scholarly journals Marrow Stromal Cell Infusion Rescues Hematopoiesis in Lethally Irradiated Mice despite Rapid Clearance after Infusion

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Xiaodong Yang ◽  
Ilango Balakrishnan ◽  
Beverly Torok-Storb ◽  
Manoj M. Pillai
Keyword(s):  
Cellular Therapy ◽  
Tissue Injury ◽  
Direct Interaction ◽  
Rt Pcr ◽  
Immune Histochemistry ◽  
Radiation Induced ◽  
Rapid Clearance ◽  
Total Body ◽  
Lethal Irradiation

Marrow stromal cells (MSCs, also termed mesenchymal stem cells) have been proposed as a promising cellular therapy for tissue injury including radiation-induced marrow failure, but evidence for a direct effect is lacking. To assess the effects of MSCs on survival after lethal irradiation, we infused syngeneic MSCs (either as immortalized MSCs clones or primary MSCs) intravenously into wild-type C57/Bl6 mice within 24 hours of lethal total body irradiation (TBI). Mice receiving either of the MSC preparations had significantly improved survival when compared to controls. In vivo imaging, immune histochemistry, and RT-PCR employed to detect MSCs indicated that the infused MSCs were predominantly localized to the lungs and rapidly cleared following infusion. Our results suggest that a single infusion of MSCs can improve survival after otherwise lethal TBI but the effect is not due to a direct interaction with, or contribution to, the damaged marrow by MSCs.

P5379Modification with CREKA improves cell retention of myocardial ischemia reperfusion

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Chen ◽  
Y N Song ◽  
Z Y Huang
Keyword(s):  
Stem Cells ◽  
Functional Recovery ◽  
Cellular Therapy ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
High Specificity ◽  
Homing Peptide ◽  
Structural Preservation

Abstract Background Poor cell homing limits efficacy of cardiac cellular therapy. The cysteine–arginine–glutamic acid–lysine–alanine (CREKA) homing peptide binds with high specificity to fibrin which is involved in repair of tissue injury. Purpose We assessed if CREKA-modified stem cells had enhanced fibrin-mediated homing ability resulting in better functional recovery and structural preservation in a rat myocardial injury model. Methods CREKA-modified mesenchymal stem cells (CREKA-MSCs) were obtained via membrane fusion with CREKA-modified liposomes. The fibrin targeting ability of CREKA-MSCs was examined both in vitro and in vivo. Results Under both static and flow conditions in vitro, CREKA significantly enhanced MSCs binding ability to fibrin clots. CREKA-MSCs showed much more higher accumulation than unmodified MSCs in injured rat myocardium, colocalizing with fibrin and resulting in better cardiac function. Stem cell-CREKA-fibrin targeting system Conclusions Modification of MSCs with the homing peptide CREKA favored their migration and retention in the infarcted area, resulting in better structural preservation and functional recovery. Fibrin is therefore a novel target for enhancing homing of transplanted cells to injured myocardium and the fibrin-targeting delivery system represents a generalizable platform technology for regenerative medicine.

Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 837-845 ◽  
Author(s):  
Thomas J. MacVittie ◽  
Ann M. Farese ◽  
Walter G. Smith ◽  
Charles M. Baum ◽  
Earl Burton ◽  
...  
Keyword(s):  
Autologous Serum ◽  
High Dose ◽  
Cell Recovery ◽  
Primate Model ◽  
Daily Schedule ◽  
X Irradiation ◽  
Radiation Induced ◽  
Total Body ◽  
Chimeric Molecules

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 (60Co) γ-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 μg/kg/d (n = 4), or 50 μg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 μg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS) , daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/μL) and thrombocytopenia (platelet < 20 000/μL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/μL) and platelets (PLT < 20 000/μL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.

scholarly journals Pegylated G-CSF Inhibits Blood Cell Depletion, Increases Platelets, Blocks Splenomegaly, and Improves Survival after Whole-Body Ionizing Irradiation but Not after Irradiation Combined with Burn

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Juliann G. Kiang ◽  
Min Zhai ◽  
Pei-Jyun Liao ◽  
David L. Bolduc ◽  
Thomas B. Elliott ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Marrow Cell ◽  
Total Body Surface Area ◽  
Body Weight Loss ◽  
Cell Depletion ◽  
Photon Radiation ◽  
Whole Body ◽  
Life Threatening ◽  
Radiation Induced ◽  
Total Body

Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury (radiation combined injury, CI) is a crucial life-threatening factor in nuclear and radiological accidents. As demonstrated in animal models, CI results in greater mortality than RI. In our laboratory, we found that B6D2F1/J female mice exposed to60Co-γ-photon radiation followed by 15% total-body-surface-area skin burns experienced an increment of 18% higher mortality over a 30-day observation period compared to irradiation alone; that was accompanied by severe cytopenia, thrombopenia, erythropenia, and anemia. At the 30th day after injury, neutrophils, lymphocytes, and platelets still remained very low in surviving RI and CI mice. In contrast, their RBC, hemoglobin, and hematocrit were similar to basal levels. Comparing CI and RI mice, only RI induced splenomegaly. Both RI and CI resulted in bone marrow cell depletion. It was observed that only the RI mice treated with pegylated G-CSF after RI resulted in 100% survival over the 30-day period, and pegylated G-CSF mitigated RI-induced body-weight loss and depletion of WBC and platelets. Peg-G-CSF treatment sustained RBC balance, hemoglobin levels, and hematocrits and inhibited splenomegaly after RI. The results suggest that pegylated G-CSF effectively sustained animal survival by mitigating radiation-induced cytopenia, thrombopenia, erythropenia, and anemia.

scholarly journals Fibronectin: blood turnover in normal animals and during intravascular coagulation

Blood ◽  
1982 ◽  
Vol 60 (3) ◽  
pp. 558-563
Author(s):  
LA Sherman ◽  
J Lee
Keyword(s):  
Amino Acids ◽  
Blood Clearance ◽  
Plasma Fibronectin ◽  
Covalent Bonds ◽  
Intravascular Coagulation ◽  
Rapid Clearance ◽  
Total Body ◽  
Made In

Plasma fibronectin (FN) binds fibrin in vitro by both noncovalent and covalent bonds and is decreased in DIC. In rabbits, conventionally purified 125I-FN had a complex blood clearance with a late t1/2 of 71 hr. A large portion was apparently altered, as evinced by rapid clearance and an intravascular/total body ratio (C1) of 0.28–0.51. 3H- labeled FN, made in vivo by injection of 3H amino acids, had a t1/2 of 73 hr. Crosstransfusion of 131I-FN and 3H-FN into a second set of animals gave similar t1/2s and C1s of 0.74–0.82, indicating the altered 125I-FN was biologically screened in the first animals. Other animals were given 125I-fibrinogen and “screened” 131I-FN. Intravenous thrombin (50–60 U/kg/1 hr) caused a 25%-50% decrease in both 125I-fibrinogen and 131I-FN. Ancrod injection reduced fibrinogen by greater than 90% but had no effect on 131I-FN. 131I-FN levels did not change when thrombin was given after ancrod. No cross-linked FN-fibrinogen alpha-chain was found in the plasma, nor was the thrombin-induced fall in FN affected by spermidine blockade. These experiments demonstrate that FN and fibrin bind in vivo during defibrination and are rapidly cleared from the blood. The abnormal fibrin resulting from ancrod either does not bind FN in vivo or does so reversibly.

scholarly journals Mesenchymal Stem Cells Attenuate Radiation-Induced Brain Injury by Inhibiting Microglia Pyroptosis

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Huan Liao ◽  
Hongxuan Wang ◽  
Xiaoming Rong ◽  
Enqin Li ◽  
Ren-He Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Inflammasome Activation ◽  
Rt Pcr ◽  
Caspase 1 ◽  
Radiation Induced ◽  
The Impact

Radiation-induced brain injury (RI) commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs) on it. BALB/c male mice (6–8 weeks) were cranially irradiated (15 Gy), and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy) were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1β. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis.

scholarly journals Zymosan-a Protects the Hematopoietic System from Radiation-Induced Damage by Targeting TLR2 Signaling Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 457-464 ◽  
Author(s):  
Jicong Du ◽  
Ying Cheng ◽  
Suhe Dong ◽  
Pei Zhang ◽  
Jiaming Guo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hematopoietic System ◽  
Zymosan A ◽  
Radiation Induced ◽  
Total Body ◽  
Tlr2 Signaling

Background/Aims: The hematopoietic system is vulnerable to ionizing radiation and is often severely damaged by radiation. Molecules affecting radioresistance include Toll-like receptor 2. We investigated whether Zymosan-A, a novel TLR2 agonist, can protect the hematopoietic system from radiation-induced damage after total body irradiation. Methods: Mice were exposed to total body radiation after treatment with Zymosan-A or normal saline, and their survival was recorded. Tissue damage was evaluated by hematoxylin–eosin staining. The number of nucleated cells in bone marrow was determined by flow cytometry. Cell viability and apoptosis assay were determined by CCK-8 assay and flow cytometry assay. Enzyme-linked immunosorbent assay was used to detect the level of cytokines. Results: Zymosan-A protected mice from radiation-induced death and prevented radiation-induced hematopoietic system damage. Zymosan-A also promoted cell viability and inhibited cell apoptosis caused by radiation, induced radioprotective effects via TLR2, upregulated IL-6, IL-11, IL-12, and TNF-α in vivo. Conclusion: Zymosan-A can provide protection against radiation-induced hematopoietic system damage by targeting the TLR2 signaling pathway. Thus, Zymosan-A can be potentially effective radioprotectant.

scholarly journals Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

2015 ◽  
Vol 308 (2) ◽  
pp. G121-G138 ◽  
Author(s):  
Daniel Talmasov ◽  
Xinjun Zhang ◽  
Bing Yu ◽  
Mandayam O. Nandan ◽  
Agnieszka B. Bialkowska ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Morphological Changes ◽  
Γ Irradiation ◽  
Γ Radiation ◽  
Proliferative Zone ◽  
Acute Response ◽  
Radiation Induced ◽  
Total Body

Gut radiation-induced injury is a concern during treatment of patients with cancer. Krüppel-like factor 4 (KLF4) is expressed in differentiated villous epithelial cells of the small intestine. We previously showed that KLF4 protects cells from apoptosis following γ-irradiation in vitro. We sought to determine whether KLF4 mediates the small intestinal response to γ-irradiation in vivo. Mice with intestinal epithelium-specific deletion of Klf4 ( Klf4 ΔIS) and control ( Klf4 fl/fl) mice were irradiated with total-body γ-radiation. Following irradiation, the Klf4 ΔIS mice had significantly increased mortality compared with irradiated Klf4 fl/fl mice. Immunohistochemistry and immunofluorescence staining were used to assess the morphological changes, levels of proliferation, and apoptosis in the intestinal epithelium. At 96 h following irradiation, there was a regenerative response manifested by an expansion of the proliferative zone in both mouse groups, with the control mice having a higher proliferative activity than the Klf4 ΔIS group. In addition, there was a significant increase in the number of Klf4/Ki67-copositive cells in the irradiated control mice compared with unirradiated mice. Also, the irradiated Klf4 ΔIS mice had a significantly higher number of crypt cells positive for apoptosis, p53, and p21 compared with irradiated Klf4 fl/fl mice. Taken together, our data suggest that Klf4 may function as a radioprotective factor against gastrointestinal syndrome in mice following γ-irradiation by inhibiting apoptosis in the acute response to irradiation and contributing to crypt regeneration.

scholarly journals Polymyxin B Attenuates LPS-Induced Death but Aggravates Radiation-Induced Death via TLR4-Myd88-IL-6 Pathway

2017 ◽  
Vol 42 (3) ◽  
pp. 1120-1126 ◽  
Author(s):  
Ying Cheng ◽  
Jicong Du ◽  
Jiaqi Han ◽  
Weimin Sun ◽  
Fu Gao ◽  
...  
Keyword(s):  
Polymyxin B ◽  
Protection Factor ◽  
Knock Out ◽  
Endotoxin Contamination ◽  
Radiation Induced ◽  
Total Body ◽  
Α Level

Background/Aims: Polymyxin B (PMB) is a cyclic cationic polypeptide antibiotic widely used to counteract the effects of endotoxin contamination, both in vitro and in vivo. Lipopolysaccharide (LPS) is an endotoxin that acts as a radiation protection factor. In this study, we focus on the role of PMB in LPS-induced and radiation-induced mortality in mice. Methods: Mice received total-body radiation or were pretreated by LPS or PMB, and the survival of mice was recorded. Elisa were used to detect the cytokines levels. Results: PMB decreased LPS-induced, but increased radiation-induced mortality in mice. Moreover, PMB could block the LPS-induced radioprotective effect. The ELISA and gene knock-out experiments indicated that PMB reduces TNF-α level to block LPS-induced mortality in mice, and inhibits IL-6, G-CSF and IL-10 to increase radiation-induced mortality via the TLR4-Myd88-IL-6 pathway. Conclusions: Our study revealed a role of PMB in LPS-induced endotoxemia and radiation exposure. We infer that the TLR4-Myd88-IL-6 pathway may play a crucial role in the process.

scholarly journals Fibronectin: blood turnover in normal animals and during intravascular coagulation

Blood ◽  
1982 ◽  
Vol 60 (3) ◽  
pp. 558-563 ◽  
Author(s):  
LA Sherman ◽  
J Lee
Keyword(s):  
Amino Acids ◽  
Blood Clearance ◽  
Plasma Fibronectin ◽  
Covalent Bonds ◽  
Intravascular Coagulation ◽  
Rapid Clearance ◽  
Total Body ◽  
Made In

Abstract Plasma fibronectin (FN) binds fibrin in vitro by both noncovalent and covalent bonds and is decreased in DIC. In rabbits, conventionally purified 125I-FN had a complex blood clearance with a late t1/2 of 71 hr. A large portion was apparently altered, as evinced by rapid clearance and an intravascular/total body ratio (C1) of 0.28–0.51. 3H- labeled FN, made in vivo by injection of 3H amino acids, had a t1/2 of 73 hr. Crosstransfusion of 131I-FN and 3H-FN into a second set of animals gave similar t1/2s and C1s of 0.74–0.82, indicating the altered 125I-FN was biologically screened in the first animals. Other animals were given 125I-fibrinogen and “screened” 131I-FN. Intravenous thrombin (50–60 U/kg/1 hr) caused a 25%-50% decrease in both 125I-fibrinogen and 131I-FN. Ancrod injection reduced fibrinogen by greater than 90% but had no effect on 131I-FN. 131I-FN levels did not change when thrombin was given after ancrod. No cross-linked FN-fibrinogen alpha-chain was found in the plasma, nor was the thrombin-induced fall in FN affected by spermidine blockade. These experiments demonstrate that FN and fibrin bind in vivo during defibrination and are rapidly cleared from the blood. The abnormal fibrin resulting from ancrod either does not bind FN in vivo or does so reversibly.

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