RESUMEN
BACKGROUND/AIM: Bone marrow cells contain nonhematopoietic cells with the ability to differentiate into osteogenic, chondrogenic, and adipogenic lineages. Mechanical stress influences osteoblast differentiation of bone marrow cells into osteogenic, chondrogenic, and adipogenic lineages, measurable as the abundance of alkaline phosphatase-positive (ALP+) colony-forming unit-fibroblasts (CFU-F); however, the effect of diode laser irradiation on osteoblast differentiation is unknown. The aim of this study was to analyze the effects of photobiomodulation on the osteogenic differentiation of mesenchymal stem cells in the bone marrow, using the CFU-F assay. MATERIALS AND METHODS: Bone marrow cells isolated from rat tibiae were cultured and irradiated with a diode laser (wavelength 808 nm) at a total energy of 0 J (control), 50 J, and 150 J. RESULTS: On day 7 after irradiation, ALP+ CFU-F were most abundant in the 50 J group and the least abundant in the 150 J group. Mineralized nodule formation was observed after long-term culture (21 days). Compared with the control group, there were significantly more nodules in the 50 J group and significantly fewer nodules in the 150 J group. Osteocalcin mRNA expression was highest in the 50 J group, and there was no difference between the control and 150 J groups. CONCLUSION: Irradiation with 50 J was effective in stimulating osteogenesis in bone marrow stem cells. These findings suggest that diode laser irradiation can induce osteogenesis in rat bone marrow cells in an energy-dependent manner, and appears suitable for application in bone regeneration therapy.
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Células de la Médula Ósea , Diferenciación Celular , Láseres de Semiconductores , Células Madre Mesenquimatosas , Osteoblastos , Osteogénesis , Animales , Diferenciación Celular/efectos de la radiación , Ratas , Osteogénesis/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Células de la Médula Ósea/citología , Células Madre Mesenquimatosas/efectos de la radiación , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/efectos de la radiación , Osteoblastos/citología , Osteoblastos/metabolismo , Células Cultivadas , Fosfatasa Alcalina/metabolismo , Fosfatasa Alcalina/genética , Masculino , Terapia por Luz de Baja Intensidad/métodos , Osteocalcina/metabolismo , Osteocalcina/genéticaRESUMEN
With the widespread application of nuclear technology across various fields, ionizing radiation-induced injuries are becoming increasingly common. The bone marrow (BM) hematopoietic tissue is a primary target organ of radiation injury. Recent researches have confirmed that ionizing radiation-induced hematopoietic dysfunction mainly results from BM hematopoietic stem cells (HSCs) injury. Additionally, disrupting and reshaping BM microenvironment is a critical factor impacting both the injury and regeneration of HSCs post radiation. However, the regulatory mechanisms of ionizing radiation injury to BM HSCs and their microenvironment remain poorly understood, and prevention and treatment of radiation injury remain the focus and difficulty in radiation medicine research. In this review, we aim to summarize the effects and mechanisms of ionizing radiation-induced injury to BM HSCs and microenvironment, thereby enhancing our understanding of ionizing radiation-induced hematopoietic injury and providing insights for its prevention and treatment in the future.
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Células Madre Hematopoyéticas , Radiación Ionizante , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Humanos , Animales , Médula Ósea/efectos de la radiación , Médula Ósea/patología , Traumatismos por Radiación/patología , Traumatismos por Radiación/etiología , Células de la Médula Ósea/efectos de la radiación , Células de la Médula Ósea/metabolismoRESUMEN
BACKGROUND/AIM: ClFdA is a second-generation antineoplastic agent that has demonstrated significant anticancer activity, particularly against acute lymphoblastic leukemia and has been shown to have radiosensitizing activity. The aim of the study was to explore the genotoxic, cytotoxic and radiosensitizing effects of clofarabine (ClFdA) on bone marrow cells (BMCs), normoblasts and leukocytes of mice in vivo. MATERIALS AND METHODS: Cytotoxicity was determined by the reduction in reticulocytes (RET), and genotoxicity was determined by the induction of micronucleated reticulocytes (MN-RET) in the peripheral blood and by DNA break induction in leukocytes determined by single-cell gel electrophoresis (SCGE). The radiosensitizing capacity of ClFdA was determined in leukocytes and BMCs by SCGE. RESULTS: Two mechanisms of MN-RET induction were identified according to the antecedents, that could be due to inhibition of DNA synthesis and demethylation of G-C regions, and subsequent chromosome fragility. ClFdA cytotoxicity causes two contiguous peaks, an early peak that seems to inhibit MN-RET induction and a second peak that seems to be caused by ribonucleotide reductase (RR) and/or DNA synthesis inhibitions. ClFdA induced early DNA damage in noncycling leukocytes, and also radiosensitizes leukocytes immediately after treatment. ClFdA-ionizing radiation (IR) causes two time-dependent episodes of DNA damage, the latest after 80 min triggers a major breakage of DNA. In terms of the number of damaged cells, leukocytes and BMCs are similarly sensitive to ionizing radiation; BMCs are slightly more sensitive than leukocytes to ClFdA, but BMCs are doubly sensitive to combined treatment. CONCLUSION: ClFdA causes early DNA damage and radiosensitivity in non-proliferating leukocytes, which rules out the most favored hypotheses of the participation of RR and DNA polymerase inhibition.
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Clofarabina , Daño del ADN , Leucocitos , Fármacos Sensibilizantes a Radiaciones , Animales , Clofarabina/farmacología , Ratones , Fármacos Sensibilizantes a Radiaciones/farmacología , Leucocitos/efectos de los fármacos , Leucocitos/efectos de la radiación , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Arabinonucleósidos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Células de la Médula Ósea/metabolismo , Nucleótidos de Adenina/farmacología , Masculino , Reticulocitos/efectos de los fármacos , Reticulocitos/efectos de la radiación , Antineoplásicos/farmacología , Pruebas de MicronúcleosRESUMEN
Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1-4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
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Transformación Celular Neoplásica , Células Dendríticas , Leucemia Mieloide Aguda , Neoplasias Cutáneas , Piel , Rayos Ultravioleta , Humanos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Células de la Médula Ósea/efectos de la radiación , Muerte Celular/efectos de la radiación , Linaje de la Célula/genética , Linaje de la Célula/efectos de la radiación , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/efectos de la radiación , Células Clonales/metabolismo , Células Clonales/patología , Células Clonales/efectos de la radiación , Células Dendríticas/metabolismo , Células Dendríticas/patología , Células Dendríticas/efectos de la radiación , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación/efectos de la radiación , Especificidad de Órganos , Análisis de Expresión Génica de una Sola Célula , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Rayos Ultravioleta/efectos adversos , Piel/patología , Piel/efectos de la radiaciónRESUMEN
OBJECTIVE: To investigate the radioprotective effect of gallic acid(GA) on mouse bone marrow cells. METHODS: Healthy male ICR mice were randomly divided into saline control group, GA control group, X-ray irradiation group and GA protection group, with 10 mice in each group. X-ray irradiation group and normal saline control group were given 0.01 mL/g normal saline gavage, GA control group and GA protection group were given 200 mg/kg GA(20 mg/mL) gavage once a day for 14 consecutive days. On the 15 th day, 4 X-ray irradiation groups and 4 GA protection groups were given one-time X-ray irradiation to the whole body of the mice, and the absorbed doses were 1.0, 2.0, 3.0 and 4.0 Gy, respectively. The saline control group and the GA control group were not irradiated. After irradiation, detected the whole blood catalase(CAT), superoxide dismutase(SOD), malondialdehyde(MDA) and micronucleus frequency of polychromatic erythrocyte in bone marrow(MN-PCE), and use flow cytometry to detect bone marrow cell cycle, early apoptosis rate and late apoptosis rate. RESULTS: The CAT activities in the serum of mice in the 1.0, 2.0, 3.0 and 4.0 Gy GA protection groups were 2.13, 1.74, 1.49 and 1.15 U/mL, respectively, which were significantly increased compared with the corresponding X-ray irradiation group(P<0.01). SOD activities were 184.69, 156.92, 139.17 and 107.15 U/mL, which were significantly increased compared with the corresponding X-ray irradiation group(P<0.01). The contents of MDA were 3.92, 4.20, 6.32 and 9.31 nmol/mL, which were significantly lower than those of the corresponding X-ray irradiation group(P<0.05, P<0.01). The bone marrow MN-PCE rate of the mice in the 1.0, 2.0, 3.0 and 4.0 Gy GA protection groups were 4.35, 8.00, 12.90 and 3.80, respectively, which were significantly lower than those in the corresponding X-ray irradiation group(P<0.01). The proportions of G_0/G_1 phase cells of bone marrow cells in the 1.0, 2.0, 3.0 and 4.0 Gy GA protection group were 81.00%, 86.28%, 92.04% and 93.15%, respectively, which were significantly reduced compared with the corresponding X-ray irradiation group(P<0.01). The proportions of G_2/M phase cells were 4.51%, 3.05%, 2.35% and 1.81%, which were significantly increased compared with the corresponding X-ray irradiation group(P<0.05, P<0.01). The proportions of S phase cells were 15.32%, 11.36%, 5.96% and 4.92%, which were significantly increased compared with the corresponding X-ray irradiation group(P<0.01). The early apoptosis rate of bone marrow cells of mice in the 1.0, 2.0, 3.0 and 4.0 Gy GA protection groups were 3.32%, 8.96%, 12.11% and 2.26%, respectively, which were significantly reduced compared with the corresponding X-ray irradiation group(P<0.01). The late apoptosis rates of bone marrow cells were 7.21%, 11.73%, 17.11% and 19.36%, which were significantly reduced compared with the corresponding X-ray irradiation group(P<0.05, P<0.01). CONCLUSION: GA can reduce the oxidative damage, DNA damage and bone marrow cell cycle arrest of the bone marrow cells of radiation-damaged mice, inhibit the apoptosis of bone marrow cells, and have radioprotective effects on the bone marrow cells of mice.
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Células de la Médula Ósea , Ácido Gálico , Animales , Médula Ósea/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Daño del ADN , Ácido Gálico/farmacología , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
This study explored the radioprotective effects and possible underlying mechanisms of KR-31831 against radiation-induced injury in a mouse model. KR-31831 (30 and 50 mg/kg) was administered to mice 24 h and 30 min before exposure to a single lethal or sublethal dose of whole-body irradiation (WBI) (7 or 4 Gy, respectively). These animals were then evaluated for changes in mortality, various hematological and biochemical parameters, and histological features in response to these treatments. In addition, RNA sequencing was used to profile the radiation-induced transcriptomic response in the bone marrow cells. The results showed that KR-31831 dose-dependently prolonged the 30-day survival period and prevented damage to radiation-sensitive organs, such as the intestine and testis, in response to WBI. Damage to the hematopoietic system was also notably improved in the KR-31831-treated mice, as evidenced by an increase in bone marrow and peripheral blood cells, as well as recovery of the histopathological characteristics of the bone marrow. These protective effects were achieved, at least in part, via the suppression of radiation-induced increases in apoptotic cell death and erythropoietin levels in the plasma. Furthermore, the gene expression profiles of the bone marrow cells of the WBI-treated mice suggested that KR-31831 upregulates the expression of the genes involved in regulating apoptosis and modulating the immune response, both of which are required for protecting the bone marrow. These results suggest the potential therapeutic efficacy of KR-31831 for protection against radiation-induced injury.
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Benzopiranos/uso terapéutico , Imidazoles/uso terapéutico , Traumatismos por Radiación/tratamiento farmacológico , Protectores contra Radiación/uso terapéutico , Irradiación Corporal Total/efectos adversos , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de la radiación , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Masculino , Ratones Endogámicos C57BL , Traumatismos por Radiación/genética , Testículo/efectos de los fármacos , Testículo/efectos de la radiación , Transcriptoma/efectos de los fármacosRESUMEN
The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using γH2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0-1.1 for 1H, 1.7-2.3 for 4He, 2.9-3.4 for 12C and 2.6-3.3 for 16O. Particle radiation did not alter the MSCs' characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as γH2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.
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Proteínas de la Ataxia Telangiectasia Mutada/genética , Quinasa de Punto de Control 2/genética , Histonas/genética , Células Madre Mesenquimatosas/efectos de la radiación , Células Madre/efectos de la radiación , Medicina Aeroespacial , Apoptosis/genética , Apoptosis/efectos de la radiación , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Células de la Médula Ósea/efectos de la radiación , Carbono/efectos adversos , Ciclo Celular/genética , Ciclo Celular/efectos de la radiación , Linaje de la Célula/genética , Linaje de la Célula/efectos de la radiación , Citometría de Flujo , Regulación de la Expresión Génica/efectos de la radiación , Helio/efectos adversos , Humanos , Células Madre Mesenquimatosas/metabolismo , Oxígeno/efectos adversos , Protones/efectos adversos , Vuelo Espacial , Células Madre/metabolismoRESUMEN
Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1-6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.
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Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de la radiación , Fraccionamiento de la Dosis de Radiación , Proteína Amiloide A Sérica/metabolismo , Tórax/efectos de la radiación , Factor de Necrosis Tumoral alfa/metabolismo , Acetilcisteína/farmacología , Animales , Proteínas Sanguíneas/metabolismo , Ciclo Celular/efectos de la radiación , Daño del ADN , Depuradores de Radicales Libres/farmacología , Lesión Pulmonar/patología , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de la radiación , Ratones Endogámicos C57BL , Proteómica , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Although functional interplay between intestinal microbiota and distant sites beyond the gut has been identified, the influence of microbiota-derived metabolites on hematopoietic stem cells (HSCs) remains unclear. This study investigated the role of microbiota-derived lactate in hematopoiesis using mice deficient in G-protein-coupled receptor (Gpr) 81 (Gpr81-/-), an established lactate receptor. We detected significant depletion of total HSCs in the bone marrow (BM) of Gpr81-/- mice compared with heterogenic (Gpr81+/-) mice in a steady state. Notably, the expression levels of stem cell factor (SCF), which is required for the proliferation of HSCs, decreased significantly in leptin receptor-expressing (LepR+) mesenchymal stromal cells (MSCs) around the sinusoidal vessels of the BM from Gpr81-/- mice compared with Gpr81+/- mice. Hematopoietic recovery and activation of BM niche cells after irradiation or busulfan treatment also required Gpr81 signals. Oral administration of lactic acid-producing bacteria (LAB) activated SCF secretion from LepR+ BM MSCs and subsequently accelerated hematopoiesis and erythropoiesis. Most importantly, LAB feeding accelerated the self-renewal of HSCs in germ-free mice. These results suggest that microbiota-derived lactate stimulates SCF secretion by LepR+ BM MSCs and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner.
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Hematopoyesis , Interacciones Microbiota-Huesped , Ácido Láctico/metabolismo , Microbiota , Receptores de Leptina/metabolismo , Factor de Células Madre/metabolismo , Nicho de Células Madre , Animales , Biomarcadores , Médula Ósea/metabolismo , Médula Ósea/efectos de la radiación , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de la radiación , Eritropoyesis , Células Madre Hematopoyéticas , Inmunofenotipificación , Ratones , Ratones Noqueados , Modelos Biológicos , Probióticos , Transducción de SeñalRESUMEN
Previous work pointed to a critical role of excessive production of reactive oxygen species (ROS) in increased radiation hematopoietic death in GFP mice. Meanwhile, enhanced antioxidant capability was not demonstrated in the mouse model of radio-induced adaptive response (RAR) using rescue of radiation hematopoietic death as the endpoint. ROS induction by ex vivo X-irradiation at a dose ranging from 0.1 to 7.5 Gy in the nucleated bone marrow cells was comparatively studied using GFP and wild type (WT) mice. ROS induction was also investigated in the cells collected from mice receiving a priming dose (0.5 Gy) efficient for RAR induction in WT mice. Significantly elevated background and increased induction of ROS in the cells from GFP mice were observed compared to those from WT mice. Markedly lower background and decreased induction of ROS were observed in the cells collected from WT mice but not GFP mice, both receiving the priming dose. GFP overexpression could alter background and induction of ROS by X-irradiation in hematopoietic cells. The results provide a reasonable explanation to the previous study on the fate of cells and mice after X-irradiation and confirm enhanced antioxidant capability in RAR. Investigations involving GFP overexpression should be carefully interpreted.
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Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Rayos X/efectos adversos , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Ratones , Ratones Endogámicos C57BLRESUMEN
It is well-known that the cytotoxicity and mutagenic effects of high dose rate (HDR) ionizing radiation (IR) are increased by increasing the dose but less is known about the effects of chronic low dose rate (LDR). In vitro, we have shown that in addition to the immediate interaction of IR with DNA (the direct and indirect effects), low doses and chronic LDR exposure induce endogenous oxidative stress. During elevated oxidative stress, reactive oxygen species (ROS) react with DNA modifying its structure. Here, BL6 mice were exposed to IR at LDR and HDR and were then sacrificed 3 hours and 3 weeks after exposure to examine early and late effects of IR. The levels of micronuclei, MN, were determined in bone marrow cells. Our data indicate that the effects of 200 mGy on MN-induction are transient, but 500 and 1000 mGy (both HDR and LDR) lead to increased levels of MN up to 3 weeks after the exposure.
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Células de la Médula Ósea/patología , Rayos gamma/efectos adversos , Micronúcleos con Defecto Cromosómico/efectos de la radiación , Irradiación Corporal Total/efectos adversos , Animales , Células de la Médula Ósea/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Ratones , Ratones Endogámicos C57BL , Pruebas de MicronúcleosRESUMEN
In this study, we evaluated cardiomyogenic differentiation of electromechanically stimulated rat bone marrow-derived stem cells (rt-BMSCs) on an acellular bovine pericardium (aBP) and we looked at the functioning of this engineered patch in a rat myocardial infarct (MI) model. aBP was prepared using a detergent-based decellularization procedure followed by rt-BMSCs seeding, and electrical, mechanical, or electromechanical stimulations (3 millisecond pulses of 5 V cm-1at 1 Hz, 5% stretching) to enhance cardiomyogenic differentiation. Furthermore, the electromechanically stimulated patch was applied to the MI region over 3 weeks. After this period, the retrieved patch and infarct region were evaluated for the presence of calcification, inflammatory reaction (CD68), patch to host tissue cell migration, and structural sarcomere protein expressions. In conjunction with any sign of calcification, a higher number of BrdU-labelled cells, and a low level of CD68 positive cells were observed in the infarct region under electromechanically stimulated conditions compared with static conditions. More importantly, MHC, SAC, Troponin T, and N-cad positive cells were observed in both infarct region, and retrieved engineered patch after 3 weeks. In a clear alignment with other results, our developed acellular patch promoted the expression of cardiomyogenic differentiation factors under electromechanical stimulation. Our engineered patch showed a successful integration with the host tissue followed by the cell migration to the infarct region.
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Materiales Biocompatibles , Estimulación Eléctrica , Infarto del Miocardio , Miocardio , Ingeniería de Tejidos/métodos , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de la radiación , Bovinos , Diferenciación Celular/efectos de los fármacos , Miocardio/citología , Miocardio/metabolismo , Miocitos Cardíacos/citología , Pericardio/citología , Pericardio/trasplante , Ratas , Células Madre/citología , Células Madre/efectos de la radiaciónRESUMEN
Acute radiation syndrome (ARS) is the radiation toxicity that can affect the hematopoietic, gastrointestinal, and nervous systems upon accidental radiation exposure within a short time. Currently, there are no effective and safe approaches to treat mass population exposure to ARS. Our study aimed to evaluate the therapeutic potential of allogeneic adipose-derived stem cells (ASCs) for total body irradiation (TBI)-induced ARS and understand the underlying mitigation mechanism. We employed 9.25 Gy TBI dose to C57BL/6 mice and studied the effect of allogeneic ASCs on mice survival and regeneration of the hematopoietic system. Our results indicate that intraperitoneal-injected ASCs migrated to the bone marrow, rescued hematopoiesis, and improved the survival of irradiated mice. Our transwell coculture results confirmed the migration of ASCs to irradiated bone marrow and rescue hematopoietic activity. Furthermore, contact coculture of ASCs improved the survival and hematopoiesis of irradiated bone marrow in vitro. Irradiation results in DNA damage, upregulation of inflammatory signals, and apoptosis in bone marrow cells, while coculture with ASCs reduces apoptosis via activation of DNA repair and the antioxidation system. Upon exposure to irradiated bone marrow cells, ASCs secrete prosurvival and hematopoietic factors, such as GM-CSF, MIP1α, MIP1ß, LIX, KC, 1P-10, Rantes, IL-17, MCSF, TNFα, Eotaxin, and IP-10, which reduces oxidative stress and rescues damaged bone marrow cells from apoptosis. Our findings suggest that allogeneic ASCs therapy is effective in mitigating TBI-induced ARS in mice and may be beneficial for clinical adaptation to treat TBI-induced toxicities. Further studies will help to advocate the scale-up and adaptation of allogeneic ASCs as the radiation countermeasure.
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Síndrome de Radiación Aguda , Apoptosis , Células de la Médula Ósea/efectos de la radiación , Trasplante de Células Madre Hematopoyéticas , Síndrome de Radiación Aguda/terapia , Tejido Adiposo/citología , Animales , Hematopoyesis , Ratones , Ratones Endogámicos C57BLRESUMEN
Exposure to moderate doses of ionizing radiation (IR), which is sufficient for causing skin injury, can occur during radiation therapy as well as in radiation accidents. Radiation-induced skin injury occasionally recovers, although its underlying mechanism remains unclear. Moderate-dose IR is frequently utilized for bone marrow transplantation in mice; therefore, this mouse model can help understand the mechanism. We had previously reported that bone marrow-derived cells (BMDCs) migrate to the epidermis-dermis junction in response to IR, although their role remains unknown. Here, we investigated the role of BMDCs in radiation-induced skin injury in BMT mice and observed that BMDCs contributed to skin recovery after IR-induced barrier dysfunction. One of the important mechanisms involved the action of CCL17 secreted by BMDCs on irradiated basal cells, leading to accelerated proliferation and recovery of apoptosis caused by IR. Our findings suggest that BMDCs are key players in IR-induced skin injury recovery.
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Células de la Médula Ósea/patología , Queratinocitos/patología , Traumatismos por Radiación/patología , Animales , Células de la Médula Ósea/efectos de la radiación , Trasplante de Médula Ósea , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Quimiocina CCL17/metabolismo , Dermis/patología , Dermis/efectos de la radiación , Epidermis/patología , Epidermis/efectos de la radiación , Eliminación de Gen , Células HaCaT , Humanos , Queratinocitos/efectos de la radiación , Macrófagos/efectos de la radiación , Ratones Endogámicos C57BL , Ratones Transgénicos , Radiación Ionizante , Receptores CCR4/deficiencia , Receptores CCR4/metabolismo , Transducción de Señal/efectos de la radiación , Piel/patología , Piel/efectos de la radiaciónRESUMEN
The loosening and displacement of prostheses after dental implantation and arthroplasty is a substantial medical burden due to the complex correction surgery. Threedimensional (3D)printed porous titanium (pTi) alloy scaffolds are characterized by low stiffness, are beneficial to bone ingrowth, and may be used in orthopedic applications. However, for the bioinert nature between host bone and implants, titanium alloy remains poorly compatible with osseointegration, especially in disease conditions, such as osteoporosis. In the present study, 3Dprinted pTi scaffolds with ideal pore size and porosity matching the bone tissue, were combined with pulse electromagnetic fields (PEMF), an exogenous osteogenic induction stimulation, to evaluate osseointegration in osteoporosis. In vitro, external PEMF significantly improved osteoporosisderived bone marrow mesenchymal stem cell proliferation and osteogenic differentiation on the surface of pTi scaffolds by enhancing the expression of alkaline phosphatase, runtrelated transcription factor2, osteocalcin, and bone morphogenetic protein2. In vivo, Microcomputed tomography analysis and histological evaluation indicated the external PEMF markedly enhanced bone regeneration and osseointegration. This novel therapeutic strategy has potential to promote osseointegration of dental implants or artificial prostheses for patients with osteoporosis.
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Aleaciones/química , Campos Electromagnéticos , Oseointegración , Osteoporosis/cirugía , Impresión Tridimensional , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Titanio/química , Fosfatasa Alcalina/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Células de la Médula Ósea/efectos de la radiación , Proteína Morfogenética Ósea 2/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Células Madre Mesenquimatosas/efectos de la radiación , Osteocalcina/metabolismo , ConejosRESUMEN
Murine bone marrow (BM) chimeras are a versatile and valuable research tool in stem cell and immunology research. Engraftment of donor BM requires myeloablative conditioning of recipients. The most common method used for mice is ionizing radiation, and Cesium-137 gamma irradiators have been preferred. However, radioactive sources are being out-phased worldwide due to safety concerns, and are most commonly replaced by X-ray sources, creating a need to compare these sources regarding efficiency and potential side effects. Prior research has proven both methods capable of efficiently ablating BM cells and splenocytes in mice, but with moderate differences in resultant donor chimerism across tissues. Here, we compared Cesium-137 to 350 keV X-ray irradiation with respect to immune reconstitution, assaying complete, syngeneic BM chimeras and a mixed chimera model of autoimmune disease. Based on dose titration, we find that both gamma and X-ray irradiation can facilitate a near-complete donor chimerism. Mice subjected to 13 Gy Cesium-137 irradiation and reconstituted with syngeneic donor marrow were viable and displayed high donor chimerism, whereas X-ray irradiated mice all succumbed at 13 Gy. However, a similar degree of chimerism as that obtained following 13 Gy gamma irradiation could be achieved by 11 Gy X-ray irradiation, about 85% relative to the gamma dose. In the mixed chimera model of autoimmune disease, we found that a similar autoimmune phenotype could be achieved irrespective of irradiation source used. It is thus possible to compare data generated, regardless of the irradiation source, but every setup and application likely needs individual optimization.
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Enfermedades Autoinmunes/inmunología , Células de la Médula Ósea/efectos de la radiación , Trasplante de Médula Ósea/métodos , Médula Ósea/efectos de la radiación , Radioisótopos de Cesio , Rayos gamma , Quimera por Radiación/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Irradiación Corporal Total , Rayos XRESUMEN
PURPOSE: To determine the early- and late-occurring damage in the bone marrow (BM) and peripheral blood cells of male CBA/Ca mice after exposure to 0, 0.1, 0.25, or 0.5 Gy of 1 GeV/n titanium (48Ti) ions (one type of space radiation). METHOD: We used the mouse in vivo blood-erythrocyte micronucleus (MN) assay for evaluating the cytogenetic effects of various doses of 1 GeV/n 48Ti ions. The MN assay was coupled with the characterization of epigenetic alterations (the levels of global 5-methylcytosine and 5-hydroxymethylcytosine) in DNA samples isolated from BM cells. These analyses were performed in samples collected at an early time-point (1 week) and a late time-point (6 months) post-irradiation. RESULTS: Our results showed that 48Ti ions induced genomic instability in exposed mice. Significant dose-dependent loss of global 5-hydroxymethylcytosine was found but there were no changes in global 5-methylcytosine levels. CONCLUSION: Since persistent genomic instability and loss of global 5-hydroxymethylcytosine are linked to cancer, our findings suggest that exposure to 48Ti ions may pose health risks.
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Células de la Médula Ósea/efectos de la radiación , Titanio/efectos adversos , Irradiación Corporal Total/efectos adversos , Animales , Células de la Médula Ósea/metabolismo , Daño del ADN , Relación Dosis-Respuesta en la Radiación , Rayos gamma/efectos adversos , Masculino , Ratones , Ratones Endogámicos CBA , Radioisótopos/efectos adversosRESUMEN
Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.
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Síndrome de Radiación Aguda/tratamiento farmacológico , Células de la Médula Ósea/efectos de los fármacos , Trastornos de Fallo de la Médula Ósea/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Síndrome de Radiación Aguda/genética , Síndrome de Radiación Aguda/patología , Animales , Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Trastornos de Fallo de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Factor Estimulante de Colonias de Granulocitos , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Macaca mulatta/genética , Masculino , Proteínas Recombinantes/farmacología , Irradiación Corporal Total/efectos adversosRESUMEN
Mouse models of radiation-induced thymic lymphoma are commonly used to study the biological effects of total-body irradiation (TBI) on the formation of hematologic malignancies. It is well documented that radiation-induced thymic lymphoma can be inhibited by protecting the bone marrow (BM) from irradiation; however, the mechanisms underlying this phenomenon are poorly understood. Here, we aimed to address this question by performing transplantation of BM cells from genetically engineered mice that have defects in tumor immunosurveillance or occupying different thymic niches. We found that BM cells from mice that have impaired tumor immunosurveillance, by deleting tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ) or perforin-1 (PRF1), remained sufficient to suppress the formation of radiation-induced thymic lymphoma. On the other hand, BM cells from Rag2-/-; γc-/- mice and Rag2-/- mice, which have defects in occupying thymic niches beyond double negative (DN2) and DN3, respectively, failed to inhibit radiation-induced lymphomagenesis in the thymus. Taken together, based on our findings, we propose a model where unirradiated BM cells suppress radiation-induced lymphomagenesis in the thymus by competing with tumor-initiating cells for thymic niches beyond the DN3 stage.
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Trasplante de Médula Ósea , Linfoma/terapia , Neoplasias Inducidas por Radiación/terapia , Neoplasias del Timo/terapia , Animales , Células de la Médula Ósea/efectos de la radiación , Modelos Animales de Enfermedad , Humanos , Linfoma/etiología , Linfoma/prevención & control , Ratones , Ratones Endogámicos C57BL , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias del Timo/etiología , Neoplasias del Timo/prevención & control , Irradiación Corporal Total/efectos adversosRESUMEN
Bone diseases such as osteomalacia, osteoporosis, and osteomyelitis are major illnesses that threaten the health of human. This study aimed to provide an idea at the molecular level of material properties determined with UV specific surface approaches. The tert-butyl hydroperoxide (t-BHP) exposure aging model bone mesenchymal stem cells (BMSCs) were reverted by using a poly-hybrid scaffold (PS), which is a carbon nanotube (CNT) coated polycaprolactone (PCL) and polylactic acid (PLA) scaffold, combined with insulin-like growth factor-1 (IGF). Then, the region-specific PS photo-immobilized with different growth factors (GFs) was obtained by interference and diffraction of ultraviolet (UV) light. Additionally, the reverted BMSCs were regionally pattern differentiated into three kinds of cells on the GF immobilized PS (GFs/PS). In vivo, the GFs/PS accelerate bone healing in injured Sprague-Dawley (SD) rats. The data showed that GFs/PS effectively promoted the differentiation of reverted BMSCs in the designated area on 21st day. These results suggest region-specific interface immobilization of GFs concurrently differentiating reverted BMSCs into three different cells in the same scaffold. This method might be considered as a short-time, low cost, and simple operational approach to scaffold modification for tissue regeneration in the future.