Abstract
BackgroundAcute radiation syndrome (ARS) is caused by acute exposure to ionizing radiation that damages multiple organ systems but especially the bone marrow (BM). We have previously shown that human macrophages educated with exosomes from human BM-derived mesenchymal stromal cells (MSCs) primed with lipopolysaccharide (LPS) prolonged survival in a xenogeneic lethal ARS model. The purpose of this study was to determine if exosomes from LPS-primed MSCs could directly educate human monocytes (LPS-EEMos) for the treatment of ARS.MethodsHuman monocytes were educated by exosomes from LPS-primed MSCs and compared to monocytes educated by unprimed MSCs (EEMos) and uneducated monocytes to assess survival and clinical improvement in a xenogeneic mouse model of ARS. Changes in surface molecule expression of exosomes and monocytes after education were determined by flow cytometry, while gene expression was determined by qPCR. Irradiated human CD34+ hematopoietic stem cells (HSCs) were co-cultured with LPS-EEMos, EEMos, or uneducated monocytes to assess effects on HSC survival and proliferation.ResultsLPS priming of MSCs led to the production of exosomes with increased expression of CD9, CD29, CD44, CD146, and MCSP. LPS-EEMos showed increases in gene expression of IL-6, IL-10, IL-15, IDO, and FGF-2 as compared to EEMos generated from unprimed MSCs. Generation of LPS-EEMos induced a lower percentage of CD14+ monocyte subsets that were CD16+, CD73+, CD86+, or CD206+ but a higher percentage of PD-L1+ cells. LPS-EEMos infused 4 h after lethal irradiation significantly prolonged survival, reducing clinical scores and weight loss as compared to controls. Complete blood counts from LPS-EEMo-treated mice showed enhanced hematopoietic recovery post-nadir. IL-6 receptor blockade completely abrogated the radioprotective survival benefit of LPS-EEMos in vivo in female NSG mice, but only loss of hematopoietic recovery was noted in male NSG mice. PD-1 blockade had no effect on survival. Furthermore, LPS-EEMos also showed benefits in vivo when administered 24 h, but not 48 h, after lethal irradiation. Co-culture of unprimed EEMos or LPS-EEMos with irradiated human CD34+ HSCs led to increased CD34+ proliferation and survival, suggesting hematopoietic recovery may be seen clinically.ConclusionLPS-EEMos are a potential counter-measure for hematopoietic ARS, with a reduced biomanufacturing time that facilitates hematopoiesis.
Highlights
Exposure to radiation from accidents or conflicts is a credible threat which poses a wide spectrum of challenges for the treatment and management of victims of radiation injury
We showed macrophages could be educated with exosomes from bone marrow (BM)-mesenchymal stromal cells (MSCs) and that the most effective exosomes were generated from MSCs primed with E. coli lipopolysaccharide (LPS) in a dose-dependent fashion [10]
Characterization of extracellular vesicles from different human MSC isolates confirmed that unprimed MSCs and LPS-primed MSCs produced exosomes that were similar in size and quantity produced
Summary
Exposure to radiation from accidents or conflicts is a credible threat which poses a wide spectrum of challenges for the treatment and management of victims of radiation injury. Radio-mitigators are delivered after exposure, but prior to the manifestation of tissue toxicity, attempting to prevent or attenuate the expression of radiation-induced side effects. No radioprotectors or radio-mitigators are currently approved by the Food and Drug Administration (FDA) for the prevention or treatment of ARS, amifostine is approved to reduce the toxicity of radiation during cancer treatment [4]. A third category, radiotherapeutics, are delivered after radiation exposure but should be able to treat radiation injury following tissue toxicity and function to cure or ameliorate ARS. PLX-R18 (Pluristem Therapeutics, Inc) is a placenta-derived, MSC product currently in testing in an open-label phase I study for the post-exposure prevention or treatment of hematopoietic ARS (NCT03797040) [7]. Acute radiation syndrome (ARS) is caused by acute exposure to ionizing radiation that damages multiple organ systems but especially the bone marrow (BM). The purpose of this study was to determine if exosomes from LPS-primed MSCs could directly educate human monocytes (LPS-EEMos) for the treatment of ARS
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