Extracellular vesicles generated by TLR4 activated MSCs to treat hematopoietic acute radiation syndrome and GVHD

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.



Bio: Research in the Shaw group combines modern analytical techniques with materials and physical chemistry to create new understanding of the molecular-level behavior at interfaces. Current and start-up projects span chemical systems that are both fundamentally intriguing and extremely relevant to current needs of our technology-driven society. Advances in these areas will allow predictive design of new, improved devices in a range of applications including energy production, polymeric materials, corrosion science, environmental remediation, microfluidics, and biomedical implanted devices. A few selected projects are outlined below. Experimental techniques encompass surface-sensitive optical spectroscopies, non-linear spectroscopies, probe microscopies, electrochemical methods, tensiometry, and novel sample preparation techniques, all targeted at revealing the interfacial properties of otherwise opaque chemical systems.
Bio: Dr. Hatzell is an Associate Professor at Princeton University in the Andlinger Center for Energy and Environment and department of Mechanical and Aerospace Engineering. Dr. Hatzell earned her Ph.D. in Material Science and Engineering at Drexel University, her M.S. in Mechanical Engineering from Pennsylvania State University, and her B.S./B.A. in Engineering/Economics from Swarthmore College. Hatzell is the recipient of several awards including the ORAU Powe Junior Faculty Award (2017), NSF CAREER Award (2019), ECS Toyota Young Investigator Award (2019), finalist for the BASF/Volkswagen Science in Electrochemistry Award (2019), the Nelson 鈥淏uck鈥 Robinson award from MRS (2019), Sloan Fellowship in 糖心vlog官方入口 (2020), and POLiS Award of Excellence for Female Researchers (2021), NASA Early Career Award (2022), ONR Young investigator award (2023) and Camille-Dreyfus Teacher-Scholar Award (2024).