Primed to go: how do stem cells plan for the future?

Primed to go: how do stem cells plan for the future?

Artistic representation of stem cell deciding its fate
How do stem cells in the embryo decide what type of cell to become?

Human embryo development is one of the most complex, important, and interesting periods in our life. A single cell must somehow divide and generate the approximately 200 different specialised cell types at the correct time and quantities to form a human body. This intricate process needs to occur reliably and robustly for the healthy development of the embryo. Research in the Reik lab is beginning to identify how many of the steps in this elaborate cellular dance are pre-programmed into the earliest cells of the embryo.

What is a stem cell?

Most of the cells in the adult human body are what we call ‘somatic cells’, which are locked into their specialised identity. For example, a skin cell is a somatic cell and unable to change its identity and suddenly become a muscle cell. However, the cells found in the early stages of embryo development are called stem cells, which are not yet restricted into a specific cell type. During development, these early stem cells start with unlimited potential, but gradually lose this ‘stem-ness’. This is because they make a series of decisions, in a process called differentiation, which determines the type of cell they will ultimately generate. Each decision they make narrows their future options.

Graphical representation of the process of differentiation
During development, stem cells make many decisions as to the
type of cell they will become in a process called differentiation.

The first of these (many) decisions is whether to become either a so-called trophoblast stem cell which go on to form the placenta, or an embryonic stem cell which go on to form the rest of the embryo. These embryonic stem cells can become almost any cell type but are now unable to become placental cells. This series of irreversible decisions ensure healthy development of the embryo by preventing tissues growing within the incorrect places and times within the embryo.

Due to its importance, scientists have long since studied this process, attempting to understand exactly how cells make these vitally important decisions and what then prevents them from escaping or falling off these specific paths. These studies have revealed that one of the key factors in this decision-making is the epigenetic regulation of our DNA.

 

Epigenetics, what is it and why is it important?

Artistic representation of how different genes are 'switched on' in different cell types
Specialised cells only require the small percentage of genes
relevant for their specific functions. Epigenetic marks hold relevant
DNA regions in an active state (ON), and unimportant parts of DNA
in an inactive state (OFF).

Epigenetics refers to marks which sit ‘on top’ of DNA. They do not change the DNA sequence itself, but instead alter how it is read by the cell. They act like post-it notes and highlighter marks in a book; directing the reader to parts to pay attention to and which bits to ignore. Two of the most common epigenetic marks that scientists study are DNA methylation (chemical labels attached directly to the DNA) and histone modifications (chemical labels attached to the proteins that DNA is wrapped around in a cell).

Almost every cell in the body contains the same copy of DNA, which contains information on how to produce every cell type in the body. So, in theory, every cell has the DNA instructions on how to become and function as any cell type they want to be. However, epigenetic marks work to both highlight DNA regions of particular importance and to inactivate regions of the DNA that are not relevant for the cell. In this manner, our skin cells are directed to pay attention to only the portions of DNA that are important for how to be a skin cell.

These epigenetic marks also act as barriers which prevent the cell from changing its identity and must be removed or reprogrammed in order to return somatic cells into stem cells; a process that naturally occurs in the generation of sperm and egg cells. 

How do stem cells plan for the future?

Technological developments in the field of epigenetics, such as single cell sequencing approaches, are allowing scientists in the Reik lab to measure epigenetic marks within the small populations of early stem cells in both mouse and human embryo development. These experiments have started to show how early embryonic stem cells begin to prepare themselves for the upcoming cell-type decisions by pre-programing specific regions of their DNA with particular epigenetic labels.

These DNA regions are labelled in the early embryonic stem cells by the removal of inactivating epigenetic marks (DNA methylation) and the addition of specific histone modifications. These marks do not fully activate these regions of DNA, but instead hold them in a pre-active state, priming them for activation at a later stage.

Artistic representation of how cells in the embryo are primed to differentiate
In early embryo stem cells many DNA regions are labelled with
epigenetic marks, preparing them for later activation. This epigenetic
priming is found at key DNA regions important in the healthy
development of many organs such as the the brain, gut and lungs.

This process of epigenetic priming appears to prepare the embryonic stem cells for transitioning towards the various cell types required during development. For example, we are now beginning to understand that epigenetic priming in embryonic stem cells is of particular importance in the establishment of the brain during embryo development, with many DNA regions important in neuron development ‘epigenetically primed’.

Our research into epigenetic priming within embryo stem cells in the Reik lab will not only be important in understanding healthy embryo and brain development, but could also potentially provide insights in generating stem cells through informed reprogramming of epigenetic marks on the DNA; an important step toward personalised therapeutic approaches in medicine which require producing stem cells from patients.