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1
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Noguchi M, Ihara T, Suzuki K, Yokoya A. Temporal Dynamic Regulation of Autophagy and Senescence Induction in Response to Radiation Exposure. Radiat Res 2023; 200:538-547. [PMID: 37902247 DOI: 10.1667/rade-23-00173.1] [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: 08/16/2023] [Accepted: 10/14/2023] [Indexed: 10/31/2023]
Abstract
Autophagy and senescence are closely related cellular responses to genotoxic stress, and play significant roles in the execution of cellular responses to radiation exposure. However, little is known about their interplay in the fate-decision of cells receiving lethal doses of radiation. Here, we report that autophagy precedes the establishment of premature senescence in normal human fibroblasts exposed to lethal doses of radiation. Activation of the p53-dependent DNA damage response caused sustained dephosphorylation of RB proteins and consequent cell cycle arrest, concurrently with Ulk1 dephosphorylation at Ser638 by PPM1D, which promoted autophagy induction 1-2 days after irradiation. In addition, mitochondrial fragmentation became obvious 1-2 days after irradiation, and autophagy was further enhanced. However, Ulk1 levels decreased significantly after 2 days, resulting in lower LC3-II levels. An autophagic flux assay using chloroquine (CQ) also revealed that the flux in irradiated cells gradually decreased over 30 days. In contrast, lysosomal augmentation started at 1 day, became significantly upregulated after 5 days, and continued for over 30 days. After a rapid decrease in autophagy, p16 expression increased and senescence was established, but autophagic activity remained reduced. These results demonstrated that X-ray irradiation triggered two processes, autophagy and senescence, with the former being temporary and regulated by DNA damage response and mitophagy, and the latter being sustained and regulated by persistent cell cycle arrest. The interplay between autophagy and senescence seems to be essential for the proper implementation of the cellular response to radiation exposure.
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Affiliation(s)
- Miho Noguchi
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
| | - Tomokazu Ihara
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
- Graduate School of Science and Engineering, Ibaraki University, 2-1-1, Bunkyo, Mito-shi, Ibaraki 310-8512, Japan
| | - Keiji Suzuki
- Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-shi, Nagasaki 852-8523, Japan
| | - Akinari Yokoya
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
- Graduate School of Science and Engineering, Ibaraki University, 2-1-1, Bunkyo, Mito-shi, Ibaraki 310-8512, Japan
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2
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Zawrzykraj M, Deptuła M, Kondej K, Tymińska A, Pikuła M. The effect of chemotherapy and radiotherapy on stem cells and wound healing. Current perspectives and challenges for cell-based therapies. Biomed Pharmacother 2023; 168:115781. [PMID: 39491418 DOI: 10.1016/j.biopha.2023.115781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/11/2023] [Accepted: 10/20/2023] [Indexed: 11/05/2024] Open
Abstract
Cancers are part of the group of diseases that carry a high mortality rate. According to World Health Organization in 2020 reported 10 million deaths due to cancers. Treatment of oncological patients is focused on chemotherapeutic agents, radiology, or immunology. Surgical interventions are also an important aspect of treatment. The above methods contribute to saving the patients' health and lives. However, cancer treatment possesses side effects. Commonly observed complications are hair loss, mucositis, nausea, diarrhea, or various skin damage. To improve the quality of medical care for cancer patients, new methods of reducing side effects are sought. Strategies include the use of stem cells (SCs). Due to unlimited proliferation potential and differentiating abilities, SCs are used in the treatment of many disease entities, including wounds. One of the most used types of stem cells supposed adipose-derived mesenchymal stromal cells (AD-MSCs). Clinical trials confirm the application of AD-MSCs in wound healing. Furthermore, in vivo studies considered the utilization of AD-MSCs in radiation injury. The use of stem cells in cancer treatment still involves many questions, such as the impact of treatment on SCs' condition and oncological safety. However, development in regenerative medicine research may contribute to the use of stem cells in personalized medicine, customized for the patient. This could represent a breakthrough step in preventing the side effects of cancer therapies, including chronic wounds.
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Affiliation(s)
| | - Milena Deptuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of Embryology, Medical University of Gdansk, Poland
| | - Karolina Kondej
- Department of Plastic Surgery, Medical University of Gdansk, Poland
| | - Agata Tymińska
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of Embryology, Medical University of Gdansk, Poland
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of Embryology, Medical University of Gdansk, Poland.
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3
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Qin Y, Ge G, Yang P, Wang L, Qiao Y, Pan G, Yang H, Bai J, Cui W, Geng D. An Update on Adipose-Derived Stem Cells for Regenerative Medicine: Where Challenge Meets Opportunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207334. [PMID: 37162248 PMCID: PMC10369252 DOI: 10.1002/advs.202207334] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/24/2023] [Indexed: 05/11/2023]
Abstract
Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most advantageous cell type for regenerative therapies owing to their easy accessibility, multipotency, and active paracrine activity. This review highlights current challenges in translating ADSC-based therapies into clinical settings and discusses novel strategies to overcome the limitations of ADSCs. To further establish ADSC-based therapies as an emerging platform for regenerative medicine, this review also provides an update on the advancements in this field, including fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, and nerve regeneration. ADSC-based therapies are expected to be more tissue-specific and increasingly important in regenerative medicine.
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Affiliation(s)
- Yi Qin
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Gaoran Ge
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Peng Yang
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Liangliang Wang
- Department of OrthopaedicsThe Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical UniversityChangzhouJiangsu213000China
| | - Yusen Qiao
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Guoqing Pan
- Institute for Advanced MaterialsSchool of Materials Science and EngineeringJiangsu UniversityZhenjiangJiangsu212013China
| | - Huilin Yang
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Jiaxiang Bai
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
| | - Wenguo Cui
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Dechun Geng
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopaedic Institute, Medical CollegeSoochow UniversitySuzhouJiangsu215006China
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4
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Stromal Vascular Fraction Cells from Individuals Who Have Previously Undergone Radiotherapy Retain Their Pro-Wound Healing Properties. J Clin Med 2023; 12:jcm12052052. [PMID: 36902839 PMCID: PMC10003870 DOI: 10.3390/jcm12052052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Beneficial effects have been observed following the transplant of lipoaspirates containing adipose-derived stem cells into chronic wounds caused by oncologic radiotherapy. It is not yet certain whether adipose-derived stem cells are resistant to radiation exposure. Therefore, the aims of this study were to isolate stromal vascular fraction from human breast tissue exposed to radiotherapy and determine the presence of adipose-derived stem cells. Stromal vascular fraction from irradiated donor tissue was compared to commercially sourced pre-adipocytes. Immunocytochemistry was used to determine the presence of adipose-derived stem cell markers. Conditioned media from stromal vascular fraction isolated from irradiated donors was used as a treatment in a scratch wound assay of dermal fibroblasts also isolated from irradiated donors and compared to pre-adipocyte conditioned media and serum free control. This is the first report of human stromal vascular fraction being cultured from previously irradiated breast tissue. Stromal vascular fraction conditioned media from irradiated donors had a similar effect in increasing the migration of dermal fibroblasts from irradiated skin to pre-adipocyte conditioned media from healthy donors. Therefore, the ability of adipose-derived stem cells in the stromal vascular fraction to stimulate dermal fibroblasts in wound healing appears to be preserved following radiotherapy. This study demonstrates that stromal vascular fraction from irradiated patients is viable, functional and may have potential for regenerative medicine techniques following radiotherapy.
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5
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Ahmed I, Verma A, Umar S, Papineni RVL. 2-deoxy-D-glucose mitigates Citrobacter rodentium and dibenzazepine-induced gastrointestinal damage and colitis: novel implications of 2-DG polypharmacopea. Int J Radiat Biol 2023; 99:681-691. [PMID: 35946994 DOI: 10.1080/09553002.2022.2110297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
PURPOSE Citrobacter rodentium (CR) infection coupled with blocking Notch/Wnt signaling via γ-secretase inhibitor dibenzazepine (DBZ) disrupts the gastro-intestinal (GI) barrier and induces colitis, akin to ionizing radiation (IR)-induced GI-injury. We investigated the effects of 2-deoxy-D-glucose (2-DG) to ameliorate the CR-DBZ-induced GI damage. MATERIALS AND METHODS NIH:Swiss outbred mice were inoculated with 109CFUs of CR orally. DBZ was administered intraperitoneally (10 μM/kg b.wt; for 10 days 2 days post-CR infection). Mice were fed with 0.4% 2-DG (w/v) daily in drinking water. For microbiota depletion, antibiotics (Abx), 1 g/l metronidazole, and 0.2 g/l ciprofloxacin were administered for 10 days in drinking water. Oxidative stress, survival assay, colonic crypt hyperplasia, Notch/Wnt downstream signaling, immunomodulation, and bacterial dysbiosis were measured. RESULTS We show that real-time visualization of reactive oxygen species (ROS) is similar during CR-induced colonic infection and IR-induced GI-damage. The histology revealed that dietary 2-DG mitigates CR + DBZ-induced colitis and improves survival compared with CR + DBZ alone. These changes were phenocopied in Abx-treated mice. Both 2-DG and Abx reduced dysbiosis, increased proliferation, inhibited pro-inflammatory response, and restored Hes-1 and β-catenin protein levels, in the crypts. CONCLUSION The energy disruptor 2-DG mitigates bacterial infection and its responsive hyperplasia/colitis, indicating its utility as a mitigator of infection/IR-induced GI-damage.
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Affiliation(s)
- Ishfaq Ahmed
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
| | | | - Shahid Umar
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
| | - Rao V L Papineni
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
- PACT & Health LLC, Branford, CT, USA
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6
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Rodman SN, Kluz PN, Hines MR, Oberley‐Deegan RE, Coleman MC. Sex-based differences in the severity of radiation-induced arthrofibrosis. J Orthop Res 2022; 40:2586-2596. [PMID: 35148568 PMCID: PMC9365890 DOI: 10.1002/jor.25297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/23/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023]
Abstract
As cancer survivorship increases, so does the number of patients that suffer from the late effects of radiation therapy. This includes arthrofibrosis, the development of stiff joints near the field of radiation. Previous reports have concentrated on skin fibrosis around the joint but largely ignored the deeper tissues of the joint. We hypothesized that fat, muscle, and the joint tissues themselves would play a more significant role in joint contracture after radiation than the skin surrounding the joint. To address this hypothesis, we irradiated the right hind flanks of mice with fractionated and unfractionated dose schedules, then monitored the mice for 3 months postradiotherapy. Mice were euthanized and physiological indications of arthrofibrosis including limb contracture and joint resting position were assessed. Stifle (knee) joints demonstrated significant arthrofibrosis, but none was observed in the hock (ankle) joints. During these studies, we were surprised to find that male and female mice showed a significantly different response to radiation injury. Female mice developed more injuries, had significantly worse contracture, and showed a greater difference in the expression of all markers studied. These results suggest that women undergoing radiation therapy might be at significantly greater risk for developing arthrofibrosis and may require specific adjustments to their care.
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Affiliation(s)
- Samuel N. Rodman
- Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer CenterUniversity of IowaIowa CityIowaUSA,Department of Orthopedics and RehabilitationUniversity of Iowa Hospitals and ClinicsIowa CityIowaUSA
| | - Paige N. Kluz
- Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer CenterUniversity of IowaIowa CityIowaUSA,Department of Orthopedics and RehabilitationUniversity of Iowa Hospitals and ClinicsIowa CityIowaUSA,Department of Pathology and Laboratory Medicine, Human Leukocyte Antigens (HLA) LaboratoryUniversity of Wisconsin‐MadisonMadisonWisconsinUSA
| | - Madeline R. Hines
- Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer CenterUniversity of IowaIowa CityIowaUSA,Department of Orthopedics and RehabilitationUniversity of Iowa Hospitals and ClinicsIowa CityIowaUSA
| | - Rebecca E. Oberley‐Deegan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Mitchell C. Coleman
- Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer CenterUniversity of IowaIowa CityIowaUSA,Department of Orthopedics and RehabilitationUniversity of Iowa Hospitals and ClinicsIowa CityIowaUSA
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7
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Papadopoulou A, Kalodimou VE, Mavrogonatou E, Karamanou K, Yiacoumettis AM, Panagiotou PN, Pratsinis H, Kletsas D. Decreased differentiation capacity and altered expression of extracellular matrix components in irradiation-mediated senescent human breast adipose-derived stem cells. IUBMB Life 2022; 74:969-981. [PMID: 35833571 DOI: 10.1002/iub.2659] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022]
Abstract
Radiotherapy is widely used for the treatment of breast cancer. However, we have shown that ionizing radiation can provoke premature senescence in breast stromal cells. In particular, breast stromal fibroblasts can become senescent after irradiation both in vitro and in vivo and they express an inflammatory phenotype and an altered profile of extracellular matrix components, thus facilitating tumor progression. Adipose-derived stem cells (ASCs) represent another major component of the breast tissue stroma. They are multipotent cells and due to their ability to differentiate in multiple cell lineages they play an important role in tissue maintenance and repair in normal and pathologic conditions. Here, we investigated the characteristics of human breast ASCs that became senescent prematurely after their exposure to ionizing radiation. We found decreased expression levels of the specific mesenchymal cell surface markers CD105, CD73, CD44, and CD90. In parallel, we demonstrated a significantly reduced expression of transcription factors regulating osteogenic (i.e., RUNX2), adipogenic (i.e., PPARγ), and chondrogenic (i.e., SOX9) differentiation; this was followed by an analogous reduction in their differentiation capacity. Furthermore, they overexpress inflammatory markers, that is, IL-6, IL-8, and ICAM-1, and a catabolic phenotype, marked by the reduction of collagen type I and the increase of MMP-1 and MMP-13 expression. Finally, we detected changes in proteoglycan expression, for example, the upregulation of syndecan 1 and syndecan 4 and the downregulation of decorin. Notably, all these alterations, when observed in the breast stroma, represent poor prognostic factors for tumor development. In conclusion, we showed that ionizing radiation-mediated prematurely senescent human breast ASCs have a decreased differentiation potential and express specific changes adding to the formation of a permissive environment for tumor growth.
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Affiliation(s)
- Adamantia Papadopoulou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Vasiliki E Kalodimou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Eleni Mavrogonatou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Konstantina Karamanou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Andreas M Yiacoumettis
- Plastic and Reconstructive Surgery Department, Metropolitan General Hospital, Athens, Greece
| | - Petros N Panagiotou
- Department of Plastic Surgery and Burns Unit, KAT General Hospital of Athens, Athens, Greece
| | - Harris Pratsinis
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Dimitris Kletsas
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
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8
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Rocheteau P, Warot G, Chapellier M, Zampaolo M, Chretien F, Piquemal F. Cryopreserved Stem Cells Incur Damages Due To Terrestrial Cosmic Rays Impairing Their Integrity Upon Long-Term Storage. Cell Transplant 2022; 31:9636897211070239. [PMID: 35170351 PMCID: PMC8855380 DOI: 10.1177/09636897211070239] [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] [Indexed: 12/05/2022] Open
Abstract
Stem cells have the capacity to ensure the renewal of tissues and organs. They
could be used in the future for a wide range of therapeutic purposes and are
preserved at liquid nitrogen temperature to prevent any chemical or biological
activity up to several decades before their use. We show that the cryogenized
cells accumulate damages coming from natural radiations, potentially inducing
DNA double-strand breaks (DSBs). Such DNA damage in stem cells could lead to
either mortality of the cells upon thawing or a mutation diminishing the
therapeutic potential of the treatment. Many studies show how stem cells react
to different levels of radiation; the effect of terrestrial cosmic rays being
key, it is thus also important to investigate the effect of the natural
radiation on the cryopreserved stem cell behavior over time. Our study showed
that the cryostored stem cells totally shielded from cosmic rays had less DSBs
upon long-term storage. This could have important implications on the long-term
cryostorage strategy and quality control of different cell banks.
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Affiliation(s)
- P Rocheteau
- Human Histopathology and Animal Models, Department of Infection & Epidemiology, Institut Pasteur, Paris, France
| | - G Warot
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - M Chapellier
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - M Zampaolo
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - F Chretien
- Human Histopathology and Animal Models, Department of Infection & Epidemiology, Institut Pasteur, Paris, France
| | - F Piquemal
- Centre d'Etudes Nucléaires de Bordeaux Gradignan, UMR 5797, Centre National de la Recherche Scientifique and Université de Bordeaux, Gradignan, France
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9
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Deleon NMD, Adem S, Lavin CV, Abbas DB, Griffin M, King ME, Borrelli MR, Patel RA, Fahy EJ, Lee D, Shen AH, Momeni A, Longaker MT, Wan DC. Angiogenic CD34+CD146+ adipose-derived stromal cells augment recovery of soft tissue after radiotherapy. J Tissue Eng Regen Med 2021; 15:1105-1117. [PMID: 34582109 DOI: 10.1002/term.3253] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 07/26/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022]
Abstract
Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy.
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Affiliation(s)
- Nestor M Diaz Deleon
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Sandeep Adem
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Christopher V Lavin
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Darren B Abbas
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Michelle Griffin
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Megan E King
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Mimi R Borrelli
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Ronak A Patel
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Evan J Fahy
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Daniel Lee
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Abra H Shen
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Arash Momeni
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Michael T Longaker
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Derrick C Wan
- Department of Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
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10
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Platoff R, Villalobos MA, Hagaman AR, Liu Y, Matthews M, DiSanto ME, Carpenter JP, Zhang P. Effects of radiation and chemotherapy on adipose stem cells: Implications for use in fat grafting in cancer patients. World J Stem Cells 2021; 13:1084-1093. [PMID: 34567427 PMCID: PMC8422936 DOI: 10.4252/wjsc.v13.i8.1084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/30/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autologous fat transplantation is a versatile tool in reconstructive surgery. Adipose-derived stem cells (ASCs) increase survival of fat grafts and thus are increasingly used for breast reconstruction in breast cancer patients. However, radiation and/or chemotherapy have been proposed to inhibit soft tissue regeneration in wound healing thus suggesting alteration in stem cell pathways. Therefore, elucidating effects of radiation and chemotherapy on ASCs is critical if one desires to enhance the survival of fat grafts in patients. This review outlines our work evaluating the function and recoverability of ASCs from radiation or chemotherapy patients, focusing specifically on their availability as a source of autologous stem cells for fat grafting and breast reconstruction in cancer patients. Even though evidence suggests radiation and chemotherapy negatively influence ASCs at the cellular level, the efficiency of the isolation and differentiation capacity did not appear influenced in patients after receiving chemotherapy treatment, although fat from radiated patients exhibited significantly altered ASC differentiation into endothelial-like cells. Further, the in vitro growth rates of patient’s ASCs do not differ significantly before or after treatment. Taken together, these studies suggest ASCs as an important new tool for grafting and reconstruction even when radiation and chemotherapy treatment are involved.
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Affiliation(s)
- Rebecca Platoff
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
| | - Miguel A Villalobos
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
| | - Ashleigh Rapp Hagaman
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
| | - Yuan Liu
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
- Department of Surgery, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Martha Matthews
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
- Department of Surgery, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Michael E DiSanto
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Jeffrey P Carpenter
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
- Department of Surgery, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Ping Zhang
- Department of Surgery, Cooper University Health Care, Camden, NJ 08103, United States
- Department of Surgery, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
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11
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Sun H, Lu J, Li B, Chen S, Xiao X, Wang J, Wang J, Wang X. Partial regeneration of uterine horns in rats through adipose-derived stem cell sheets. Biol Reprod 2019; 99:1057-1069. [PMID: 29931041 DOI: 10.1093/biolre/ioy121] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 06/19/2018] [Indexed: 12/15/2022] Open
Abstract
Severe uterine damage and infection lead to intrauterine adhesions, which result in hypomenorrhea, amenorrhea and infertility. Cell sheet engineering has shown great promise in clinical applications. Adipose-derived stem cells (ADSCs) are emerging as an alternative source of stem cells for cell-based therapies. In the present study, we investigated the feasibility of applying ADSCs as seed cells to form scaffold-free cell sheet. Data showed that ADSC sheets expressed higher levels of FGF, Col I, TGFβ, and VEGF than ADSCs in suspension, while increased expression of this gene set was associated with stemness, including Nanog, Oct4, and Sox2. We then investigated the therapeutic effects of 3D ADSCs sheet on regeneration in a rat model. We found that ADSCs were mainly detected in the basal layer of the regenerating endometrium in the cell sheet group at 21 days after transplantation. Additionally, some ADSCs differentiated into stromal-like cells. Moreover, ADSC sheets transplanted into partially excised uteri promoted regeneration of the endometrium cells, muscle cells and stimulated angiogenesis, and also resulted in better pregnancy outcomes. Therefore, ADSC sheet therapy shows considerable promise as a new treatment for severe uterine damage.
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Affiliation(s)
- Huijun Sun
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Jie Lu
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Bo Li
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Shuqiang Chen
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Xifeng Xiao
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Jun Wang
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Jingjing Wang
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
| | - Xiaohong Wang
- Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd., Xian 710038, China
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12
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Spiegel JL, Hambrecht M, Kohlbauer V, Haubner F, Ihler F, Canis M, Schilling AF, Böker KO, Dressel R, Streckfuss-Bömeke K, Jakob M. Radiation-induced sensitivity of tissue-resident mesenchymal stem cells in the head and neck region. Head Neck 2019; 41:2892-2903. [PMID: 31017352 DOI: 10.1002/hed.25768] [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: 09/26/2018] [Revised: 01/03/2019] [Accepted: 03/25/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tissue-resident mesenchymal stem cells (MSCs) possess the ability to migrate to areas of inflammation and promote the regeneration of damaged tissue. However, it remains unclear how radiation influences this capacity of MSC in the head and neck region. METHODS Two types of MSCs of the head and neck region (mucosa [mMSC] and parotid gland [pMSC]) were isolated, cultured and exposed to single radiation dosages of 2 Gy/day up to 10 days. Effects on morphology, colony forming ability, apoptosis, chemokine receptor expression, cytokine secretion, and cell migration were analyzed. RESULTS Although MSC preserved MSC-specific regenerative abilities and immunomodulatory properties following irradiation in our in vitro model, we found a deleterious impact on colony forming ability, especially in pMSC. CONCLUSIONS MSC exhibited robustness and activation upon radiation for the support of tissue regeneration, but lost their potential to replicate, thus possibly leading to depletion of the local MSC-pool after irradiation.
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Affiliation(s)
- Jennifer L Spiegel
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Mario Hambrecht
- Department of Otorhinolaryngology, Universitaetsmedizin Goettingen, University Medical Center Goettingen, Goettingen, Germany
| | - Vera Kohlbauer
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Frank Haubner
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Friedrich Ihler
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany.,German Center for Vertigo and Balance Disorders, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Martin Canis
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Arndt F Schilling
- Department of Trauma Surgery, Orthopedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Kai O Böker
- Department of Trauma Surgery, Orthopedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Ralf Dressel
- Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, Goettingen, Germany
| | - Katrin Streckfuss-Bömeke
- Department of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Goettingen, Goettingen, Germany
| | - Mark Jakob
- Department of Otorhinolaryngology, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
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13
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Bohoun CA, Goto T, Morisako H, Nagahama A, Tanoue Y, Ohata K. Skull Base Dural Repair Using Autologous Fat as a Dural Substitute: An Efficient Technique. World Neurosurg 2019; 127:e896-e900. [PMID: 30959259 DOI: 10.1016/j.wneu.2019.03.293] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 11/25/2022]
Abstract
BACKGROUND Dural repair during skull base approaches remains challenging, especially in the presence of significant defects. The autologous fat has become an alternative to various substitute materials being used previously. We report here our experience and technique for the repair of notable skull base dural defects using autologous fat as a dural substitute. METHODS Over a period of 5 years, 71 consecutive patients operated on for skull base pathologies with an important intraoperative dural defect repaired using autologous fat tissue as replacement material were reviewed. The graft, withdrawn from the abdomen or thigh, was flattened and applied to the defect. The clinical findings and outcomes were assessed. RESULTS Main pathologies included schwannomas (45%) and meningiomas (35.21%), with no side predilection. Surgical approaches such as transcondylar fossa, suboccipital, and frontotemporal approaches were used. Dural defects were mainly located in the posterior (73.2%) and middle cranial fossae (25.4%). No harvesting site-related complication occurred. In 7 cases, transitory subcutaneous fluid collection spontaneously resorbing after 8 days to 2 months was observed. No external cerebrospinal fluid leakage, infection, or other complication was noted during the following period. CONCLUSIONS Dural repair can be effectively and durably achieved using autologous fat graft as a dural substitute during skull base approaches, even in cases of extended defects. The observed characteristics of the fat graft along with the achieved outcome make it an ideal dural substitute.
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Affiliation(s)
- Christian A Bohoun
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Takeo Goto
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroki Morisako
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsufumi Nagahama
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuta Tanoue
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kenji Ohata
- Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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14
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Impact of X-ray Exposure on the Proliferation and Differentiation of Human Pre-Adipocytes. Int J Mol Sci 2018; 19:ijms19092717. [PMID: 30208657 PMCID: PMC6163807 DOI: 10.3390/ijms19092717] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/06/2018] [Accepted: 09/07/2018] [Indexed: 01/20/2023] Open
Abstract
Radiotherapy is a widely used treatment option for cancer patients as well as for patients with musculoskeletal disorders. Adipocytes, the dominant cell type of adipose tissue, are known to constitute an active part of the tumor microenvironment. Moreover, adipocytes support inflammatory processes and cartilage degradation in chronic inflammatory diseases, i.e., rheumatoid and osteoarthritis. Since the production of inflammatory factors is linked to their differentiation stages, we set out to explore the radiation response of pre-adipocytes that may influence their inflammatory potential and differentiation capacity. This is the first study investigating the effects of X-ray irradiation on the proliferation and differentiation capacity of human primary pre-adipocytes, in comparison to Simpson–Golabi–Behmel Syndrome (SGBS) pre-adipocytes, an often-used in vitro model of human primary pre-adipocytes. Our results demonstrate a dose-dependent reduction of the proliferation capacity for both cell strains, whereas the potential for differentiation was mostly unaffected by irradiation. The expression of markers of adipogenic development, such as transcription factors (PPARγ, C/EBPα and C/EBPβ), as well as the release of adipokines (visfatin, adiponectin and leptin) were not significantly changed upon irradiation. However, after irradiation with high X-ray doses, an increased lipid accumulation was observed, which suggests a radiation-induced response of adipocytes related to inflammation. Our results indicate that pre-adipocytes are radio-resistant, and it remains to be elucidated whether this holds true for the overall inflammatory response of adipocytes upon irradiation.
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15
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Rühle A, Xia O, Perez RL, Trinh T, Richter W, Sarnowska A, Wuchter P, Debus J, Saffrich R, Huber PE, Nicolay NH. The Radiation Resistance of Human Multipotent Mesenchymal Stromal Cells Is Independent of Their Tissue of Origin. Int J Radiat Oncol Biol Phys 2018; 100:1259-1269. [PMID: 29452769 DOI: 10.1016/j.ijrobp.2018.01.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/10/2017] [Accepted: 01/03/2018] [Indexed: 12/17/2022]
Abstract
PURPOSE Human mesenchymal stromal cells (MSCs) may aid the regeneration of ionizing radiation (IR)-induced tissue damage. They can be harvested from different tissues for clinical purposes; however, the role of the tissue source on the radiation response of human MSCs remains unknown. METHODS AND MATERIALS Human MSCs were isolated from adipose tissue, bone marrow, and umbilical cord, and cellular survival, proliferation, and apoptosis were measured after irradiation. The influence of IR on the defining functions of MSCs was assessed, and cell morphology, surface marker expression, and the differentiation potential were examined. Western blot analyses were performed to assess the activation of DNA damage signaling and repair pathways. RESULTS MSCs from adipose tissue, bone marrow, and umbilical cord exhibited a relative radioresistance independent of their tissue of origin. Defining properties including cellular adhesion and surface marker expression were preserved, and irradiated MSCs maintained their potential for multilineage differentiation irrespective of their tissue source. Analysis of activated DNA damage recognition and repair pathways demonstrated an efficient repair of IR-induced DNA double-strand breaks in MSCs from different tissues, thereby influencing the induction of apoptosis. CONCLUSIONS These data show for the first time that MSCs are resistant to IR and largely preserve their defining functions after irradiation irrespective of their tissue of origin. Efficient repair of IR-induced DNA double-strand breaks and consecutive reduction of apoptosis induction may contribute to the tissue-independent radiation resistance of MSCs.
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Affiliation(s)
- Alexander Rühle
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Oliver Xia
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ramon Lopez Perez
- Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thuy Trinh
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Wiltrud Richter
- Research Center for Experimental Orthopedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Anna Sarnowska
- Translative Platform for Regenerative Medicine, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
| | - Patrick Wuchter
- Institute of Transfusion Medicine and Immunology, German Red Cross Donor Blood Service Baden-Württemberg-Hessen, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Jürgen Debus
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rainer Saffrich
- Institute of Transfusion Medicine and Immunology, German Red Cross Donor Blood Service Baden-Württemberg-Hessen, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Department of Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter E Huber
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nils H Nicolay
- Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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