Stem cell behavior revealed by a combination of modeling and microscopy
The renewal of cells in a healthy stomach is being studied by A*STAR researchers through a multidisciplinary approach that combines cell lineage tracing experiments and mathematical modeling1. The models provide a valuable baseline for studying gastric diseases, and the approach can be used to investigate the developmental dynamics of other organs.
Nick Barker's team at A*STAR's Institute of Medical Biology studied the development of flask-shaped pockets in the lining of the stomach's pyloric region, known as pyloric glands, which secrete gastrin and mucus into the stomach. Within each gland is a dividing pool of stem cells that contributes to two essential processes. Some of the daughter cells remain undifferentiated and slowly replace other stem cells within the gland, while others migrate upwards and differentiate to renew the stomach lining relatively rapidly. The researchers used stochastic models to study these two processes, using observations of fluorescently labeled cells to fit the models.
Since stem cells divide and replace other stem cells, eventually all of the cells in a gland will have descended from a single stem cell. To investigate this process, the team extended an earlier model that assumed the process starts with a single stem cell, rather than a pool. By building a model without this assumption, the team discovered that only a few of the stem cells are in a position for their descendants to effectively expand to the entire gland.
By integrating stochastic models and experiments they showed that the processes of proliferation and differentiation are tightly coupled; stem cells normally divide at the same rate as their daughters differentiate, ensuring that the pool remains the same size.
The team also applied this approach to quantify stem cell proliferation and differentiation under conditions that resembled disease, when these processes become uncoupled.
These models will help understand gastric diseases as well as normal pyloric gland development. "For instance, we can examine whether gastric cancer is the result of an imbalance between stem cell proliferation and differentiation or is associated with a slower replacement of stem cells, meaning that faulty stem cells are not replaced early enough" says Carmen Pin, a visiting researcher from the Institute of Food Research in the UK who undertook the study with Barker and Marc Leushacke from the A*STAR team.
"The same approach could be used to study the dynamics of any population of cells which can be genetically labeled and traced in other organs," they added.