Biomedical Technology · Published 2026-01-28 · DOI 10.1016/j.bmt.2025.100132
Background: Tardigrades have attracted widespread research attention due to their extraordinary radiotolerance, of which the damage suppressor protein (DSUP) is regarded as a key molecule responsible for their robust DNA repair capability. How to translate these findings into safe and efficacious radioprotection strategies for humans remains an ongoing research challenge. Technology: Given that ionizing radiation (IR)-induced hematopoietic failure caused by depletion of bone marrow hematopoietic stem/progenitor cells (HSPCs) is a major cause of mortality, we propose using gene editing and stem cell technologies to precisely knock in DSUP gene into isolated murine HSPCs, thereby generating HSPCs with enhanced radiotolerance. In this study, we first obtained DSUP-modified mouse HSPCs by isolating, culturing, and transfecting mouse HSPCs using lentivirus transfection, as well as DSUP-modified human HSPCs via three stages of hematopoietic induction and differentiation from DSUP-modified human pluripotent stem cells (PSCs). Results: The radioprotection capacity of DSUP-modified stem cells was confirmed by a series of in vitro assays. Given the differentiation potential of myeloid progenitor cells (MPCs) and without requirement for human leukocyte antigen matching during hematopoietic stem cell transplant, we then obtained DSUP-modified mouse MPCs by differentiated from the expanded mouse HSPCs in polyvinyl alcohol (PVA) culture system for more than 30 days. DSUP-modified MPCs can also maintain lower radiation-induced apoptosis and DNA damage. Pre-infusion of DSUP-modified MPCs improves irradiated-mice survival rate by 30 % without long-term side effects. While not residing in bone marrow or spleen, these cells alleviated hematopoietic failure by restoring peripheral red blood cells and platelets and accelerated hematopoietic recovery. Mechanistically, DSUP forms phase separation structures that can recruit DNA repair proteins to double-strand breaks, promoting homologous recombination repair. Taken together, our results demonstrated DSUP-modified MPCs offer a promising stem cell-based radioprotection technology, highlighting a novel biomimetic approach for radioprotection.
Abstract from DOAJ. Public domain (CC0 1.0).
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