger decreases of time to reach the target at low concentrations than high concentrations**
Time to reach the target showed a parabolic trend when varying rate of intracellular release, until the cells could no longer reach the target
- Cells with very low rates of release took a long time to reach the target
- Cells with low-medium rates of release took the least time
- Cells with medium-high rates of release began to take longer
- Past a certain rate, time to reach the target increased drastically, until the cluster could not reach the target
The overall trend shows a parabolic shape, where very low/high cell number lead to longer travel times and medium cell number leads to shorter travel times.
- Low cell number leads to low chemoattractant secretion, resulting in cells become scattered. One cell arrives at the target early, other cells follow later.
- Large cell number leads to high chemoattractant secretion. Increasing attraction between cells overpowers the attraction of the target, increasing travel time, or even leading to failure to reach the target.
- Overall, the optimal situation would be when cells are attracted to each other but still experience a strong attraction to the target, which enables them to move fast but also move together as one whole group.
There is no clear relationship between adhesion and time taken to reach the target.
- Migratory cells traveled to target at various levels of adhesion
- Overall, chemoattractant secreted by cells help cells to keep together whether or not they adhere
(1) Cell cluster at the early migration, circle at top right is the target site. (2) Cell cluster at intermediate time. (3) Cell cluster arrival at target site.
- Morpheus is a computational tool that we use to simulate cell chemotaxis towards a fixed chemoattractant target
- We asked how varying cell properties affects the migration pattern and rate of cell migration
- A cluster of 20 adhering cells is simulated. The cells secrete a constant level of chemoattractant.
- We assumed a fixed target that secrets the same chemoattractant as the cells but at a higher intensity.
- We investigated the time it takes the cells to reach the target as a function of the level of adhesion, intracellular chemoattractant release and number of cells.
Left: Mean squared displacement (MSD) of the cell cluster plotted against time
Right: Movement of each individual cell throughout the simulation.
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