Understanding the function of hematopoietic stem cells (HSCs) that provide life-long all components of our immune system requires research under physiological conditions in a living organism (in vivo).
To study their proper control and potency, HSCs are transplanted into appropriate recipients. However, there have been two major obstacles preventing engraftment of donor HSCs into recipients: 1. In cases of genetically unrelated donors and recipients, the donor cells are rejected by the recipient's immune system. 2.
HSCs rarely enter the stem cell 'niche', which is a specialized space structure in the bone marrow. To open access for HSCs to these stem cell niches, and to suppress rejection of donor HSCs, recipients are usually irradiated. A team from the University of Ulm around Claudia Waskow (now at the Center for Regenerative Therapies Dresden - CRTD) and Hans-Reimer Rodewald, together with Rosel Blasig from the Leibniz-Institute for Molecular Pharmacology in Berlin, developed a new mouse model, which allows the transplantation of HSCs without the need for previous irradiation, facilitating the analysis of stem cell function.
In the current issue of Nature Methods, the scientists reveal the trick: "We combined three genetic mutations and could show that only this combined triple mutant allows for successful HSC transplantation without irradiation", explains Dr. Claudia Waskow of the CRTD. 'All three mutations were known, but we went one step further and brought them all together in one single mouse strain.' Normally, donors and recipients are histoincompatible, i.e. their immune systems reject each others tissues. This is also true for donor HSCs that are attacked by the recipient's immune system and consequently rejected. Irradiation reduces the risk of graft rejection, because it destroys cells of the recipient's immune system. However, irradiation is harmful for the body and has strong side effects on many cell types, for example gut cells. The second hurdle in HSC transplantation is to make donor HSCs efficiently enter and continuously stay in the specialized niches that support the survival and function of all HSCs. In a healthy recipient, these niches are occupied by endogenous blood stem cells. While they are damaged and depleted by irradiation, they can be replaced by donor HSCs. With the newly developed mouse model, irradiation is no longer required: The mutation in the growth factor receptor Kit (KitW/Wv) 'weakens' the recipient's stem cell compartment and therefore makes space for incoming donor stem cells. The other two mutations that were introduced into these 'universal recipients' are known to prevent rejection of donor HSCs by the recipient's immune system. Thus, these mice appear to accept all blood stem cells regardless of the mouse strain origin of the HSCs.
What exactly is now the advance in using a non-irradiated living organism? 'It is only possible to study the regeneration of HSCs in vivo. Observations in tissue culture are often not applicable to in vivo situations', states Waskow. 'Because we do not need to irradiate the mice anymore, all organs including the bone marrow remain undamaged, which helps us to study the normal physiological behavior of transplanted HSCs and the normal HSC niches much better'. Important processes of blood stem cells such as the 'homing' of HSCs can now be studied under more natural conditions. 'Homing' of HSCs to their appropriate locations in the body occurs when transplanted cells move from the blood into the bone marrow after transplantation.
It remains to be seen whether the new mouse line will accept human HSCs in a better or more sustained manner than in currently available mouse models. If so, the results of this study could lead to a better understanding of the regulation of human blood formation. Even studies on human infectious diseases or cancer may become feasible. In future studies, Claudia Waskow and Hans-Reimer Rodewald want to concentrate on these possibilities and thereby contribute to a better understanding of the generation and maintenance of the immune system by HSCs
Claudia Waskow, Vikas Madan, Susanne Bartels, Céline Costa, Rosel Blasig, Hans-Reimer Rodewald "Hematopoietic stem cell transplantation without irridation" Nature Methods. Online publication ahead: march 8, 2009 | doi: 10.1038/nmeth.1309.
The abstract of the article can be viewed under specification of the doi-Number from March 8., 6pm here: http://dx.doi.org/. For the full article please contact firstname.lastname@example.org or the press office of the CRTD.Background: DFG-Center for Regenerative Therapies Dresden (CRTD)
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