Mesenchymal stem cell-mediated Notch2 activation overcomes radiation-induced injury of the hematopoietic system

Radiation exposure severely damages the hematopoietic system. Although several radio-protectors have been proposed to prevent radiation-induced damage, most agents have limited efficacy. In the present study, we investigated whether mesenchymal stem cells (MSCs) could contribute to the expansion of hematopoietic cells and mitigate radiation-induced hematopoietic injury in vitro and in vivo. We found that co-culture with MSCs promoted hematopoietic progenitor/stem cell (HPSCs) maintenance by providing a bone marrow-like microenvironment. In addition, we showed that MSCs prevented radiation-induced damage to HPSCs, as evidenced by the lack of DNA damage and apoptosis. Intravenously injected MSCs rapidly migrated to the bone marrow (BM) and prevented loss of BM cellularity, which reduced lethality and ameliorated pancytopenia in the BM of whole body-irradiated mice. We demonstrated that MSC-derived Jagged1 attenuated radiation-induced cytotoxicity of HPSCs, and that this was mediated by Notch signaling and expression of downstream proteins Bcl2 and p63 in HPSCs. In addition, Notch2 depletion significantly reduced the MSC-mediated radio-protective effect in human- and mouse-derived HPSCs. Collectively, our data show that activation of Notch and its associated downstream signaling pathways prevent radiation-induced hematopoietic injury. Therefore, enhancing Jagged1-Notch2 signaling could provide therapeutic benefit by protecting the hematopoietic system against damage after radiation.