Mesenchymal Stromal Cell-Derived Extracellular Vesicles Provide Long-Term Survival After Total Body Irradiation Without Additional Hematopoietic Stem Cell Support.

The therapeutic effect of mesenchymal stromal cells (MSC) in tissue regeneration is based mainly on the secretion of bioactive molecules. Here, we report that the radioprotective effect of mouse bone marrow derived mesenchymal stromal cells (mMSC) can be attributed to extracellular vesicles (EV) released from mMSC. The transplantation of mMSC-derived EV into lethally irradiated mice resulted in long-term survival but no improvement in short-term reconstitution of the recipients. Importantly, the radiation rescue was efficient without additional hematopoietic support. In vitro we show a protection by EV of irradiated hematopoietic stem cells but not progenitor cells using stroma-cell cultures and colony-forming assays. After systemic infusion into lethally irradiated recipients, labeled EV traveled freely through the body reaching the bone marrow within 2 hours. We further show that long-term repopulating Sca-1 positive and c-kit low-positive stem cells were directly targeted by EV leading to long-term survival. Collectively, our data suggest EV as an effective first-line treatment to combat radiation-induced hematopoietic failure which might also be helpful in alleviating myelosuppression due to chemotherapy and toxic drug reaction. We suggest the infusion of MSC-derived EV as efficient and immediate treatment option after irradiation injuries. Stem Cells 2017;35:2379-2389.