Treatment of Acute Radiation Syndromes with Transplantation of Bone Marrow-derived Mesenchymal Stromal Cells.

Survival in radiation induced bone marrow (BM) failure depends on the dose of radiation received and the intensity of supportive care which can protect from otherwise lethal infection and give surviving stem cells a chance to expand. In cases of limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. The acute radiation syndrome (ARS) similarly to myelosuppression after total body irradiation (TBI) is not restricted to the BM function but can lead to development of multiple organ dysfunctions. Damage of the whole organism is related to a systemic inflammatory response caused by a release of inflammatory cytokines. Management of ARS therefore relies on tissue damage repair processes that might be supported by therapies directed at mitigation of inflammation.
We have shown previously the regenerative and immunomodulating effects of BM-derived mesenchymal stromal cells (MSC) e.g. in acute kidney injury. Furthermore, MSC augment hematopoietic recovery after chemo- or radiotherapy transplanted in conjunction with hematopoietic stem cells and are effective in the treatment of steroid resistant graft versus host disease. Therefore we tested the potency of MSC as a treatment option after severe radiation exposure.
As a first step, human MSC were subjected to in vitro differentiation into hematopoietic and endothelial lineages. In a second approach, mouse MSC were isolated from BM of mice and i.v. transplanted into lethally irradiated recipients. For long-term observation, leukocyte and thrombocyte counts were determined regularly. After 7 months, all available tissues were investigated for the presence of donor cells. Short-term detection of donor cells was done using quantitative PCR. BM from HSC- and MSC-transplanted animals at day 21 was investigated for differential gene expression.
In vitro we showed aquisition of hematopoietic and endothelial characteristics, albeit to a rather low degree. In vivo, the transplantation of mouse MSC led to normalization of white blood cells within 4 weeks. Quantitative evaluation of donor cells in recipients revealed a fast disappearance of donor MSC. Although donor MSC did not home to the BM, the gene expression profile in BM changed significantly. Genes involved in cell cycle, oxidative stress protection, anti-inflammation and detoxification showed upregulation in the BM of MSC-transplanted animals whereas genes responsive for inflammation, protein degradation, adhesion/matrix formation, lipid synthesis and lymphoid development were downregulated, emphasizing the beneficial role of MSC in endogenous hematopoietic reconstitution.
In conclusion, we showed a complete reconstitution of the blood system in lethally irradiated mice through transplantation of MSC even without HSC support. Because no homing of donor MSC to the BM was evident we concluded that MSC help to recover from lethal myelosuppression and salvage endogenous HSC. This conclusion was supported by chimerism analysis showing no differentiation of donor cells into HSC in vivo. Instead, the milieu in the BM is changed towards a survival-promoting environment counteracting deleterious effects provoked by irradiation. Potential mechanisms of this highly effective trophic mechanism of MSC and its perspectives will be discussed.