Enhancement of Regenerative Properties of Multipotent Mesenchymal Stromal Cells Through Modulation of Autophagy in a Model of Acute Radiation Syndrome

BACKGROUND: Multipotent mesenchymal stromal cells (MSC) are widely used for cell and tissue regeneration, which is particularly relevant for rapidly renewing tissues such as myeloid tissue. The application of MSCs demonstrates therapeutic potential; however, there are limiting factors for this therapy. The results obtained from studies using these cells are contradictory and require further investigation. Modulating the level of autophagy in MSCs is considered a potential way to enhance the efficacy of this therapy. AIM: To analyze changes in hematopoiesis depending on the level of autophagy in transplanted multipotent mesenchymal stromal cells in a model of acute radiation syndrome. METHODS: An experimental study was conducted both in vitro and in vivo on male ICR (CD1) mice. MSCs were isolated from the placental chorion and cultured with autophagy modulators (rapamycin and 3-methyladenine). Cell viability, levels of autophagy, proteins (Beclin-1 and LC3B) and secretion of hematopoietic growth factors were assessed. In the in vivo experiment, acute radiation syndrome was modeled, followed by an assessment of bone marrow cellularity and blood cells on day 7. RESULTS: Activation of autophagy by rapamycin increased the production of hematopoietic growth factors: SCF +70.5%, G-CSF +59.6%, FLT3 +62.3% (p≤ 0.0001). Upon transplantation of MMSCs with activated autophagy, a significant increase in bone marrow cellularity was observed across all differentiation lineages: granulocytic +4.5% (p=0.026), lymphocytic +18.8% (p ≤0.0001), megakaryocytic +30.5% (p=0.011). Inhibition of autophagy in MSC negated their therapeutic potential. CONCLUSION: Activation of autophagy in MSCs is a promising approach to enhancing their therapeutic potential in the treatment of acute radiation syndrome.