Blood is a hard cell to explain

New research is revolutionising the way we understand the production of red and white blood cells, with potentially life-changing results

SOMETHING remarkable is going on inside your blood system as you read these words. By the time you finish reading the first few paragraphs, your body will have produced 100 million new red blood cells.

And these are only the red cells. This same system is churning out hundreds of millions of the various white blood cells that you need to fight off infections.

“This is an amazing factory of cells. It is just extraordinary when you realise how few mistakes are made,” says NUI Galway’s Prof Rhodri Ceredig.

It is also remarkable that the many blood cell types needed by the body all arise from a single source, the haematopoietic stem cell. Ceredig is interested in how the body accomplishes this remarkable feat, how particular types of stem cells, such as haematopoietic stem cells, can transform into white and red blood cells, or how mesenchymal stem cells can change into muscle and cartilage.

The process itself is crucial for our survival. The conversion of blood stem cells into the various cell types is dynamic and “real time”, with the system producing the specific types of blood cells needed at any given moment.

The emphasis is on red cells, say, during pregnancy, when the mother needs extra oxygen supplies, Ceredig says. The presence of an infection will prompt the blood system to ramp up supplies of the various microbe-fighting white blood cells. Last month, he was the co-author of a "perspectives" article in Nature Review Immunologyon blood stem cells, with Dr Geoffrey Brown from the University of Birmingham and Prof Antonius Rolink of the University of Basel.

The authors presented a much more powerful model to help explain the latest findings in blood stem cell research, including a recent discovery that stem cells which have already changed into a given cell type can wind back the clock, changing back into a stem cell.

“None of the currently published work fits in with the old models, so the field needed a change of direction,” says Ceredig.

Brown did the original work and now this has been updated to take account of the new research.

“Others have picked it up because the data fits better than [with] the traditional models,” says Ceredig, who is a Science Foundation Ireland (SFI) Stokes Professor and principal investigator at Galway’s Regenerative Medicine Institute, Remedi.

THE AUTHORS WORKEDtheir way through a wide selection of papers looking at the processes involved in changing a stem cell into B-cells and monocytes, natural killer cells and T-cells.

What emerged was a much more comprehensive picture of the process, which is controlled via proteins known as transcription factors. Transcription factors are proteins that can attach themselves to genes, switching on some while switching off others, Ceredig explains.

The traditional view held that the stem cell would reach a fork in the pathway leading to a given cell type, with the transcription factor dictating whether a left or right turn was taken. It is far more complex than this, however.

“When a cell decides to change, it is guided down a lineage caused by a series of transcription factors,” Ceredig says.

It has long been assumed this was a one-way street, but this is not the case. “The latest papers show you can go all the way back. You can take a cell and return the cell back all the way to the beginning.”

The authors’ new model takes account of the latest findings and also helps clarify the paths taken by stem cells as they change and mature into a finished cell. Understanding these pathways is essential, as they could point towards new treatments for blood disorders such as leukaemia.

Ceredig is also keenly interested, given work underway at Remedi in the area of mesenchymal stem cells. These change into muscle, tendon and similar tissues. The hope is that these stem cells could be used to repair muscle damage caused by heart attack or replace the lost joint cartilage seen in patients with crippling osteoarthritis.

Yet, while we have a good understanding of the pathways taken by haematopoietic stem cells, very little is understood about mesenchymal stem cells.

“We have no idea exactly how a stem cell of that lineage decides which way to go,” Ceredig says. “We need the basic information.”