New strategy for the investigation of haematopoietic stem cells
Researchers from Ulm, Dresden and Leipzig have developed a mouse model that enables the transplantation of haematopoietic stem cells without irradiation. Additional investigations will have to be carried out in order to clarify whether this method can also be used for human cells. Should this prove possible, then these animals might also be suitable for investigations into the function of human haematopoietic stem cells, infectious diseases or tumours.
Informative value only “in vivo”
Information on how haematopoietic stem cells function can be best investigated in the living organism; insights gained in vitro, i.e. outside an organism, are regarded as having too little informative value. In order to be able to investigate the behaviour of donated haematopoietic stem cells, they have to be transplanted into a recipient.
However, until now, there have been two major obstacles preventing the engraftment of donor haematopoietic stem cells into recipients. First, the recipients' immune system has to be weakened to a degree that prevents it from rejecting the donor cells. Second, the recipients' own stem cells have to be damaged so that the transplanted haematopoietic stem cells are able to enter the stem cell niche and grow.
Transplanted cells grow without the need of irradiation
At the University of Ulm, a team of immunologists led by Claudia Waskow (now at the DFG Research Centre for Regenerative Therapies in Dresden) and Hans-Reimer Rodewald, in cooperation with Rosel Blasig from the Leibniz Institute for Molecular Pharmacology in Berlin, have developed a mouse model which allows the transplantation of haematopoietic stem cells without the need for prior irradiation, facilitating the analysis of stem cell function.
The researchers explained their method in the recent issue of Nature Methods: "We combined three known genetic mutations with each other. Only this combined triple mutant allows for successful haematopoietic stem cell transplantation without irradiation," said Dr. Claudia Waskow.
One weakens, the other two make room
With the newly developed mouse model, irradiation is no longer required. While the mutation in the growth factor receptor Kit (KitW/Wv) weakens the recipient’s stem cell compartment and makes room for the incoming donor cells, the other two mutations are known to prevent rejection of donor haematopoietic stem cells by the recipient’s immune system. Thus, these mice appear to accept all blood stem cells, regardless of the mouse strain origin of the haematopoietic stem cells and hence compatibility with their own tissue.
”Because we do no longer need to irradiate the mice, all organs, including the bone marrow, remain undamaged.” Important processes of the blood stem cells such as homing (homing of the haematopoietic stem cells occurs when transplanted cells move from the blood into the bone marrow after transplantation) can now be studied under more natural conditions.
C. Waskow, V. Madan, S. Bartels, C. Costa, R. Blasig, H.-R. Rodewald: Hematopoietic stem cell transplantation without irridation, in: Nature Methods, online 8.3. 09 (doi:10.1038/nmeth.1309)