Christian Capitini, MD
Jean R. Finley Professor in Pediatric Hematology and Oncology
Acting Director, UW Health | Carbone Cancer Center
Professor of Pediatrics
Chief, Division of Pediatric Hematology, Oncology, Transplant and Cellular Therapy
University of Wisconsin School of Medicine and Public Health
Abstract: Whole-body exposure to ionizing radiation can lead to cellular DNA damage that affects the bone marrow, causing hematopoietic acute radiation syndrome (H-ARS). Bone marrow (BM) derived mesenchymal stromal cells (MSCs) have been used for H-ARS but with limited success, and as a cellular therapy present unique challenges for rapid deployment on the battlefield. Allogeneic bone marrow transplant is currently used to rescue H-ARS, but can cause lethal complications like graft-versus-host-disease (GVHD). Known to be involved in orchestrating tissue homeostasis and wound repair, the therapeutic effects by MSCs are largely mediated by extracellular vesicles (EVs). Secreted EVs contain functional cargo such as miRNA, mRNA, and cytokines and are transferred to recipient effector cells such as monocytes and macrophages. Depending on the cargo within the EVs, monocytes and macrophages can be polarized into a M1 pro-inflammatory phenotype involved in direct host-defense against pathogens or cancer, or an M2 phenotype associated with wound healing and tissue repair. Overall, the ability to polarize MSC-EVs makes their direct use an attractive 鈥渙ff-the-shelf鈥, cell-free approach to treat injuries associated with ARS. Our results indicate that a single infusion of EVs effectively protected mice from lethal H-ARS and GVHD in vivo. The EVs promoted hematological recovery by restoring CBCs and BM cellularity. TLR4 priming with CRX-527 signals MSCs to produce radio-protective EVs, which in turn prime monocytes and macrophages in vivo to produce both anti-inflammatory molecules and growth factors that facilitate immune reconstitution, BM tissue repair and hematopoiesis. CRX-EVs can be produced in large quantities, cryopreserved, and then thawed for immediate use after a radiation mass casualty event. Overall, ease of use and potential for large-scale production make CRX-EVs an attractive 鈥渙ff-the-shelf鈥 countermeasure against radiological and nuclear threats.