|New genetic barcoding technology allows scientists to identify|
differences in origin between individual blood cells.
Credit: Camargo Lab
A 7-year-project to develop a barcoding and tracking system for tissue stem cells has revealed previously unrecognized features of normal blood production. New data suggests, surprisingly, that the billions of blood cells that we produce each day are made not by blood stem cells, but rather their less pluripotent descendants, called progenitor cells. The researchers hypothesize that blood comes from stable populations of different long-lived progenitor cells that are responsible for giving rise to specific blood cell types, while blood stem cells likely act as essential reserves.
The work, published in Nature, suggests that progenitor cells could potentially be just as valuable as blood stem cells for blood regeneration therapies. This new research challenges what textbooks have long read: That blood stem cells maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants, a fact that still remains true. But because of a lack of tools to study how blood forms in a normal context, nobody had been able to track the origin of blood cells without doing a transplant.
The researchers addressed this problem with a tool that generates a unique barcode in the DNA of all blood stem cells and their progenitor cells in a mouse. When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of stem cells/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.
People have previously tried using viruses to tag blood cells, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues. The researchers wanted to figure out a way to label blood cells inside of the body, and they tried to use mobile genetic elements called transposons. A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to an enzyme called transposase. Camargo's approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells. When one of these mice is exposed to transposase, each of its blood cells' transposons changes location. The location in the DNA where a transposon moves acts as an individual cell's barcode, so that if the mouse's blood is taken a few months later, any cells with the same transposon location can be linked back to its parent cell.
With the original question of how blood arises in a non-transplant context answered, the researchers are now planning to explore many more applications for their barcode tool. They want to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging, to the normal immune response.