Axolotls and arteries

The genetic control of blood formation

A curious branch of the salamander family could help us understand how blood stem cells are created. The results could be important in the treatment of blood disorders and even in tissue repair.

Within the bone marrow are blood-cell factories, constantly churning out the nine different types of blood cell we need to stay alive. These factories - the blood stem cells - are astonishingly productive, generating 3-10 billion new cells every hour (rising to 100 billion in hours of need). Blood stem cells are the subject of intense research worldwide, not only because of their known clinical importance to major blood diseases such as thalassaemia (an anaemia caused by faulty haemoglobin synthesis) and sickle cell anaemia, but also because they could possibly one day be used to repair body tissues damaged by disease.

Unlike many factory production lines, blood stem cells generate more than one product line - a range of different blood cells - and they retain this ability from cradle to grave. "It’s an incredibly important biological aspect of stem cells," says Dr Roger Patient, who has been investigating blood stem cells for more than a decade, most recently at the University of Nottingham. "The blood stem cells are built - or specified - during the development of the embryo, and you then have to go through your entire life and keep them as stem cells: if they differentiated, you wouldn’t be able to make more blood and you would die."

In the very earliest stages of an embryo’s development, all the cells are ‘generalists’ - theoretically able to become any of the myriad different cell types that make up the final body. But different groups of cells quickly begin to specialise, becoming committed to forming one particular tissue or cell type, such as muscle cells, nerve cells or liver cells. Only a few types of cell - the stem cells - retain the capacity to produce more than one type of cell. "We want to understand how the stem cells are programmed to have these properties," says Dr Patient. "As the control centre for a cell is the nucleus, we need to know how the genes in the nucleus are programmed. By and large, this is down to transcription factors turning genes on and off. If we can understand that, there is some hope of manipulating their activity."

About ten years ago, Dr Patient set out to find when and where the blood develops in the embryo. To do this, his group went hunting for the transcription factors turning key genes on and off in the embryos of zebrafish and frogs. These model organisms, staples of laboratory research, have recently been joined by an exotic relative - the Mexican axolotl (see box below). "This type of comparative analysis - looking at similarities and differences in the development of different organisms - is very powerful," says Dr Patient. "We’ve been comparing fish and frogs for ten years; we can use the same technology to study axolotls, which we think will tell us a lot about how blood stem cells develop in mammals."

GATA matters

Of particular relevance to the blood is the GATA family of transcription factors. "The GATA-1 gene is strongly associated with red blood cells, while GATA-3 is associated with T lymphocytes," says Dr Patient. "But from our point of view the most interesting one is the GATA-2 gene, which has a strong association with the blood stem cell. GATA-2 is an essential gene, quite possibly because it keeps the cells as stem cells: if you knock out the gene, you take out blood production completely."

By looking for very early embryonic cells producing GATA-2, the parents of the blood stem cell can be identified. But not all of these parents turn into blood stem cells: some also give rise to the blood vessels and heart. "This has become something of a theme for us," says Dr Patient. "We look at these apparently different processes, and can sometimes glean information from what they have in common."

A crucial factor in the development of the heart cells and possibly the blood stem cells is the GATA-6 protein. This protein stops heart-cell precursors from differentiating until they have moved to the position in the embryo where the heart will develop. GATA-6 is then downregulated, and the cells can differentiate into cardiac muscle. "Without GATA-6 it is possible that the cells would start twitching in the wrong place," says Dr Patient.

Changing fates

Such discoveries - although undoubtedly just part of the complex picture of stem-cell biology - will ultimately underpin the development of new therapies. Together they will provide a clearer picture of how the switching on or off of genes controls the creation of particular types of cell - knowledge that could be used for practical benefits. "If we can understand how the globin genes are controlled during the production of red blood cells, we could help people with beta thalassaemia or sickle cell anaemia," says Dr Patient. "Or if we could find a way to activate GATA-6 in heart-cell precursors artificially, we might be able to help regenerate heart muscle damaged by heart attacks or heart disease."

Ultimately, the uses of blood stem cells might extend even beyond therapies for blood disorders. "The idea that the blood stem cell can be manipulated to repair liver or brain is quite controversial at present, but they may well be more plastic than we first thought," says Dr Patient. "But there are certainly a lot of possibilities for their future manipulation and use for tissue repair."

Return of the axolotl

Native to a lake outside Mexico City, the axolotl is a fascinating creature not only because of its odd appearance and its ability to regenerate - the axolotl can regrow an entire limb if necessary - but also because it is one of nature’s permanent teenagers. Most amphibians undergo metamorphosis from egg to larva, and finally to adult form, but the axolotl remains in its larval form throughout its life, retaining its gills and fins and living entirely underwater.

"There are two major lines of amphibians, the salamanders and the frogs," says Dr Andrew Johnson, a US researcher who has recently moved to Nottingham to work with Dr Patient. "The embryos look very similar early in development, but they are in fact quite different. The axolotl is a salamander, and many of the fundamental discoveries in vertebrate embryology came from studies of axolotl embryos. So, about seven years ago, when I was interested in choosing a salamander to study, the axolotl was the obvious choice."

Dr Johnson’s interest in germ cells - the stem cells that give rise to sperm and eggs - dovetails neatly with Dr Patient’s studies of blood stem cells. "The germ cells are totipotent, they can become any kind of cell," says Dr Johnson. "So I’ve always wanted to know how, during development, these cells are maintained with the totipotent property. There are two entirely different ways of making germ cells in amphibians. In frogs, the germ cells are set aside from the earliest stages of development. But in salamanders the germ cells appear later in development, induced by certain factors, and they form right next to the blood stem cells."

This close relationship between the axolotl germ stem cells and blood stem cells raises the possibility that they come from the same population of stem cell. "Roger and I are trying to understand what makes the two kinds of cells different - how one type of cell can develop into anything, while the other can produce only blood cells. We’d like to find out the conditions needed to make a germline stem cell, and how we can switch those cells into blood stem cells."

External links

Professor Roger Patient awarded funding boost for stem cell research