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Project description:Radiation causes a collapse of bone marrow cells and elimination of microvasculature. Bone marrow has a limited regenerative ability and the mechanism governing such recovery is largely unknown. Mesenchymal lineage cells provide supportive microenvironment for hematopoiesis and angiogenesis in bone. We recently discovered a non-proliferative mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), that express most adipogenic markers with no lipid accumulation. To investigate the acute radiation effects, we performed single cell RNA-sequencing (scRNA-seq) on bone marrow mesenchymal lineage cells at day 3 after focal radiation. Interestingly, computational analysis revealed that MALPs become highly proliferative and acquire myofibroblast features after radiation. Using an adipocyte-specific Adipoq-Cre to label MALPs in vivo, we found that radiation indeed rapidly and transiently expands MALPs. MALPs have a cell body with multiple cell processes that form a 3D network inside bone marrow. Shortly after radiation, MALPs lost most of cell processes, became more elongated, and highly expressed myofibroblast-related genes, coinciding with marrow vessel dilation and diminished bone marrow cellularity. Later when vessels and hematopoietic cells recovered, MALPs returned to the baseline number and a normal reticular shape. Ablation of MALPs completely blocked the recovery of bone marrow vasculature and cellularity, including hematopoietic stem and progenitors. MALPs highly express several hematopoietic and angiogenic factors. Depleting one of them, VEGFa, specifically in MALPs, delayed bone marrow recovery after radiation. Taken together, our research demonstrates a critical role of MALPs in mediating the marrow repair after radiation injury and sheds light on a new cellular target for treating marrow suppression after radiotherapy.
2022-05-01 | GSE166129 | GEO
Project description:The continuous production of all mature blood cell lineages is maintained by Hematopoietic stem cells (HSCs), but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Therefore, devising the therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and radiation therapy patients. Here, we prepared an injectable hydrogel based on RGD-alginate and Laponite by a simple mixing method to release IL-12 (RGD-Alg/Laponite@IL-12) slowly and locally. The localization administration of RGD-Alg/Laponite@IL-12 substantially increased the survival and promoted the hematopoietic recovery of mice following sublethal-dose irradiation. These results suggested that local intra-bone marrow injection of RGD-Alg/Laponite@IL-12 hydrogel can effectively stimulate IL12R-PI3K/AKT signaling axis, which promotes proliferation and hematopoietic growth factors (HGFs) secretion of bone marrow mesenchymal stem/stromal cells (BM-MSCs). This signaling axis facilitates hematopoietic microenvironment repair and plays a pivotal role in hematopoietic reconstitution. In conclusion, our study attempted a biomaterial-sustained release of IL-12 for the treatment of irradiated hematopoietic injury and provided a new therapeutic strategy for hematopoietic acute radiation syndrome (H-ARS).
2024-09-18 | GSE267635 | GEO
Project description:The development of a biodosimetric assay based on the combined gene expression analysis of ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation has been developed. Gene expression profile signature of human radiation injury into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) has been shown to discriminate 6 radiation dose levels in human PB. Candidate gene lists were first developed assaying human ex vivo and human TBI samples on the Affymetrix platform. For the Ex Vivo samples, healthy consented adult donor was randomly assigned to a radiation group and labeled with the target dose of 0 cGy, 150 cGy, 300 cGy, or 600 cGy. In addition to the radiation exposures, the samples were also treated with either no treatment, GCSF, or LPS at time points 6 hours and 24 hours. Radiation expire times from the Cs137 irradiator were calculated to achieve target doses specific for tubes filled with blood and inserted in the roaring test tube holder. The dose rate was 480 cGy/min for the duration of the study. The healthy donors were enrolled to participate in this study following a protocol to collect PB samples that was previously approved by the Duke University Institutional Review Board. For the TBI samples, adult patients, ages 21 to 66, were evaluated at the Duke University Adult Bone Marrow Transplantation Program enrolled in a Duke IRB-approved protocol to collect PB prior to and post TBI conditioning. With approval from the Duke University Institutional Review Board (IRB), between 5-12 mL of peripheral blood was collected from consented patients prior to and 6 hours following TBI with 150-200 cGy as part of their pre-transplantation conditioning. All patients receiving non-myeloablative conditioning were treated with 200 cGy of TBI from a linear accelerator at a dose rate of 20 cGy/min. All patients who underwent TBI-based myeloablative allogeneic or autologous stem-cell transplantation received radiation fractionated at 150 cGy per fraction at 20 cGy/min. All patients had PB collected (50 ml) prior to and 6 hours following exposure to either 200 cGy or 150 cGy radiation treatment. The dose exposure for TBI patients used in this study were 0 cGy, 150 cGy, 450 cGy and 1050 cGy at 0, 6, 30 and 78 hours post irradiation. Total RNA was extracted and assayed on the Affymetrix platform.
2014-10-21 | E-GEOD-58613 | biostudies-arrayexpress
Project description:Radiation-induced intestinal injury is one of the most common complications of abdominal and pelvic radiotherapy. Severe intestinal injury caused by ionizing radiation (IR) has a high mortality rate, which is a worldwide problem requiring urgent attention. IR can cause intestinal tissue damage, inflammatory cell infiltration and pro-inflammatory cytokine release. However, methods to protect against radiation-induced intestinal injury are limited. CBLB502, a Toll-like receptor 5 (TLR5) agonist from Salmonella flagellin, has radioprotective effects on various tissues and organs. In order to further explore the molecular mechanism of IR-induced intestinal injury and the mechanism of protective effect of CBLB502 on IR-induced intestinal injury, mice were given CBLB502 and irradiated with different doses at different times. The survival rate, body weight, hemogram and histopathology of the mice were analyzed. The results showed that CBLB502 before IR can reduce intestinal injury induced by IR. RNA-seq analysis showed that different doses and different time of IR induced different damage mechanisms to promote gene regulation patterns. In addition, CBLB502 exerts its protective effect on IR-induced intestinal injury mainly through biological processes such as immune response. Notably, CBLB502 protected against intestinal injury only after IR, and might play a protective role by reversing the regulation of IR-induced genes. Therefore, this paper basically describes the mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, which provides a basis for further research on functional genes and molecular mechanisms that mediate protection against IR-induced injury in the future.
2023-11-10 | GSE246176 | GEO
Project description:Analysis of differentially expressed genes in wild type A4573 Ewing Sarcoma cells when compared to A4573 Ewing Sarcoma cells that received six 4 Gy fractions (cumulative dose of 24 Gy) of ionizing radiation (radiation-adapted cell line). The hypothesis tested being that repeated ionizing radiation exposure of modifies radiation therapy response in Ewing Sarcoma.
2017-05-10 | GSE98706 | GEO
Project description:Analysis of differentially expressed genes in wild type SK-ES1 Ewing Sarcoma cells when compared to SK-ES1 Ewing Sarcoma cells that received six 4 Gy fractions (cumulative dose of 24 Gy) of ionizing radiation (radiation-adapted cell line). The hypothesis tested being that repeated ionizing radiation exposure of modifies radiation therapy response in Ewing Sarcoma.
2017-05-10 | GSE98711 | GEO
Project description:We report that bone marrow transplantation suppresses atherosclerosis by reducing LDL accumulation in the intima. Radiation exposure enhances endothelial endolysosomal trafficking and cholesterol efflux pathways, thus preventing reducing the abundance of LDL particles that traverse the endothelial layer to deposit in the sub-endothelial space.
2021-03-31 | GSE163206 | GEO
Project description:Analysis of differentially expressed genes in wild type MHH-ES-1 Ewing Sarcoma cells when compared to MHH-ES-1 Ewing Sarcoma cells that received six 4 Gy fractions (cumulative dose of 24 Gy) of ionizing radiation (radiation-adapted cell line). The hypothesis tested being that repeated ionizing radiation exposure of modifies radiation therapy response in Ewing Sarcoma.
2017-05-10 | GSE98709 | GEO
Project description:Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6 mice fed a control low fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (4×0.75 Gy). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Both HF diet and irradiation resulted in increased oxidative damage, H2AX levels and proliferation in C57BL/6 mouse liver. Using methylation-specific PCR, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6 mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6 mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress. C57BL/6J mice were fed a normal or a high-fat diet and exposed to 4 x 0.75 Gy X-rays. miRNA expression was measured in the livers of 3 mice for each experimental group.
2013-11-09 | E-GEOD-47956 | biostudies-arrayexpress
Project description:Acute exposure to high-dose gamma radiation can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used to model acute, early stage RILI in vitro. Both lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6h of radiation exposure, and greater damage is observed in the endothelium. The alveolus chips are exposed to radiation injury at 16 Gy and shows effects that resemble the human lung greater than animal preclinical models. The Alveolus Chip is also used to evaluate the potential ability of two drugs to suppress the effects of acute RILI. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative approach for studying the molecular basis of acute RILI towards screening radiation countermeasure therapeutics.
2023-09-13 | GSE242706 | GEO