Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis

Abstract

The only available option to treat radiation-induced hematopoietic syndrome is allogeneic hematopoietic cell transplantation, a therapy unavailable to many patients undergoing treatment for malignancy, which would also be infeasible in a radiological disaster. Stromal cells serve as critical components of the hematopoietic stem cell niche and are thought to protect hematopoietic cells under stress. Prior studies that have transplanted mesenchymal stromal cells (MSCs) without co-administration of a hematopoietic graft have shown underwhelming rescue of endogenous hematopoiesis and have delivered the cells within 24 h of radiation exposure. Herein, we examine the efficacy of a human bone marrow-derived MSC therapy delivered at 3 h or 30 h in ameliorating radiation-induced hematopoietic syndrome and show that pancytopenia persists despite MSC therapy. Animals exposed to radiation had poorer survival and experienced loss of leukocytes, platelets, and red blood cells. Importantly, mice that received a therapeutic dose of MSCs were significantly less likely to die but experienced equivalent collapse of the hematopoietic system. The cause of the improved survival was unclear, as complete blood counts, splenic and marrow cellularity, numbers and function of hematopoietic stem and progenitor cells, and frequency of niche cells were not significantly improved by MSC therapy. Moreover, human MSCs were not detected in the bone marrow. MSC therapy reduced crypt dropout in the small intestine and promoted elevated expression of growth factors with established roles in gut development and regeneration, including PDGF-A, IGFBP-3, IGFBP-2, and IGF-1. We conclude that MSC therapy improves survival not through overt hematopoietic rescue but by positive impact on other radiosensitive tissues, such as the intestinal mucosa. Collectively, these data reveal that MSCs could be an effective countermeasure in cancer patients and victims of nuclear accidents but that MSCs alone do not significantly accelerate or contribute to recovery of the blood system.

Mitigating multiple stresses in Pangasianodon hypophthalmus with a novel dietary mixture of selenium nanoparticles and Omega-3-fatty acid

“…Arsenic can target several sites on hypothalamus-pituitary-interrenal axis which might be the reason for increased cortisol secretion in this study. Arsenic can alter the ACTH and effect blood cortisol levels in fish 3 , 35 , 72 . In the current study, the cortisol was remarkably reduced with combinatorial mixture of Se-NPs and EPA + DHA at 0.4 and 0.2% diet.…”

“…Se-NPs have essential role in passing the signal from peptides to antigen cells and have their own function such as seleno-methionine. It has role in regulation of HSP during stress condition 4 , 35 . Data from present study suggested that Se-NPs and EPA + DHA at 0.4 or 0.2% might also be helping in synthesis for maintenance of the cellular homeostasis through correct folding of nascent and stress-accumulated misfolded proteins in the cell 82 , 83 .…”

“…After that, supernatant was mixed with 2 M sodium selenite (200 ml) on a shaker for 96 h. The final solution was centrifuged at 6000 rpm at 15 min at 4 °C and then pellet was obtained. The pellet was isolated and dried for 5 h. Before diet preparation, Se-NPs were crushed in to a fine powder 35 , 36 . Se-NPs were characterized through a spectrophotometer in an absorption spectrum at 360–380 nm.…”

“…Selenium is also known to antagonize toxicity of elements such as cadmium and arsenite in fishes, primarily by attenuation of oxidative stress 33 , 34 . Our previous works have demonstrated that Se-NPs supplementation in fish diet could stimulate growth performance, immunity, anti-oxidative status and thermal tolerance 35 – 39 in fish. Moreover, Se-NPs are more efficient and less toxic than the usual form of elemental selenium 40 .…”

Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease

“…PLX-R18 is given intramuscularly to subjects who got exposure or suspected exposure of IR of ≥ 1 Gy based on Radiation Emergency Medical Management guidelines (NCT03797040). Preclinical studies have shown that xenogeneic, syngeneic or allogeneic MSCs can protect animals from lethal IR injury from ARS by ameliorating damage to the GI tract, CNS, and lungs ( 41 – 53 ). Our results demonstrate that IFNγ licensed allogeneic MSCs mitigate dosimetry grade ARS lethality.…”