Extracellular vesicles from mesenchymal stromal cells primed with synthetic toll-like receptor 4 agonists treat hematopoietic acute radiation syndrome. Stem Cells Transl Med 2026 Jan 09;15(1)
Date
01/09/2026Pubmed ID
41510819Pubmed Central ID
PMC12784198DOI
10.1093/stcltm/szaf068Scopus ID
2-s2.0-105027041495 (requires institutional sign-in at Scopus site)Abstract
Whole-body exposure to ionizing radiation can lead to cellular DNA damage to bone marrow (BM), causing lethal hematopoietic acute radiation syndrome (H-ARS). Extracellular vesicles (EVs) from human BM-derived mesenchymal stromal cells were primed with CRX-527 (CRX), a synthetic TLR4 agonist, characterized and tested as a radiomitigator therapy. Using a xenogeneic H-ARS mouse model, a single in vivo treatment with CRX-EVs administered 4 or 24 hours after lethal irradiation significantly improved weight loss, clinical scores and prolonged survival compared to control treatments. Ex vivo generation of CRX-EV educated monocytes (CRX-EEMos) were also effective in a H-ARS model when administered 24 hours after lethal irradiation. CRX-EVs or CRX-EEMos significantly promoted hematopoiesis in BM and potentially the spleen, leading to restoration of peripheral complete blood counts. CRX-EEMos showed increased gene expression of IL-6 and IL-10: enriched for PD-L1 but low for CD16 in CD14-expressing monocytes. Antisense inhibition of Let-7 microRNAs in CRX-EEMos suppressed IL-10 gene expression and protein secretion, implicating a novel role for Let-7 in radioprotection. CRX-EVs can effectively treat H-ARS by increasing the secretion of anti-inflammatory molecules while stimulating monocytes to promote hematopoiesis in BM. The potential for large-scale production of CRX-EVs as an "off-the-shelf" treatment for H-ARS makes them a potential medical countermeasure for radiological and nuclear threats.
Author List
Kink JA, Forsberg MH, Krismer DM, Thickens AS, Chinnadurai R, Chen AS, Chacko DJ, Graham M, Hematti P, Capitini CMAuthor
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute Radiation SyndromeAnimals
Extracellular Vesicles
Hematopoiesis
Humans
Mice
Toll-Like Receptor 4
