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Sun GC, Xu WD, Yao H, Chen J, Chai RN. Protective effects of autologous bone marrow-derived mesenchymal stem cell transplantation on acute radioactive enteritis in Beagle dogs. World J Gastroenterol 2025; 31:97599. [PMID: 39991676 PMCID: PMC11755250 DOI: 10.3748/wjg.v31.i7.97599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/25/2024] [Accepted: 12/18/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Radiation enteritis is a common complication of radiation therapy in which the surrounding normal intestinal tissue is damaged by ionising radiation, and there is no standard pharmacological prophylaxis or treatment regimen available. Mesenchymal stem cell transplantation can be used for radiation protection and the treatment of acute radiation injury, but its therapeutic mechanism of action remains unclear. AIM To investigate the protective effects of autologous bone marrow-derived mesenchymal stem cell (ABMSC) transplantation on radiation-induced intestinal injury. METHODS A model of acute radioactive enteritis was established in dogs by applying abdominal intensity-modulated radiation at a single X-ray dose of 12 Gy. ABMSCs were transplanted into the mesenteric artery with the technology of femoral artery puncture and DSA imaging two days after radiation. Visual and histopathological changes of the experimental dogs were observed. Different kinds of cytokines from intestinal samples were tested using Quantibody Canine Cytokine Array method. Enzyme-linked immunosorbent assay (ELISA) was also used to evaluate the cytokines changes in serum. RESULTS The ABMSCs group showed significant improvements in survival status compared with the blank and saline treatment groups. Histological observations revealed that the former had lower histological scores than the later after treatment (P < 0.05). Compared to the control groups, interleukin (IL)-10 and monocyte chemotactic protein (MCP)-1 from intestinal samples showed a remarkable increase and ELISA of serum samples proved higher secretion of the two target cytokines in the ABMSCs group (P < 0.05). CONCLUSION Our data suggest that transplantation of ABMSCs promotes intestinal recovery after acute radioactive injury in Beagle dogs. The cytokines of IL-10 and MCP-1 might play an important role in this process.
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Affiliation(s)
- Guang-Chen Sun
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110000, Liaoning Province, China
- Department of Respiratory Medicine, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Wen-Da Xu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Hui Yao
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
| | - Ruo-Nan Chai
- Department of Respiratory Medicine, General Hospital of Northern Theater Command, Shenyang 110000, Liaoning Province, China
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Chugh RM, Bhanja P, Zitter R, Gunewardena S, Badkul R, Saha S. Modulation of β-Catenin promotes WNT expression in macrophages and mitigates intestinal injury. Cell Commun Signal 2025; 23:78. [PMID: 39934819 PMCID: PMC11818365 DOI: 10.1186/s12964-025-02065-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/25/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Macrophages are the major source of WNT ligands. However, the regulation of WNT expression in macrophages has not been studied. In the present study, we have discovered that activation of canonical β-Catenin signaling suppresses WNT expression in macrophages. EVs from these pre-conditioned macrophages promoted intestinal stem cell regeneration and mitigated intestinal injury. METHOD ChIP-seq analysis and validation studies using recombinant DNA construct expressing Luciferase reporter under WNT promoter (e.g. WNT5a and WNT9b) were conducted to demonstrate the involvement of β-Catenin in the transcriptional regulation of WNT expression. The regulatory role of β-Catenin in WNT expression in macrophages was examined by treating these cells with a Tankyrase inhibitor. In addition, the gene expressing β-Catenin was deleted in macrophages using Csf1r.iCre; Ctnnb1fl/fl mice model. Both pharmacological and genetically modulated macrophages were examined for WNT expression and activity by qPCR and TCF/LEF luciferase assay respectively. Additionally, Csf1r.iCre; Ctnnb1fl/fl mice were exposed to irradiation to compare the radiosensitivity with their wildtype littermate. Extracellular vesicles (EVs) were isolated from pre-conditioned WNT-enriched macrophages and infused in irradiated C57BL/6 and Lgr5/eGFP-IRES-Cre-ERT2; R26-ACTB-tdTomato-EGFP mice to determine the regenerative response of intestinal stem cell (ISC) and epithelial repair. Regenerative effects of EVs were also examined in mice model DSS induced colitis. RESULT ChIP-seq analysis and subsequent validation study suggested physical association of β-Catenin with WNT promoters to suppress WNT expression. Macrophage specific deletion of gene expressing β-Catenin or pharmacological inhibition of Tankyrase improves the WNT expression in macrophages several folds compared to control. Transfusion of these preconditioned macrophages or EVs from these cells delivers optimum level of morphogenic WNT to injured epithelium, activates ISC regeneration and mitigated radiation induced intestinal injury. Intestinal epithelium in Csf1r.iCre; Ctnnb1fl/fl mice also showed radioresistance compared to wild type littermate. Moreover, EVs derived from WNT enriched macrophages can mitigate intestinal injury in mice model of DSS induced acute colitis. CONCLUSION The study provides substantial evidence that macrophage-targeted modulation of canonical WNT signaling induces WNT expression in macrophages. Treatment with preconditioned macrophage derived WNT-enriched EVs can be a promising therapeutic approach against intestinal injury.
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Affiliation(s)
- Rishi Man Chugh
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Payel Bhanja
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Ryan Zitter
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Sumedha Gunewardena
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Rajeev Badkul
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Subhrajit Saha
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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Miura Y, Fujii S, Ichinohe T. Cell-based and extracellular vesicle-based MSC therapies for acute radiation syndrome affecting organ systems. JOURNAL OF RADIATION RESEARCH 2024; 65:i80-i87. [PMID: 39679884 DOI: 10.1093/jrr/rrae009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/28/2024] [Indexed: 12/17/2024]
Abstract
Exposure to ionizing radiation can induce harmful biological effects on the human body, particularly in cases of high-dose γ-irradiation affecting the gastrointestinal tract, bone marrow, skin and lung. Such exposures lead to lethal outcomes as individuals experience a breakdown in their immune system's ability to defend against pathogens, predisposing them to sepsis-induced multiple organ failures. Mesenchymal stromal/stem cells (MSCs) possess diverse biological characteristics, including immunomodulation, anti-inflammation and tissue regeneration. Off-the-shelf culture-expanded human bone marrow- or adipose tissue-derived MSCs are clinically available to treat graft-versus-host disease following hematopoietic cell transplantation and perianal fistulas in Crohn's disease in Japan. While preclinical studies showcase encouraging outcomes in radiation-induced injuries, the effectiveness of MSC transplantation in addressing acute radiation syndrome affecting organs in irradiated individuals is limited. Recent studies have highlighted MSC-releasing extracellular vesicles as nanoparticle substances responsible for outlining the mechanism of action and have identified various components, including proteins and microRNA, that serve as functional molecules. MSC-releasing extracellular vesicle-based therapy emerges as a promising avenue, offering a potential solution to the challenges posed by radiation-induced injuries. However, further investigation is required, especially regarding whether MSC-releasing extracellular vesicles have regenerative effects on tissue-resident stem cells. These unresolved issues represent key aspects that need to be addressed to optimize the therapeutic potential of cell-based and extracellular vesicle-based MSC therapies for interventions in the context of radiation-induced injuries.
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Affiliation(s)
- Yasuo Miura
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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Nagesh PKB, Monette S, Shamu T, Giralt S, Jean SCS, Zhang Z, Fuks Z, Kolesnick R. Anti-ceramide Single-Chain Variable Fragment Mitigates Gastrointestinal-Acute Radiation Syndrome and Improves Marrow Reconstitution, Rendering Near-Normal 90-Day Autopsies. Int J Radiat Oncol Biol Phys 2024; 120:558-569. [PMID: 37815783 PMCID: PMC10947531 DOI: 10.1016/j.ijrobp.2023.07.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 07/18/2023] [Accepted: 07/29/2023] [Indexed: 10/11/2023]
Abstract
PURPOSE After September 11, 2001, nuclear threat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality. METHODS AND MATERIALS For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GI-ARS lethal dose for this mouse strain. RESULTS Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy + BMT + scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these findings, mice receiving 15 Gy + BMT + scFv exhibit prolonged survival. At day 90, before sacrifice, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined. CONCLUSIONS Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies.
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Affiliation(s)
- Prashanth K B Nagesh
- Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sebastien Monette
- Laboratory of Comparative Pathology, Rockefeller University, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center, New York, New York
| | - Tambudzai Shamu
- Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sergio Giralt
- Division of Hematologic Malignancies, Adult BMT Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samantha C St Jean
- Laboratory of Comparative Pathology, Rockefeller University, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zhigang Zhang
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zvi Fuks
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Champalimaud Center, Lisbon, Portugal
| | - Richard Kolesnick
- Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
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Chugh RM, Bhanja P, Zitter R, Gunewardena S, Badkul R, Saha S. Modulation of β-Catenin is important to promote WNT expression in macrophages and mitigate intestinal injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.21.614209. [PMID: 39345507 PMCID: PMC11429945 DOI: 10.1101/2024.09.21.614209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Macrophages are the major source of WNT ligands. Macrophage-derived WNT is one of the most potent regenerative signals to mitigate intestinal injury. However, regulation of WNT expression in macrophages has not been studied. In the present study, we discovered that activation of canonical β-Catenin suppresses WNT expression in macrophages. Our CHIP-seq and validation study demonstrated the involvement of β-Catenin in the transcriptional regulation of WNT expression. Genetic and pharmacological approaches to de-stabilize/inactivate β-Catenin induce WNT expression in macrophages. Extracellular vesicles (EVs) are a major career of WNT ligands. Transfusion of EVs from pre-conditioned WNT-enriched macrophages demonstrated significant regenerative benefit over native macrophage-derived EVs to mitigate radiation-induced intestinal injury. Transfusion of WNT-enriched EVs also reduces DSS-induced colitis. Our study provides substantial evidence to consider that macrophage-targeted modulation of canonical WNT signaling to induce WNT expression followed by treatment with WNT-enriched EVs can be a lead therapy against intestinal injury.. SUMMARY Activation of β-Catenin suppresses WNT expression in macrophages. Macrophage-targeted pharmacological modulation of canonical WNT signaling followed by adoptive transfer mitigate radiation injury in intestine. EVs from these preconditioned macrophages mitigate chemical or radiation induced intestinal injury.
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Down JD, Cornwall-Brady MR, Huang W, Hurwitz M, Floyd SR, Yilmaz OH. Selecting the Most Relevant Mouse Strains for Evaluating Radiation-Induced Multiple Tissue Injury after Leg-Shielded Partial-Body Gamma Irradiation. Radiat Res 2024; 202:510-522. [PMID: 39066627 DOI: 10.1667/rade-24-00058.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 05/24/2024] [Indexed: 07/28/2024]
Abstract
Animal studies are needed that best simulate a large-scale, inhomogeneous body exposure after a radiological or nuclear incident and that provides a platform for future development of medical countermeasures. A partial-body irradiation (PBI) model using 137Cs gamma rays with hind limb (tibia) shielding was developed and assessed for the sequalae of radiation injuries to gastrointestinal tract, bone marrow (BM) and lung and among different genetic mouse strains (C57BL/6J, C57L/J, CBA/J and FVB/NJ). In this case, a marginal level of BM shielding (∼2%) provided adequate protection against lethality from infection and hemorrhage and enabled escalation of radiation doses with evaluation of both acute and delayed radiation syndromes. A steep radiation dose-dependent body weight loss was observed over the first 5 days attributed to enteritis with C57BL/6J mice appearing to be the most sensitive strain. Peripheral blood cell analysis revealed significant depression and recovery of leukocytes and platelets over the first month after PBI and were comparable among the four different mouse strains. Latent pulmonary injury was observed on micro-CT imaging at 4 months in C57L/J mice and confirmed histologically as severe pneumonitis that was lethal at 12 Gy. The lethality and radiological densitometry (HUs) dose responses were comparable to previous studies on C57L/J mice after total-body irradiation (TBI) and BM transplant rescue as well as after localized whole-thorax irradiation (WTI). Indeed, the lethal radiation doses and latency appeared similar for pneumonitis appearing in rhesus macaques after WTI or PBI as well as predicted for patients given systemic radiotherapy. In contrast, PBI treatment of C57BL/6 mice at a higher dose of 14 Gy had far longer survival times and developed extreme and debilitating pIeural effusions; an anomaly as similarly reported in previous thorax irradiation studies on this mouse strain. In summary, a radiation exposure model that delivers PBI to unanesthetized mice in a device that provides consistent shielding of the hind limb BM was developed for 137Cs gamma rays with physical characteristics and relevance to relatively high photon energies expected from the detonation of a nuclear device or accidental release of ionizing radiation. Standard strains such as C57BL/6J mice may be used reliably for early GI or hematological radiation syndromes while the C57L/J mouse strain stands out as the most appropriate for evaluating the delayed pulmonary effects of acute radiation exposure and recapitulating this disease in humans.
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Affiliation(s)
- Julian D Down
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Milton R Cornwall-Brady
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Wei Huang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Martina Hurwitz
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Scott R Floyd
- Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Omer H Yilmaz
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
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Winters TA, Marzella L, Molinar-Inglis O, Price PW, Han NC, Cohen JE, Wang SJ, Fotenos AF, Sullivan JM, Esker JI, Lapinskas PJ, DiCarlo AL. Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures. Radiat Res 2024; 201:628-646. [PMID: 38616048 PMCID: PMC11658916 DOI: 10.1667/rade-23-00196.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/14/2024] [Indexed: 04/16/2024]
Abstract
There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.
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Affiliation(s)
- Thomas A. Winters
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
| | - Libero Marzella
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Olivia Molinar-Inglis
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
| | - Paul W. Price
- Office of Regulatory Affairs, DAIT, NIAID, NIH, Rockville, Maryland
| | - Nyun Calvin Han
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Jonathan E. Cohen
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Sue-Jane Wang
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Anthony F. Fotenos
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Julie M. Sullivan
- Center for Devices for Radiological Health (CDRH), FDA, Silver Spring, Maryland
| | - John I. Esker
- Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC
| | - Paula J. Lapinskas
- Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
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Tamarat R, Satyamitra MM, Benderitter M, DiCarlo AL. Radiation-induced gastrointestinal and cutaneous injuries: understanding models, pathologies, assessments, and clinically accepted practices. Int J Radiat Biol 2024; 100:969-981. [PMID: 38787685 PMCID: PMC11494497 DOI: 10.1080/09553002.2024.2356544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE A U. S. and European joint effort fostering the development of medical countermeasures (MCMs) operable in case of radiological or nuclear emergencies. METHODS Based on the joint engagement between the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the French Institut de Radioprotection et de Sûreté Nucléaire (IRSN), a Statement of Intent to Collaborate was signed in 2014 and a series of working group meeting were established. In December 2022, the NIAID and IRSN hosted a five-day, U.S./European meeting titled 'Radiation-Induced Cutaneous and Gastrointestinal Injuries: Advances in Understanding Pathologies, Assessment, and Clinically Accepted Practices' in Paris, France. The goals of the meeting were to bring together U.S. and European investigators to explore new research avenues for the medical management of skin and gastrointestinal injuries, including specific diagnostics for each organ system, animal models, and promising medical countermeasures (MCMs) to mitigate radiation damage. There was also an emphasis on exploring additional areas of medicine and response to understand best practices from other emergency scenarios, which could be leveraged to improve radiation preparedness, and the importance of accurate dosimetry in preclinical work. RESULTS Subsequent to the workshop, seven collaborative projects, funded by both organizations, were established on topics ranging from MCMs and predictive biomarkers, and using physical methods to assess cutaneous radiation injuries, to mechanistic studies to understand radiation-induced damage in multiple organ systems. The importance of accurate dosimetry in preclinical works was highlighted and two recently published U.S./European commentaries that focus on the need for dosimetry standardization in the reported literature had their origins in this meeting. This commentary summarizes the workshop and open discussions among academic investigators, industry researchers, and U.S. and IRSN program representatives. CONCLUSIONS Given the substantive progress made due to these interactions, both groups plan to expand out these meetings by incorporating high-level investigators from across the globe, while endeavoring to maintain the informal setting that was conducive to in-depth scientific discussion and enhanced the state of the science in radiation research.
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Affiliation(s)
- Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Merriline M. Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Marc Benderitter
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
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9
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Chaudary N, Hill RP, Milosevic M. Targeting the CXCL12/CXCR4 pathway to reduce radiation treatment side effects. Radiother Oncol 2024; 194:110194. [PMID: 38447871 DOI: 10.1016/j.radonc.2024.110194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 02/20/2024] [Accepted: 02/26/2024] [Indexed: 03/08/2024]
Abstract
High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.
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Affiliation(s)
- Naz Chaudary
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Richard P Hill
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Michael Milosevic
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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10
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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11
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Molinar-Inglis O, DiCarlo AL, Lapinskas PJ, Rios CI, Satyamitra MM, Silverman TA, Winters TA, Cassatt DR. Radiation-induced multi-organ injury. Int J Radiat Biol 2024; 100:486-504. [PMID: 38166195 PMCID: PMC11874064 DOI: 10.1080/09553002.2023.2295298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/19/2023] [Accepted: 11/15/2023] [Indexed: 01/04/2024]
Abstract
PURPOSE Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). METHODS The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.
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Affiliation(s)
- Olivia Molinar-Inglis
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Paula J. Lapinskas
- Biomedical Advanced Research and Development Authority (BARDA), Administration for Strategic Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA
| | - Carmen I. Rios
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Merriline M. Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Toby A. Silverman
- Biomedical Advanced Research and Development Authority (BARDA), Administration for Strategic Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA
| | - Thomas A. Winters
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - David R. Cassatt
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
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Zitter RC, Chugh RM, Bhanja P, Kimler BF, Saha S. LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity. Cells 2023; 13:46. [PMID: 38201250 PMCID: PMC10778194 DOI: 10.3390/cells13010046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Tissue radiosensitivity plays a critical role in the overall outcome of radiation therapy. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data have suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In a mouse model of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity were not dependent on sex hormones, as we demonstrated similar sex-specific radiosensitivity differences in pre-pubescent mice. In an ex vivo study, we found that patient-derived intestinal organoid (PID) from males showed higher sensitivity to radiation compared to females as evident from loss of budding crypts, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation-induced upregulation of mitochondrial oxidative metabolism in males compared to females, a possible mechanism for radiosensitivity differences.
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Affiliation(s)
- Ryan C. Zitter
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.C.Z.); (R.M.C.); (P.B.); (B.F.K.)
| | - Rishi Man Chugh
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.C.Z.); (R.M.C.); (P.B.); (B.F.K.)
| | - Payel Bhanja
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.C.Z.); (R.M.C.); (P.B.); (B.F.K.)
| | - Bruce F. Kimler
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.C.Z.); (R.M.C.); (P.B.); (B.F.K.)
| | - Subhrajit Saha
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.C.Z.); (R.M.C.); (P.B.); (B.F.K.)
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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13
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Zitter RC, Chugh RM, Bhanja P, Saha S. LGR5+ Intestinal Stem Cells Display Sex Dependent Radiosensitivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.05.570158. [PMID: 38106083 PMCID: PMC10723330 DOI: 10.1101/2023.12.05.570158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Radiosensitivity, the susceptibility of cells to ionizing radiation, plays a critical role in understanding the effects of radiation therapy and exposure on tissue health and regeneration. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In mice models of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity are not dependent on sex hormones as we demonstrated similar sex-specific radiosensitivity differences in pediatric mice. In an ex-vivo study, we found that human patient-derived intestinal organoids (PID) derived from males showed higher sensitivity to irradiation compared to females as evidenced by loss of budding crypt, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation induced upregulation of mitochondrial oxidative metabolism in males compared to females' possible mechanism for radiosensitivity differences.
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Bensemmane L, Milliat F, Treton X, Linard C. Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b + cell-dependent mechanism. Stem Cell Res Ther 2023; 14:325. [PMID: 37953266 PMCID: PMC10641938 DOI: 10.1186/s13287-023-03562-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Stromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes-macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2. METHODS Mice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses. RESULTS Using flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b+Ly6C+CCR2+ population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80+CX3CR1+ macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C-MCHII+CX3CR1+ population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b+ being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b+ treatment impaired F4/80+CX3CR1+macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival. CONCLUSIONS These data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS.
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Affiliation(s)
- Lydia Bensemmane
- PSE-SANTE/SERAMED/LRMed, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260, Fontenay-Aux-Roses, France
| | - Fabien Milliat
- PSE-SANTE/SERAMED/LRMed, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260, Fontenay-Aux-Roses, France
| | | | - Christine Linard
- PSE-SANTE/SERAMED/LRMed, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260, Fontenay-Aux-Roses, France.
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15
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Yang Q, Qin B, Hou W, Qin H, Yin F. Pathogenesis and therapy of radiation enteritis with gut microbiota. Front Pharmacol 2023; 14:1116558. [PMID: 37063268 PMCID: PMC10102376 DOI: 10.3389/fphar.2023.1116558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/07/2023] [Indexed: 04/03/2023] Open
Abstract
Radiotherapy is widely used in clinic due to its good effect for cancer treatment. But radiotherapy of malignant tumors in the abdomen and pelvis is easy to cause radiation enteritis complications. Gastrointestinal tract contains numerous microbes, most of which are mutualistic relationship with the host. Abdominal radiation results in gut microbiota dysbiosis. Microbial therapy can directly target gut microbiota to reverse microbiota dysbiosis, hence relieving intestinal inflammation. In this review, we mainly summarized pathogenesis and novel therapy of the radiation-induced intestinal injury with gut microbiota dysbiosis and envision the opportunities and challenges of radiation enteritis therapy.
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Affiliation(s)
- Qilin Yang
- Research Institute of Intestinal Diseases, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- School of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Bingzhi Qin
- Research Institute of Intestinal Diseases, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Weiliang Hou
- Research Institute of Intestinal Diseases, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Cancer Institute, Renji Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Weiliang Hou, ; Huanlong Qin, ; Fang Yin,
| | - Huanlong Qin
- Research Institute of Intestinal Diseases, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- *Correspondence: Weiliang Hou, ; Huanlong Qin, ; Fang Yin,
| | - Fang Yin
- Research Institute of Intestinal Diseases, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- *Correspondence: Weiliang Hou, ; Huanlong Qin, ; Fang Yin,
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16
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Kim WH, Yoo JH, Yoo IK, Kwon CI, Hong SP. Effects of Mesenchymal Stem Cells Treatment on Radiation-Induced Proctitis in Rats. Yonsei Med J 2023; 64:167-174. [PMID: 36825342 PMCID: PMC9971437 DOI: 10.3349/ymj.2022.0342] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 02/25/2023] Open
Abstract
PURPOSE There are no effective treatment methods with which to control complications of radiation proctitis with fistula or recurrent bleeding following radiation treatment for prostate, cervical, or rectal cancer. Mesenchymal stem cells (MSCs) can induce immune modification, resulting in tissue repair and regeneration. Therefore, we used a rat model of radiation-induced proctitis and observed the effects of using human placenta-derived (PD) and adipose tissue-derived (AD) MSCs. MATERIALS AND METHODS Female Sprague Dawley rats were irradiated at the pelvic area with 25 Gy. We injected 1×106 cells of human PD-MSCs, human AD-MSCs, human foreskin fibroblasts, and control media into the rectal submucosa following irradiation. We sacrificed rats for pathologic evaluation. RESULTS Fibrosis on the rectum was reduced in both MSC groups, compared to the control group. Mucosal Ki-67 indices of both MSC injected groups were higher than those in the control group. Although caspase-3 positive cells in the mucosa gradually increased and decreased in the control group, those in both MSC injected groups increased rapidly and decreased thereafter. CONCLUSION We demonstrated the effects of regional MSC injection treatment for radiation-induced proctitis in rats. MSC injection reduced fibrosis and increased proliferation in rat mucosa. Human AD-MSCs and PD-MSCs had similar effectiveness.
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Affiliation(s)
- Won Hee Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jun Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - In Kyung Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Chang Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
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Kim JM, Kim H, Oh SH, Jang WI, Lee SB, Park M, Kim S, Park S, Shim S, Jang H. Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models. Int J Mol Sci 2022; 23:ijms232314827. [PMID: 36499155 PMCID: PMC9739896 DOI: 10.3390/ijms232314827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/02/2022] Open
Abstract
Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.
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Affiliation(s)
- Jung Moon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Department of Veterinary Surgery, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Hyewon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Su Hyun Oh
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Won Il Jang
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Seung Bum Lee
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Mineon Park
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Soyeon Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Sunhoo Park
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
| | - Sehwan Shim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Correspondence: (S.S.); (H.J.); Tel.: +82-2-3399-5873 (S.S.); +82-2-970-1302 (H.J.)
| | - Hyosun Jang
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
- Correspondence: (S.S.); (H.J.); Tel.: +82-2-3399-5873 (S.S.); +82-2-970-1302 (H.J.)
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Bell BI, Vercellino J, Brodin NP, Velten C, Nanduri LSY, Nagesh PK, Tanaka KE, Fang Y, Wang Y, Macedo R, English J, Schumacher MM, Duddempudi PK, Asp P, Koba W, Shajahan S, Liu L, Tomé WA, Yang WL, Kolesnick R, Guha C. Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation. Cancer Res 2022; 82:2678-2691. [PMID: 35919990 PMCID: PMC9354647 DOI: 10.1158/0008-5472.can-22-0656] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/15/2022] [Accepted: 06/10/2022] [Indexed: 02/05/2023]
Abstract
Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. SIGNIFICANCE Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.
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Affiliation(s)
- Brett I. Bell
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Justin Vercellino
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - N. Patrik Brodin
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Christian Velten
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | | | - Prashanth K.B. Nagesh
- Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Kathryn E. Tanaka
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yanan Fang
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yanhua Wang
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Rodney Macedo
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Jeb English
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Michelle M. Schumacher
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Patrik Asp
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Wade Koba
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shahin Shajahan
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Laibin Liu
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Wolfgang A. Tomé
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Weng-Lang Yang
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Richard Kolesnick
- Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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Takamiya S, Kawabori M, Yamazaki K, Yamaguchi S, Tanimori A, Yamamoto K, Ohnishi S, Seki T, Konno K, Tha KK, Hashimoto D, Watanabe M, Houkin K, Fujimura M. Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury. PLoS One 2022; 17:e0270606. [PMID: 35802703 PMCID: PMC9269969 DOI: 10.1371/journal.pone.0270606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 06/13/2022] [Indexed: 11/19/2022] Open
Abstract
Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.
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Affiliation(s)
- Soichiro Takamiya
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masahito Kawabori
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- * E-mail:
| | - Kazuyoshi Yamazaki
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Sho Yamaguchi
- Regenerative Medicine and Cell Therapy Laboratories, Kaneka Corporation, Kobe, Hyogo, Japan
| | - Aki Tanimori
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Koji Yamamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Toshitaka Seki
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kotaro Konno
- Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Khin Khin Tha
- Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Daigo Hashimoto
- Department of Hematology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Masahiko Watanabe
- Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kiyohiro Houkin
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Miki Fujimura
- Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Chugh RM, Bhanja P, Olea XD, Tao F, Schroeder K, Zitter R, Arora T, Pathak H, Kimler BF, Godwin AK, Perry JM, Saha S. Human Peripheral Blood Mononucleocyte Derived Myeloid Committed Progenitor Cells Mitigate H-ARS by Exosomal Paracrine Signal. Int J Mol Sci 2022; 23:5498. [PMID: 35628308 PMCID: PMC9142131 DOI: 10.3390/ijms23105498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/28/2022] [Accepted: 05/11/2022] [Indexed: 01/27/2023] Open
Abstract
Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient's hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome.
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Affiliation(s)
- Rishi Man Chugh
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Payel Bhanja
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Ximena Diaz Olea
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Fang Tao
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
| | - Kealan Schroeder
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
| | - Ryan Zitter
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Tanu Arora
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Harsh Pathak
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
| | - Bruce F. Kimler
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Andrew K. Godwin
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
| | - John M. Perry
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
- Department of Pediatrics, University of Kansas Medical Center, Kansas City, MO 66160, USA
- Departments of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Subhrajit Saha
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
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21
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Kim MJ, Moon W, Heo J, Lim S, Lee SH, Jeong JY, Lee SJ. Optimization of adipose tissue-derived mesenchymal stromal cells transplantation for bone marrow repopulation following irradiation. World J Stem Cells 2022; 14:245-263. [PMID: 35432736 PMCID: PMC8968216 DOI: 10.4252/wjsc.v14.i3.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/12/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bone marrow (BM) suppression is one of the most common side effects of radiotherapy and the primary cause of death following exposure to irradiation. Despite concerted efforts, there is no definitive treatment method available. Recent studies have reported using mesenchymal stromal cells (MSCs), but their therapeutic effects are contested. AIM We administered and examined the effects of various amounts of adipose-derived MSCs (ADSCs) in mice with radiation-induced BM suppression. METHODS Mice were divided into three groups: Normal control group, irradiated (RT) group, and stem cell-treated group following whole-body irradiation (WBI). Mouse ADSCs (mADSCs) were transplanted into the peritoneal cavity either once or three times at 5 × 105 cells/200 μL. The white blood cell count and the levels of, plasma cytokines, BM mRNA, and BM surface markers were compared between the three groups. Human BM-derived CD34+ hematopoietic progenitor cells were co-cultured with human ADSCs (hADSCs) or incubated in the presence of hADSCs conditioned media to investigate the effect on human cells in vitro. RESULTS The survival rate of mice that received one transplant of mADSCs was higher than that of mice that received three transplants. Multiple transplantations of ADSCs delayed the repopulation of BM hematopoietic stem cells. Anti-inflammatory effects and M2 polarization by intraperitoneal ADSCs might suppress erythropoiesis and induce myelopoiesis in sub-lethally RT mice. CONCLUSION The results suggested that an optimal amount of MSCs could improve survival rates post-WBI.
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Affiliation(s)
- Min-Jung Kim
- Department of Biochemistry, Cancer Research Institute Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Jeonghoon Heo
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Sangwook Lim
- Department of Radiation Oncology, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Seung-Hyun Lee
- Department of General Surgery, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Cancer Research Institute Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Sang Joon Lee
- Department of Ophthalmology, Gospel Hospital, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea.
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22
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Liao Z, Hu C, Gao Y. Mechanisms modulating the activities of intestinal stem cells upon radiation or chemical agent exposure. JOURNAL OF RADIATION RESEARCH 2022; 63:149-157. [PMID: 35021216 PMCID: PMC8944320 DOI: 10.1093/jrr/rrab124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/04/2021] [Indexed: 06/14/2023]
Abstract
Intestinal stem cells (ISCs) are essential for the regeneration of intestinal cells upon radiation or chemical agent damage. As for radiation-induced damage, the expression of AIM2, YAP, TLR3, PUMA or BVES can aggravate ISCs depletion, while the stimulation of TLR5, HGF/MET signaling, Ass1 gene, Slit/Robo signaling facilitate the radio-resistance of ISCs. Upon chemical agent treatment, the activation of TRAIL or p53/PUMA pathway exacerbate injury on ISCs, while the increased levels of IL-22, β-arrestin1 can ease the damage. The transformation between reserve ISCs (rISCs) maintaining quiescent states and active ISCs (aISCs) that are highly proliferative has obtained much attention in recent years, in which ISCs expressing high levels of Hopx, Bmi1, mTert, Krt19 or Lrig1 are resistant to radiation injury, and SOX9, MSI2, clusterin, URI are essential for rISCs maintenance. The differentiated cells like Paneth cells and enteroendocrine cells can also obtain stemness driven by radiation injury mediated by Wnt or Notch signaling. Besides, Mex3a-expressed ISCs can survive and then proliferate into intestinal epithelial cells upon chemical agent damage. In addition, the modulation of symbiotic microbes harboring gastrointestinal (GI) tract is also a promising strategy to protect ISCs against radiation damage. Overall, the strategies targeting mechanisms modulating ISCs activities are conducive to alleviating GI injury of patients receiving chemoradiotherapy or victims of nuclear or chemical accident.
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Affiliation(s)
| | | | - Yue Gao
- Corresponding author. Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine; 27 Taiping Road, Beijing, 100850, People’s Republic of China. E-mail:
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23
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Shen H, Han J, Liu C, Cao F, Huang Y. Grape Seed Proanthocyanidins Exert a Radioprotective Effect on the Testes and Intestines Through Antioxidant Effects and Inhibition of MAPK Signal Pathways. Front Med (Lausanne) 2022; 8:836528. [PMID: 35141259 PMCID: PMC8818786 DOI: 10.3389/fmed.2021.836528] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/29/2021] [Indexed: 11/15/2022] Open
Abstract
The testes and intestines are highly sensitive to ionizing radiation. Low-dose radiation can cause infertility and enteritis. However, there is a lack of safe and efficient radioprotective agents. This study aims to investigate the radioprotective effects of grape seed proanthocyanidins (GSPs) on testicular and intestinal damage induced by ionizing radiation. In vitro, GSPs reduced the apoptosis and proliferation inhibition of mouse testicular stromal cells TM3 and human small intestinal crypt epithelial cells HIEC induced by ionizing radiation, and alleviated DNA double-strand breaks. In vivo, GSPs ameliorated the pathological damage of the testes and intestines induced by ionizing radiation, and protected the endocrine function of the testes and the barrier function of the intestines. In addition, we preliminarily proved that the radioprotective effect of GSPs is related to its antioxidant effect and inhibition of MAPK signaling pathways. Our results indicate that GSPs are expected to be a safe and effective radioprotective drug.
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Affiliation(s)
- Hui Shen
- Department of Central Laboratory, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jun Han
- Department of Radiology, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Chunlei Liu
- Department of Radiation Oncology, Chifeng Municipal Hospital, Chifeng Clinical Medical School of Inner Mongolia Medical University, Chifeng, China
| | - Fei Cao
- Department of Radiotherapy, Changhai Hospital of Shanghai, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yijuan Huang
- Department of Radiology, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
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24
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Applications of 3D Bioprinting in Tissue Engineering and Regenerative Medicine. J Clin Med 2021; 10:jcm10214966. [PMID: 34768485 PMCID: PMC8584432 DOI: 10.3390/jcm10214966] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Regenerative medicine is an emerging field that centers on the restoration and regeneration of functional components of damaged tissue. Tissue engineering is an application of regenerative medicine and seeks to create functional tissue components and whole organs. Using 3D printing technologies, native tissue mimics can be created utilizing biomaterials and living cells. Recently, regenerative medicine has begun to employ 3D bioprinting methods to create highly specialized tissue models to improve upon conventional tissue engineering methods. Here, we review the use of 3D bioprinting in the advancement of tissue engineering by describing the process of 3D bioprinting and its advantages over other tissue engineering methods. Materials and techniques in bioprinting are also reviewed, in addition to future clinical applications, challenges, and future directions of the field.
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25
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Leibowitz BJ, Zhao G, Wei L, Ruan H, Epperly M, Chen L, Lu X, Greenberger JS, Zhang L, Yu J. Interferon b drives intestinal regeneration after radiation. SCIENCE ADVANCES 2021; 7:eabi5253. [PMID: 34613772 PMCID: PMC8494436 DOI: 10.1126/sciadv.abi5253] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/16/2021] [Indexed: 05/14/2023]
Abstract
The cGAS-STING cytosolic DNA sensing pathway is critical for host defense. Here, we report that cGAS-STING–dependent type 1 interferon (IFN) response drives intestinal regeneration and animal recovery from radiation injury. STING deficiency has no effect on radiation-induced DNA damage or crypt apoptosis but abrogates epithelial IFN-β production, local inflammation, innate transcriptional response, and subsequent crypt regeneration. cGAS KO, IFNAR1 KO, or CCR2 KO also abrogates radiation-induced acute crypt inflammation and regeneration. Impaired intestinal regeneration and survival in STING-deficient mice are fully rescued by a single IFN-β treatment given 48 hours after irradiation but not by wild-type (WT) bone marrow. IFN-β treatment remarkably improves the survival of WT mice and Lgr5+ stem cell regeneration through elevated compensatory proliferation and more rapid DNA damage removal. Our findings support that inducible IFN-β production in the niche couples ISC injury and regeneration and its potential use to treat acute radiation injury.
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Affiliation(s)
- Brian J. Leibowitz
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Guangyi Zhao
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Liang Wei
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Hang Ruan
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Michael Epperly
- Department of Radiation Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Lujia Chen
- Department of Medical Informatics, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Xinghua Lu
- Department of Medical Informatics, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Joel S. Greenberger
- Department of Radiation Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Lin Zhang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
| | - Jian Yu
- Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
- Department of Radiation Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
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26
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Nishiyama Y, Morita A, Wang B, Sakai T, Ramadhani D, Satoh H, Tanaka K, Sasatani M, Ochi S, Tominaga M, Ikushima H, Ueno J, Nenoi M, Aoki S. Evaluation of sodium orthovanadate as a radioprotective agent under total-body irradiation and partial-body irradiation conditions in mice. Int J Radiat Biol 2021; 97:1241-1251. [PMID: 34125648 DOI: 10.1080/09553002.2021.1941377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. METHODS Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. RESULTS TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. CONCLUSION Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.
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Affiliation(s)
- Yuichi Nishiyama
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Akinori Morita
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Bing Wang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Takuma Sakai
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Dwi Ramadhani
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
- Center for Radiation Safety Technology and Metrology, National Nuclear Energy Agency of Indonesia, Jakarta, Indonesia
| | - Hidetoshi Satoh
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
| | - Kaoru Tanaka
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Megumi Sasatani
- Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Shintaro Ochi
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Masahide Tominaga
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Hitoshi Ikushima
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Junji Ueno
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Mitsuru Nenoi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Shin Aoki
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
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27
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Checker R, Patwardhan RS, Jayakumar S, Maurya DK, Bandekar M, Sharma D, Sandur SK. Chemical and biological basis for development of novel radioprotective drugs for cancer therapy. Free Radic Res 2021; 55:595-625. [PMID: 34181503 DOI: 10.1080/10715762.2021.1876854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ionizing radiation (IR) causes chemical changes in biological systems through direct interaction with the macromolecules or by causing radiolysis of water. This property of IR is harnessed in the clinic for radiotherapy in almost 50% of cancers patients. Despite the advent of stereotactic radiotherapy instruments and other advancements in shielding techniques, the inadvertent deposition of radiation dose in the surrounding normal tissue can cause late effects of radiation injury in normal tissues. Radioprotectors, which are chemical or biological agents, can reduce or mitigate these toxic side-effects of radiotherapy in cancer patients and also during radiation accidents. The desired characteristics of an ideal radioprotector include low chemical toxicity, high risk to benefit ratio and specific protection of normal cells against the harmful effects of radiation without compromising the cytotoxic effects of IR on cancer cells. Since reactive oxygen species (ROS) are the major contributors of IR mediated toxicity, plethora of studies have highlighted the potential role of antioxidants to protect against IR induced damage. However, owing to the lack of any clinically approved radioprotector against whole body radiation, researchers have shifted the focus toward finding alternate targets that could be exploited for the development of novel agents. The present review provides a comprehensive insight in to the different strategies, encompassing prime molecular targets, which have been employed to develop radiation protectors/countermeasures. It is anticipated that understanding such factors will lead to the development of novel strategies for increasing the outcome of radiotherapy by minimizing normal tissue toxicity.
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Affiliation(s)
- Rahul Checker
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Sundarraj Jayakumar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Dharmendra Kumar Maurya
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Mayuri Bandekar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
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28
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Bensemmane L, Squiban C, Demarquay C, Mathieu N, Benderitter M, Le Guen B, Milliat F, Linard C. The stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome in mice. Stem Cell Res Ther 2021; 12:309. [PMID: 34051871 PMCID: PMC8164266 DOI: 10.1186/s13287-021-02373-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/09/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The intestine is particularly sensitive to moderate-high radiation dose and the development of gastrointestinal syndrome (GIS) leads to the rapid loss of intestinal mucosal integrity, resulting in bacterial infiltration, sepsis that comprise patient survival. There is an urgent need for effective and rapid therapeutic countermeasures. The stromal vascular fraction (SVF) derived from adipose tissue is an easily accessible source of cells with angiogenic, anti-inflammatory and regenerative properties. We studied the therapeutic impact of SVF and its action on the intestinal stem cell compartment. METHODS Mice exposed to the abdominal radiation (18 Gy) received a single intravenous injection of stromal vascular fraction (SVF) (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Mortality was evaluated as well as intestinal regeneration by histological analyses and absorption function. RESULTS The SVF treatment limited the weight loss of the mice and inhibited the intestinal permeability and mortality after abdominal irradiation. Histological analyses showed that SVF treatment stimulated the regeneration of the epithelium by promoting numerous enlarged hyperproliferative zones. SVF restored CD24+/lysozyme- and Paneth cell populations in the ISC compartment with the presence of Paneth Ki67+ cells. SVF has an anti-inflammatory effect by repressing pro-inflammatory cytokines, increasing M2 macrophages in the ileum and anti-inflammatory monocyte subtypes CD11b+Ly6clowCX3CR1high in the spleen. CONCLUSIONS Through the pleiotropic effects that contribute to limiting radiation-induced lethality, SVF opens up attractive prospects for the treatment of emergency GIS.
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Affiliation(s)
- Lydia Bensemmane
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | - Claire Squiban
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | - Christelle Demarquay
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | - Noëlle Mathieu
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | - Marc Benderitter
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | | | - Fabien Milliat
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France
| | - Christine Linard
- Institute of Radiological Protection and Nuclear Safety, Laboratory of Medical Radiobiology, Fontenay-aux-Roses, France.
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29
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Nanduri LSY, Duddempudi PK, Yang WL, Tamarat R, Guha C. Extracellular Vesicles for the Treatment of Radiation Injuries. Front Pharmacol 2021; 12:662437. [PMID: 34084138 PMCID: PMC8167064 DOI: 10.3389/fphar.2021.662437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023] Open
Abstract
Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.
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Affiliation(s)
- Lalitha Sarad Yamini Nanduri
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Phaneendra K. Duddempudi
- Department of Biochemistry, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Weng-Lang Yang
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Urology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Institute for Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
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30
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Bandekar M, Maurya DK, Sharma D, Sandur SK. Preclinical Studies and Clinical Prospects of Wharton's Jelly-Derived MSC for Treatment of Acute Radiation Syndrome. CURRENT STEM CELL REPORTS 2021; 7:85-94. [PMID: 33936933 PMCID: PMC8080090 DOI: 10.1007/s40778-021-00188-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 02/07/2023]
Abstract
Purpose of Review Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) have received widespread attention from researchers owing to the remarkable benefits offered by these cells over other stem cells. The primitive nature of WJ-MSCs, ease of isolation, differentiation ability, and immuno-modulatory nature make these cells superior to bone marrow MSCs and ideal to treat various human ailments. This review explores ability of WJ-MSCs to mitigate acute radiation syndrome caused by planned or unplanned radiation exposure. Recent Findings Recent reports suggest that WJ-MSCs home to damaged tissues in irradiated host and mitigate radiation induced damage to radiosensitive tissues such as hematopoietic and gastrointestinal systems. WJ-MSCs and conditioned media were found to protect mice from radiation induced mortality and also prevent radiation dermatitis. Local irradiation-induced lung toxicity in mice was significantly reduced by CXCR4 over-expressing WJ-MSCs. Summary Emerging evidences support safety and effectiveness of WJ-MSCs for treatment of acute radiation syndrome and lung injury after planned or accidental exposure. Additionally, conditioned media collected after culturing WJ-MSCs can also be used for mitigation of radiation dermatitis. Clinical translation of these findings would be possible after careful evaluation of resilience, effectiveness, and molecular mechanism of action of xenogeneic WJ-MSCs in non-human primates.
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Affiliation(s)
- Mayuri Bandekar
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085 India.,University of Mumbai, Kalina, Mumbai, 400098 India
| | - Dharmendra K Maurya
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085 India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094 India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085 India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094 India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085 India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094 India
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31
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Deng F, Yan J, Lu J, Luo M, Xia P, Liu S, Wang X, Zhi F, Liu D. M2 Macrophage-Derived Exosomal miR-590-3p Attenuates DSS-Induced Mucosal Damage and Promotes Epithelial Repair via the LATS1/YAP/ β-Catenin Signalling Axis. J Crohns Colitis 2021; 15:665-677. [PMID: 33075119 DOI: 10.1093/ecco-jcc/jjaa214] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS M2 phenotype macrophages are involved in the resolution of inflammation and intestinal repair. Exosomes are emerging as important mediators of intercellular communication in the mucosal microenvironment. METHODS M2 macrophages were transfected with or without miR-590-3p. Exosomes derived from M2 macrophages were isolated and identified. Proliferation and wound healing were tested in vitro and compared between groups. The mechanism involving LATS1, and activation of YAP and β-catenin signalling was investigated by using plasmid transfection, western blotting, immunofluorescence and luciferase reporter assays. The effect of exosomes in vivo was detected in dextran saline sulphate [DSS]-induced murine colitis. RESULTS First, we demonstrated that M2 macrophages promoted colonic epithelial cell proliferation in an exosome-dependent manner. Epithelial YAP mediated the effect of M2 macrophage-derived exosomes [M2-exos] in epithelial proliferation. Moreover, miR-590-3p, which was significantly enriched in M2-exos, could be transferred from macrophages into epithelial cells, resulting in the enhanced proliferation and wound healing of epithelial cells. Mechanistically, miR-590-3p suppressed the expression of LATS1 by binding to its coding sequence and subsequently activated the YAP/β-catenin-modulated transcription process to improve epithelial cell wound-healing ability. miR-590-3p also inhibited the induction of pro-inflammatory cytokines, including tumour necrosis factor-α, interleukin-1β [IL-1β] and IL-6. More importantly, repression of miR-590-3p in M2-exos resulted in more severe mucosal damage and impaired colon repair of mice compared with those in M2-exo-treated mice after DSS-induced colitis. CONCLUSION M2 macrophage-derived exosomal miR-590-3p reduces inflammatory signals and promotes epithelial regeneration by targeting LATS1 and subsequently activating YAP/β-catenin-regulated transcription, which could offer a new opportunity for clinical therapy for ulcerative colitis.
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Affiliation(s)
- Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Jin Yan
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Jiaxi Lu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Min Luo
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Pianpian Xia
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Siliang Liu
- Guangdong Provincial Key Laboratory of Gastroenterology; Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xuehong Wang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Fachao Zhi
- Guangdong Provincial Key Laboratory of Gastroenterology; Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
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Li S, Shao L, Xu T, Jiang X, Yang G, Dong L. An indispensable tool: Exosomes play a role in therapy for radiation damage. Biomed Pharmacother 2021; 137:111401. [PMID: 33761615 DOI: 10.1016/j.biopha.2021.111401] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/19/2022] Open
Abstract
Radiotherapy is one of the three main treatments for tumors. Almost 70% of tumor patients undergo radiotherapy at different periods. Although radiotherapy can enhance the local control rate of tumors and patients' quality of life, normal tissues often show radiation damage following radiotherapy. In recent years, several studies have shown that exosomes could be biomarkers for diseases and be involved in the treatment of radiation damage. Exosomes are nanoscale vesicles containing complex miRNAs and proteins. They can regulate the inflammatory response, enhance the regeneration effect of damaged tissue, and promote the repair of damaged tissues and cells, extending their survival time. In addition, their functions are achieved by paracrine signaling. In this review, we discuss the potential of exosomes as biomarkers and introduce the impact of exosomes on radiation damage in different organs and the hematopoietic system in detail.
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Affiliation(s)
- Sijia Li
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China.
| | - Lihong Shao
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China.
| | - Tiankai Xu
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China.
| | - Xin Jiang
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China.
| | - Guozi Yang
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China.
| | - Lihua Dong
- Department of Radiation Oncology and Therapy, Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Jilin, Changchun, 130000, China; NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China.
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Li L, Zhang S, Ge C, Ji L, Lv Y, Zhao C, Xu L, Zhang J, Song C, Chen J, Wei W, Fang Y, Yuan N, Wang J. HSCs transdifferentiate primarily to pneumonocytes in radiation-induced lung damage repair. Aging (Albany NY) 2021; 13:8335-8354. [PMID: 33686967 PMCID: PMC8034935 DOI: 10.18632/aging.202644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/12/2020] [Indexed: 11/25/2022]
Abstract
Accumulative radiation exposure leads to hematopoietic or tissue aging. Whether hematopoietic stem cells (HSCs) are involved in lung damage repair in response to radiation remains controversial. The aim of this study is to identify if HSC can transdifferentiate to pneumonocytes for radiation-induced damage repair. To this end, HSCs from male RosamT/mG mice were isolated by fluorescence-activated cell sorting (FACS) and transplanted into lethally irradiated female CD45.1 mice. 4 months after transplantation, transplanted HSC was shown to repair the radiation-induced tissue damage, and donor-derived tdTomato (phycoerythrin, PE) red fluorescence cells and Ddx3y representing Y chromosome were detected exclusively in female recipient lung epithelial and endothelial cells. Co-localization of donor-derived cells and recipient lung tissue cells were observed by laser confocal microscopy and image flow cytometry. Furthermore, the results showed HSC transplantation replenished radiation-induced lung HSC depletion and the PE positive repaired lung epithelial cells were identified as donor HSC origin. The above data suggest that donor HSC may migrate to the injured lung of the recipient and some of them can be transdifferentiated to pneumonocytes to repair the injury caused by radiation.
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Affiliation(s)
- Lei Li
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Suping Zhang
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,State Key Laboratory of Radiation Medicine and Protection, Soochow University School of Medicine, Suzhou 215123, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Chaorong Ge
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Li Ji
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yaqi Lv
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Chen Zhao
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Li Xu
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Jingyi Zhang
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Chenglin Song
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jianing Chen
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wen Wei
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Yixuan Fang
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,State Key Laboratory of Radiation Medicine and Protection, Soochow University School of Medicine, Suzhou 215123, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Na Yuan
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,State Key Laboratory of Radiation Medicine and Protection, Soochow University School of Medicine, Suzhou 215123, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
| | - Jianrong Wang
- Hematology Center of Cyrus Tang Medical Institute, Soochow University School of Medicine, Suzhou 215123, China.,National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.,State Key Laboratory of Radiation Medicine and Protection, Soochow University School of Medicine, Suzhou 215123, China.,Department of Hematopoietic Engineering, Susky Life SciTech (Suzhou) Co., Ltd., Suzhou 215124, China
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Tirado FR, Bhanja P, Castro-Nallar E, Olea XD, Salamanca C, Saha S. Radiation-induced toxicity in rectal epithelial stem cell contributes to acute radiation injury in rectum. Stem Cell Res Ther 2021; 12:63. [PMID: 33451351 PMCID: PMC7811242 DOI: 10.1186/s13287-020-02111-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/21/2020] [Indexed: 12/19/2022] Open
Abstract
Background Radiation-induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients with pelvic malignancies. Unlike small bowel and colon, effect of radiation in rectal stem cells has not been explored extensively. Here we demonstrate that Lgr5-positive rectal stem cells are radiosensitive and organoid-based transplantation of rectal stem cells mitigates radiation damage in rectum. Methods C57Bl6 male mice (JAX) at 24 h were exposed to pelvic irradiation (PIR) to determine the radiation effect in pelvic epithelium. Effect of PIR on Lgr5-positive rectal stem cells (RSCs) was determined in Lgr5-EGFP-Cre-ERT2 mice exposed to PIR. Effect of PIR or clinically relevant fractionated PIR on regenerative response of Lgr5-positive RSCs was examined by lineage tracing assay using Lgr5-eGFP-IRES-CreERT2; Rosa26-CAG-tdTomato mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from Lgr5-EGFP-Cre-ERT2 mice. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Organoids from Lgr5-EGFP-ires-CreERT2-TdT mice were transplanted in C57Bl6 male mice exposed to PIR. Engraftment and repopulation of Lgr5-positive RSCs were determined after tamoxifen administration to activate Cre recombinase in recipient mice. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tail t test. Result Exposure to pelvic irradiation significantly damaged rectal epithelium with the loss of Lgr5+ve rectal stem cells. Radiosensitivity of rectal epithelium was also observed with exposure to clinically relevant fractionated pelvic irradiation. Regenerative capacity of Lgr5+ve rectal stem cells was compromised in response to fractionated pelvic irradiation. Ex vivo organoid study demonstrated that Lgr5+ve rectal stem cells are sensitive to both single and fractionated radiation. Organoid-based transplantation of Lgr5+ve rectal stem cells promotes repair and regeneration of rectal epithelium. Conclusion Lgr5-positive rectal stem cells are radiosensitive and contribute to radiation-induced rectal epithelial toxicity. Transplantation of Lgr5-positive rectal stem cells mitigates radiation-induced rectal injury and promotes repair and regeneration process in rectum. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02111-w.
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Affiliation(s)
- Felipe Rodriguez Tirado
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Payel Bhanja
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Eduardo Castro-Nallar
- Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Ximena Diaz Olea
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Catalina Salamanca
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Subhrajit Saha
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA. .,Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
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Obrador E, Salvador R, Villaescusa JI, Soriano JM, Estrela JM, Montoro A. Radioprotection and Radiomitigation: From the Bench to Clinical Practice. Biomedicines 2020; 8:E461. [PMID: 33142986 PMCID: PMC7692399 DOI: 10.3390/biomedicines8110461] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
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Affiliation(s)
- Elena Obrador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Rosario Salvador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Juan I. Villaescusa
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
| | - José M. Soriano
- Food & Health Lab, Institute of Materials Science, University of Valencia, 46980 Valencia, Spain;
- Joint Research Unit in Endocrinology, Nutrition and Clinical Dietetics, University of Valencia-Health Research Institute IISLaFe, 46026 Valencia, Spain
| | - José M. Estrela
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Alegría Montoro
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
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Kim YH, Han SH, Kim H, Lee SJ, Joo HW, Kim MJ, Shim S, Kim K, Lee J, Jang WS, Park S, Jang H, Lee SB. Evaluation of the radiation response and regenerative effects of mesenchymal stem cell-conditioned medium in an intestinal organoid system. Biotechnol Bioeng 2020; 117:3639-3650. [PMID: 32833232 DOI: 10.1002/bit.27543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/07/2020] [Accepted: 08/17/2020] [Indexed: 11/10/2022]
Abstract
Intestinal organoids have recently emerged as an in vitro model relevant to the gut system owing to their recapitulation of the native intestinal epithelium with crypt-villus architecture. However, it is unclear whether intestinal organoids reflect the physiology of the in vivo stress response. Here, we systemically investigated the radiation response in organoids and animal models using mesenchymal stem cell-conditioned medium (MSC-CM), which contains secreted paracrine factors. Irradiated organoids exhibited sequential induction of viability loss and regrowth after irradiation (within 12 days), similar to the response of the native intestinal epithelium. Notably, treatment with MSC-CM facilitated the reproliferation of intestinal stem cells (ISCs) and restoration of damaged crypt-villus structures in both models. Furthermore, Wnt/Notch signaling pathways were commonly upregulated by MSC-CM, but not radiation, and pharmacologically selective inhibition of Wnt or Notch signaling attenuated the enhanced recovery of irradiated organoids, with increases in ISCs, following MSC-CM treatment. Interestingly, the expression of Wnt4, Wnt7a, and active β-catenin was increased, but not notch family members, in MSC-CM-treated organoid after irradiation. Treatment of recombinant mouse Wnt4 and Wnt7a after irradiation improved to some extent intestinal epithelial regeneration both in vitro and in vivo. Overall, these results suggested that intestinal organoids recapitulated the physiological stress response of the intestinal epithelium in vivo. Thus, our findings provided important insights into the physiology of intestinal organoids and may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
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Affiliation(s)
- Young-Heon Kim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Sung-Hoon Han
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Hyewon Kim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Sun-Joo Lee
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Hyun-Woo Joo
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Min-Jung Kim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Sehwan Shim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Kyuchang Kim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Janet Lee
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Won-Suk Jang
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Sunhoo Park
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Hyosun Jang
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Seung Bum Lee
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
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Qian L, Cen J. Hematopoietic Stem Cells and Mesenchymal Stromal Cells in Acute Radiation Syndrome. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8340756. [PMID: 32855768 PMCID: PMC7443042 DOI: 10.1155/2020/8340756] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/02/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023]
Abstract
With the extensive utilization of radioactive materials for medical, industrial, agricultural, military, and research purposes, medical researchers are trying to identify new methods to treat acute radiation syndrome (ARS). Radiation may cause injury to different tissues and organs, but no single drug has been proven to be effective in all circumstances. Radioprotective agents are always effective if given before irradiation, but many nuclear accidents are unpredictable. Medical countermeasures that can be beneficial to different organ and tissue injuries caused by radiation are urgently needed. Cellular therapy, especially stem cell therapy, has been a promising approach in ARS. Hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) are the two main kinds of stem cells which show good efficacy in ARS and have attracted great attention from researchers. There are also some limitations that need to be investigated in future studies. In recent years, there are also some novel methods of stem cells that could possibly be applied on ARS, like "drug" stem cell banks obtained from clinical grade human induced pluripotent stem cells (hiPSCs), MSC-derived products, and infusion of HSCs without preconditioning treatment, which make us confident in the future treatment of ARS. This review focuses on major scientific and clinical advances of hematopoietic stem cells and mesenchymal stromal cells on ARS.
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Affiliation(s)
- Liren Qian
- Department of Hematology, The Sixth Medical Center, Chinese PLA General Hospital, Fucheng Road #6, Beijing 100048, China
| | - Jian Cen
- Department of Hematology, The Sixth Medical Center, Chinese PLA General Hospital, Fucheng Road #6, Beijing 100048, China
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Bandekar M, Maurya DK, Sharma D, Checker R, Gota V, Mishra N, Sandur SK. Xenogeneic transplantation of human WJ-MSCs rescues mice from acute radiation syndrome via Nrf-2-dependent regeneration of damaged tissues. Am J Transplant 2020; 20:2044-2057. [PMID: 32040239 DOI: 10.1111/ajt.15819] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 01/25/2023]
Abstract
There is an unmet medical need for radiation countermeasures that can be deployed for treatment of exposed individuals during ionizing radiation (IR) accidents or terrorism. Wharton's jelly mesenchymal stem cells (WJ-MSCs) from human umbilical cord have been shown to avoid allorecognition and induce a tissue-regenerating microenvironment, which makes them an attractive candidate for mitigating IR injury. We found that WJ-MSCs protected mice from a lethal dose of IR even when transplanted up to 24 hours after irradiation, and a combination of WJ-MSCs and antibiotic (tetracycline) could further expand the window of protection offered by WJ-MSCs. This combinatorial approach mitigated IR-induced damage to the hematopoietic and gastrointestinal system. WJ-MSCs increased the serum concentration of the cytoprotective cytokines granulocyte colony-stimulating factor (G-CSF) and IL-6 in mice. Knockdown of G-CSF and IL-6 in WJ-MSCs before injection to lethally irradiated mice or transplantation of WJ-MSCs to lethally irradiated Nrf-2 knockout mice significantly nullified the therapeutic protective efficacy. Hence, WJ-MSCs could be a potential cell-based therapy for individuals accidentally exposed to radiation.
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Affiliation(s)
- Mayuri Bandekar
- Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India.,University of Mumbai, Kalina, Mumbai, India
| | - Dharmendra K Maurya
- Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Deepak Sharma
- Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Rahul Checker
- Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Vikram Gota
- Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | | | - Santosh K Sandur
- Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
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Fritsch SD, Weichhart T. Metabolic and immunologic control of intestinal cell function by mTOR. Int Immunol 2020; 32:455-465. [PMID: 32140726 PMCID: PMC7617511 DOI: 10.1093/intimm/dxaa015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 02/28/2020] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelium is one of the most quickly dividing tissues in our body, combining the absorptive advantages of a single layer with the protection of a constantly renewing barrier. It is continuously exposed to nutrients and commensal bacteria as well as microbial and host-derived metabolites, but also to hazards such as pathogenic bacteria and toxins. These environmental cues are sensed by the mucosa and a vast repertory of immune cells, especially macrophages. A disruption of intestinal homeostasis in terms of barrier interruption can lead to inflammatory bowel diseases and colorectal cancer, and macrophages have an important role in restoring epithelial function following injury. The mammalian/mechanistic target of rapamycin (mTOR) signalling pathway senses environmental cues and integrates metabolic responses. It has emerged as an important regulator of intestinal functions in homeostasis and disease. In this review, we are going to discuss intestinal mTOR signalling and metabolic regulation in different intestinal cell populations with a special focus on immune cells and their actions on intestinal function.
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Affiliation(s)
- Stephanie D Fritsch
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Währinger Straße, Vienna, Austria
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Währinger Straße, Vienna, Austria
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Huh JW, Tanksley J, Chino J, Willett CG, Dewhirst MW. Long-term Consequences of Pelvic Irradiation: Toxicities, Challenges, and Therapeutic Opportunities with Pharmacologic Mitigators. Clin Cancer Res 2020; 26:3079-3090. [PMID: 32098770 DOI: 10.1158/1078-0432.ccr-19-2744] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 01/17/2020] [Accepted: 02/21/2020] [Indexed: 11/16/2022]
Abstract
A percentage of long-term cancer survivors who receive pelvic irradiation will develop treatment-related late effects, collectively termed pelvic radiation disease. Thus, there is a need to prevent or ameliorate treatment-related late effects in these patients. Modern radiotherapy methods can preferentially protect normal tissues from radiation toxicities to permit higher doses to targets. However, concerns about chronic small bowel toxicity, for example, still constrain the prescription dose. This provides strong rationale for considering adding pharmacologic mitigators. Implementation of modern targeted radiotherapy methods enables delivery of focused radiation to target volumes, while minimizing dose to normal tissues. In prostate cancer, these technical advances enabled safe radiation dose escalation and better local tumor control without increasing normal tissue complications. In other pelvic diseases, these new radiotherapy methods have not resulted in the low probability of normal tissue damage achieved with prostate radiotherapy. The persistence of toxicity provides rationale for pharmacologic mitigators. Several new agents could be readily tested in clinical trials because they are being or have been studied in human patients already. Although there are promising preclinical data supporting mitigators, no clinically proven options to treat or prevent pelvic radiation disease currently exist. This review highlights therapeutic options for prevention and/or treatment of pelvic radiation disease, using pharmacologic mitigators. Successful development of mitigators would reduce the number of survivors who suffer from these devastating consequences of pelvic radiotherapy. It is important to note that pharmacologic mitigators to ameliorate pelvic radiation disease may be applicable to other irradiated sites in which chronic toxicity impairs quality of life.
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Affiliation(s)
- Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Jarred Tanksley
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Junzo Chino
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Christopher G Willett
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Mark W Dewhirst
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
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Singh VK, Seed TM. Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert Opin Pharmacother 2020; 21:317-337. [PMID: 31928256 PMCID: PMC6982586 DOI: 10.1080/14656566.2019.1702968] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/06/2019] [Indexed: 12/20/2022]
Abstract
Introduction: There is a limited array of currently available medicinals that are useful for either the prevention, mitigation or treatment of bodily injuries arising from ionizing radiation exposure.Area covered: In this brief article, the authors review those pharmacologic agents that either are currently being used to counter the injurious effects of radiation exposure, or those that show promise and are currently under development.Expert opinion: Although significant, but limited progress has been made in the development and fielding of safe and effective pharmacotherapeutics for select types of acute radiation-associated injuries, additional effort is needed to broaden the scope of drug development so that overall health risks associated with both short- and long-term injuries in various organ systems can be reduced and effectively managed. There are several promising radiation countermeasures that may gain regulatory approval from the government in the near future for use in clinical settings and in the aftermath of nuclear/radiological exposure contingencies.
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Affiliation(s)
- Vijay K. Singh
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Thomas M Seed
- Tech Micro Services, 4417 Maple Avenue, Bethesda, MD 20814, USA
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Blutt SE, Klein OD, Donowitz M, Shroyer N, Guha C, Estes MK. Use of organoids to study regenerative responses to intestinal damage. Am J Physiol Gastrointest Liver Physiol 2019; 317:G845-G852. [PMID: 31589468 PMCID: PMC7132322 DOI: 10.1152/ajpgi.00346.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intestinal organoid cultures provide an in vitro model system for studying pathways and mechanisms involved in epithelial damage and repair. Derived from either embryonic or induced pluripotent stem cells or adult intestinal stem cells or tissues, these self-organizing, multicellular structures contain polarized mature cells that recapitulate both the physiology and heterogeneity of the intestinal epithelium. These cultures provide a cutting-edge technology for defining regenerative pathways that are induced following radiation or chemical damage, which directly target the cycling intestinal stem cell, or damage resulting from viral, bacterial, or parasitic infection of the epithelium. Novel signaling pathways or biological mechanisms identified from organoid studies that mediate regeneration of the epithelium following damage are likely to be important targets of preventive or therapeutic modalities to mitigate intestinal injury. The evolution of these cultures to include more components of the intestinal wall and the ability to genetically modify them are key components for defining the mechanisms that modulate epithelial regeneration.
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Affiliation(s)
- Sarah E. Blutt
- 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Ophir D. Klein
- 2Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, California,3Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, California
| | - Mark Donowitz
- 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland,5Department of Medicine, Gastroenterology and Hepatology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Noah Shroyer
- 6Department of Medicine, Divisions of Gastroenterology and Hepatology and Infectious Diseases, Baylor College of Medicine, Houston, Texas
| | - Chandan Guha
- 7Department of Radiation Oncology, Albert Einstein, Bronx, New York
| | - Mary K. Estes
- 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas,6Department of Medicine, Divisions of Gastroenterology and Hepatology and Infectious Diseases, Baylor College of Medicine, Houston, Texas
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Khalifa J, François S, Rancoule C, Riccobono D, Magné N, Drouet M, Chargari C. Gene therapy and cell therapy for the management of radiation damages to healthy tissues: Rationale and early results. Cancer Radiother 2019; 23:449-465. [PMID: 31400956 DOI: 10.1016/j.canrad.2019.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022]
Abstract
Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.
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Affiliation(s)
- J Khalifa
- Départment de radiothérapie, institut Claudius-Regaud, institut universitaire du cancer de Toulouse - Oncopole, 1, avenue Irène-Joliot-Curie, 31100 Toulouse, France.
| | - S François
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Rancoule
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - D Riccobono
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - N Magné
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - M Drouet
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Chargari
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France; Service de santé des armées, école du Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France; Département de radiothérapie, Gustave-Roussy Cancer Campus, 114, rue Édouard-Vailant, 94805 Villejuif, France
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Singh VK, Seed TM, Olabisi AO. Drug discovery strategies for acute radiation syndrome. Expert Opin Drug Discov 2019; 14:701-715. [PMID: 31008662 DOI: 10.1080/17460441.2019.1604674] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach. Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims. Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a 'hybrid' strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.
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Affiliation(s)
- Vijay K Singh
- a Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine , Uniformed Services University of the Health Sciences , Bethesda , MD , USA.,b Scientific Research Department , Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences , Bethesda , MD , USA
| | | | - Ayodele O Olabisi
- b Scientific Research Department , Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences , Bethesda , MD , USA
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Garg S, Sadhukhan R, Banerjee S, Savenka AV, Basnakian AG, McHargue V, Wang J, Pawar SA, Ghosh SP, Ware J, Hauer-Jensen M, Pathak R. Gamma-Tocotrienol Protects the Intestine from Radiation Potentially by Accelerating Mesenchymal Immune Cell Recovery. Antioxidants (Basel) 2019; 8:antiox8030057. [PMID: 30845647 PMCID: PMC6466604 DOI: 10.3390/antiox8030057] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/24/2019] [Accepted: 02/28/2019] [Indexed: 12/12/2022] Open
Abstract
Natural antioxidant gamma-tocotrienol (GT3), a vitamin E family member, provides intestinal radiation protection. We seek to understand whether this protection is mediated via mucosal epithelial stem cells or sub-mucosal mesenchymal immune cells. Vehicle- or GT3-treated male CD2F1 mice were exposed to total body irradiation (TBI). Cell death was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Villus height and crypt depth were measured with computer-assisted software in tissue sections. Functional activity was determined with an intestinal permeability assay. Immune cell recovery was measured with immunohistochemistry and Western blot, and the regeneration of intestinal crypts was assessed with ex vivo organoid culture. A single dose of GT3 (200 mg/kg body weight (bwt)) administered 24 h before TBI suppressed cell death, prevented a decrease in villus height, increased crypt depth, attenuated intestinal permeability, and upregulated occludin level in the intestine compared to the vehicle treated group. GT3 accelerated mesenchymal immune cell recovery after irradiation, but it did not promote ex vivo organoid formation and failed to enhance the expression of stem cell markers. Finally, GT3 significantly upregulated protein kinase B or AKT phosphorylation after TBI. Pretreatment with GT3 attenuates TBI-induced structural and functional damage to the intestine, potentially by facilitating intestinal immune cell recovery. Thus, GT3 could be used as an intestinal radioprotector.
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Affiliation(s)
- Sarita Garg
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Ratan Sadhukhan
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Sudip Banerjee
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Alena V Savenka
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Alexei G Basnakian
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
- Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
| | - Victoria McHargue
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Junru Wang
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Snehalata A Pawar
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Sanchita P Ghosh
- Armed Forces Radiobiology Research Institute, USUHS, Bethesda, MD 20814, USA.
| | - Jerry Ware
- Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Martin Hauer-Jensen
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Farese AM, Bennett AW, Gibbs AM, Hankey KG, Prado K, Jackson W, MacVittie TJ. Efficacy of Neulasta or Neupogen on H-ARS and GI-ARS Mortality and Hematopoietic Recovery in Nonhuman Primates After 10-Gy Irradiation With 2.5% Bone Marrow Sparing. HEALTH PHYSICS 2019; 116:339-353. [PMID: 30281533 PMCID: PMC6349470 DOI: 10.1097/hp.0000000000000878] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
A nonhuman primate model of acute, partial-body, high-dose irradiation with minimal (2.5%) bone marrow sparing was used to assess endogenous gastrointestinal and hematopoietic recovery and the ability of Neulasta (pegylated granulocyte colony-stimulating factor) or Neupogen (granulocyte colony-stimulating factor) to enhance recovery from myelosuppression when administered at an increased interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neulasta or Neupogen on mortality and morbidity due to the hematopoietic acute radiation syndrome and concomitant gastrointestinal acute radiation syndrome. Nonhuman primates were exposed to 10.0 Gy, 6 MV, linear accelerator-derived photons delivered at 0.80 Gy min. All nonhuman primates received subject-based medical management. Nonhuman primates were dosed daily with control article (5% dextrose in water), initiated on day 1 postexposure; Neulasta (300 μg kg), administered on days 1, 8, and 15 or days 3, 10, and 17 postexposure; or Neupogen (10 μg kg), administered daily postexposure following its initiation on day 1 or day 3 until neutrophil recovery (absolute neutrophil count ≥1,000 cells μL for 3 consecutive days). Mortality in the irradiated cohorts suggested that administration of Neulasta or Neupogen on either schedule did not affect mortality due to gastrointestinal acute radiation syndrome or mitigate mortality due to hematopoietic acute radiation syndrome (plus gastrointestinal damage). Following 10.0 Gy partial-body irradiation with 2.5% bone marrow sparing, the mean duration of neutropenia (absolute neutrophil count <500 cells μL) was 22.4 d in the control cohort vs. 13.0 and 15.3 d in the Neulasta day 1, 8, 15 and day 3, 10, 17 cohorts, relative to 16.2 and 17.4 d in the Neupogen cohorts initiated on day 1 and day 3, respectively. The absolute neutrophil count nadirs were 48 cells μL in the controls; 117 cells μL and 40 cells μL in the Neulasta days 1, 8, and 15 or days 3, 10, and 17 cohorts, respectively; and 75 cells μL and 37 cells μL in the Neupogen day 1 and day 3 cohorts, respectively. Therefore, the earlier administration of Neulasta or Neupogen was more effective in this model of marginal 2.5% bone marrow sparing. The approximate 2.5% bone marrow sparing may approach the threshold for efficacy of the lineage-specific medical countermeasure. The partial-body irradiation with 2.5% bone marrow sparing model can be used to assess medical countermeasure efficacy in the context of the concomitant gastrointestinal and hematopoietic acute radiation syndrome sequelae.
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Affiliation(s)
- Ann M. Farese
- University of Maryland School of Medicine, Baltimore, MD
| | | | | | - Kim G. Hankey
- University of Maryland School of Medicine, Baltimore, MD
| | - Karl Prado
- University of Maryland Medical System, Department of Radiation Oncology, Baltimore, MD
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Jiang A, Okabe H, Popovic B, Preziosi ME, Pradhan-Sundd T, Poddar M, Singh S, Bell A, England SG, Nagarajan S, Monga SP. Loss of Wnt Secretion by Macrophages Promotes Hepatobiliary Injury after Administration of 3,5-Diethoxycarbonyl-1, 4-Dihydrocollidine Diet. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:590-603. [PMID: 30610845 PMCID: PMC6436111 DOI: 10.1016/j.ajpath.2018.11.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 11/17/2018] [Accepted: 11/20/2018] [Indexed: 02/07/2023]
Abstract
Exposure of mice to a diet containing 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) induces porphyrin accumulation, cholestasis, immune response, and hepatobiliary damage mimicking hepatic porphyria and sclerosing cholangitis. Although β-catenin signaling promotes hepatocyte proliferation, and macrophages are a source of Wnts, the role of macrophage-derived Wnts in modulating hepatobiliary injury/repair remains unresolved. We investigated the effect of macrophage-specific deletion of Wntless, a cargo protein critical for cellular Wnt secretion, by feeding macrophage-Wntless-knockout (Mac-KO) and wild-type littermates a DDC diet for 14 days. DDC exposure induced Wnt11 up-regulation in macrophages. Mac-KO mice on DDC showed increased serum alkaline phosphatase, aspartate aminotransferase, direct bilirubin, and histologic evidence of more cell death, inflammation, and ductular reaction. There was impaired hepatocyte proliferation evidenced by Ki-67 immunostaining, which was associated with decreased hepatocyte β-catenin activation and cyclin-D1 in Mac-KO. Mac-KO also showed increased CD45, F4/80, and neutrophil infiltration after DDC diet, along with increased expression of several proinflammatory cytokines and chemokines. Gene expression analyses of bone marrow-derived macrophages from Mac-KO mice and F4/80+ macrophages isolated from DDC-fed Mac-KO livers showed proinflammatory M1 polarization. In conclusion, this study shows that a lack of macrophage Wnt secretion leads to more DDC-induced hepatic injury due to impaired hepatocyte proliferation and increased M1 macrophages, which promotes immune-mediated cell injury.
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Affiliation(s)
- An Jiang
- National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Hirohisa Okabe
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Graduate School of Life Sciences, Kumamoto University, Chuo-Ku Kumamoto, Japan
| | - Branimir Popovic
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Morgan E Preziosi
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Tirthadipa Pradhan-Sundd
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Minakshi Poddar
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Aaron Bell
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Steven G England
- Division of Future Therapeutics and Technologies, Abbvie, North Chicago, Illinois
| | - Shanmugam Nagarajan
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Zhang J, Han X, Zhao Y, Xue X, Fan S. Mouse serum protects against total body irradiation-induced hematopoietic system injury by improving the systemic environment after radiation. Free Radic Biol Med 2019; 131:382-392. [PMID: 30578918 DOI: 10.1016/j.freeradbiomed.2018.12.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 12/04/2018] [Accepted: 12/17/2018] [Indexed: 12/31/2022]
Abstract
Reactive oxygen species (ROS) play a critical role in total body irradiation (TBI)-induced hematopoietic system injury. However, the mechanisms involved in ROS production in hematopoietic stem cells (HSCs) post TBI need to be further explored. In this study, we demonstrated that hematopoietic system injury in mice radiated with TBI was effectively alleviated when the blood circulation environment was changed via the injection of serum from non-radiated mice. Serum injection increased the survival of radiated mice and ameliorated TBI-induced hematopoietic system injury through attenuating myeloid skew, increasing HSC frequency, and promoting the reconstitution of radiated HSCs. Serum injection also decreased ROS levels in HSCs and regulated oxidative stress-related proteins. A serum proteome sequence array showed that proteins related to tissue injury and oxidative stress were regulated, and a serum-derived exosome microRNA sequence assay showed that the PI3K-Akt and Hippo signaling pathways were affected in radiated mice injected with serum from non-radiated mice. Furthermore, a significant increase in cell viability and a decrease in ROS were observed in radiated lineage-c-kit+ cells treated with serum-derived exosomes. Similarly, an improvement in the impaired differentiation of HSCs was observed in radiated mice injected with serum-derived exosomes. Taken together, our observations suggest that serum from non-radiated mice alleviates HSC injury in radiated mice by improving the systemic environment after radiation, and exosomes contribute to this radioprotective effect as important serum active component.
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Affiliation(s)
- Junling Zhang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science/Peking Union Medical College, Tianjin 300192, China.
| | - Xiaodan Han
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science/Peking Union Medical College, Tianjin 300192, China; Department of Radiation Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Yu Zhao
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science/Peking Union Medical College, Tianjin 300192, China
| | - Xiaolei Xue
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science/Peking Union Medical College, Tianjin 300192, China; Baokang Hospital, University of Tianjin Traditional Chinese Medicine, Tianjin 300193, China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science/Peking Union Medical College, Tianjin 300192, China.
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Yang C, Ni X, Mao D, Ren C, Liu J, Gao Y, Ding D, Liu J. Seeing the fate and mechanism of stem cells in treatment of ionizing radiation-induced injury using highly near-infrared emissive AIE dots. Biomaterials 2019; 188:107-117. [DOI: 10.1016/j.biomaterials.2018.10.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 09/21/2018] [Accepted: 10/09/2018] [Indexed: 02/08/2023]
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50
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Pinzur L, Akyuez L, Levdansky L, Blumenfeld M, Volinsky E, Aberman Z, Reinke P, Ofir R, Volk HD, Gorodetsky R. Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells. J Cachexia Sarcopenia Muscle 2018; 9:1079-1092. [PMID: 30334381 PMCID: PMC6240751 DOI: 10.1002/jcsm.12342] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 07/09/2018] [Accepted: 07/17/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Most current cell-based regenerative therapies are based on the indirect induction of the affected tissues repair. Xenogeneic cell-based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX-RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX-RAD cells in the rescue of the irradiated mice. METHODS The mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 × 106 PLX-RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX-RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX-RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors. RESULTS A 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 × 106 PLX-RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P < 0,0001). This was associated with a significant faster haematopoiesis recovery from day 9 onwards (P < 0.01). Nine out of the 65 human proteins tested were highly significantly elevated in the mouse circulation, peaking on days 6-9 after irradiation, relative to negligible levels in non-irradiated PLX-RAD injected mice (P < 0.01). The highly elevated proteins included human G-CSF, GRO, MCP-1, IL-6 and lL-8, reaching >500 pg/mL, while MCP-3, ENA, Eotaxin and fractalkine levels ranged between ~60-160pg/mL. The detected radiation-induced PLX-RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation-induced PLX-RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP-1 and IL-6. Additional supportive in vitro studies also confirmed the ability of cultured PLX-RAD secretome to induce accelerated migration of BM progenitors. CONCLUSIONS A well-regulated and orchestrated secretion of major pro-regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX-RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS-related stress signals activating the IM injected PLX-RAD cells for the remote secretion of the relevant human proteins deserve further investigation.
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Affiliation(s)
- Lena Pinzur
- Pluristem LTD, Haifa, Israel.,Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Institute of Medical Immunology and Department of Nephrology and Intensive Care, Charité-University Medicine Berlin, Berlin, Germany
| | - Levent Akyuez
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Institute of Medical Immunology and Department of Nephrology and Intensive Care, Charité-University Medicine Berlin, Berlin, Germany
| | - Lilia Levdansky
- Laboratory of Biotechnology and Radiobiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | | | - Evgenia Volinsky
- Laboratory of Biotechnology and Radiobiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | | | - Petra Reinke
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Institute of Medical Immunology and Department of Nephrology and Intensive Care, Charité-University Medicine Berlin, Berlin, Germany
| | | | - Hans-Dieter Volk
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Institute of Medical Immunology and Department of Nephrology and Intensive Care, Charité-University Medicine Berlin, Berlin, Germany
| | - Raphael Gorodetsky
- Laboratory of Biotechnology and Radiobiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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