DSUP modified mesenchymal stem cells exert significant radiation protective effect by enhancing the hematopoietic niche

Background: Radiation induced hematopoietic failure was the primary cause of death after exposure to a moderate or high dose of whole body irradiation, causing increased challenge for nuclear or radiological treatment, so it is an urgent need to develop radioprotectors for attenuating hematopoietic damage caused by acute radiation syndrome (ARS). Given the excellent therapeutic effects and special benefits of mesenchymal stem cells (MSCs) in radiation damaged hematopoietic stem/progenitor cells (HSPCs) recovery and hematopoietic niche reconstruction, enhancing the hematopoietic niche with the radiotolerance MSCs can be an alternative solution to prevent and attenuate hematopoietic radiation damage, which needs to be studied.

Methods: Here, we constructed MSCs modified with Damage Suppressor Protein (DSUP), a radiotolerance gene identified from tardigrade Ramazzotius varieornatus, and verify its radiation protection effect in HSPCs-MSCs co-culture model in vitro and radiation damaged mice model in vivo.

Results: Our results showed that DSUP protein had no significant toxic side effects on the basic stemness properties and differentiation potential of MSCs, and significantly enhanced the radiation tolerance and DNA protection ability of MSCs. Compared with the control (CON) group MSCs, the DSUP modified MSCs after radiation damage suffered less DNA damage, preserved most of proliferation activity and migration ability. In the HSPCs-MSCs co-culture model, DSUP modified MSCs have significant protective effect on HSPCs by providing a functional hematopoietic niche after radiation damage. The DSUP group irradiated HSPCs exhibited more rapid recovery, the higher HSPCs ratio and better hematopoietic differentiation potential. In animal studies, pre infusion of DSUP modified MSCs reduce irradiated mice mortality rate, reduce hematopoietic failure incidence, and provide a protective effect against radiation injury by protecting hematopoietic microenvironment and promoting HSCs recovery. DSUP modified MSCs can be used as a radioprotector and existed significant radiation protection effect for ARS at doses below 7 Gy total-body irradiation (TBI) of X-ray in both immunodeficient and immunocompetent mice models.

Conclusions: DSUP modified MSCs may serve as a new radioprotector for ARS. DSUP modified MSCs could attenuate radiation damage of HSPCs and promote HSPCs rapid recovery as well as hematopoietic reconstruction by providing a more functional niche after radiation, thereby reducing the occurrence of hematopoietic failure and improving survival rate.