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Slautin V, Ivanov V, Bugakov A, Chernysheva A, Gavrilov I, Maklakova I, Bazarnyi V, Grebnev D, Kovtun O. Preconditioning with Rapamycin Improves Therapeutic Potential of Placenta-Derived Mesenchymal Stem Cells in Mouse Model of Hematopoietic Acute Radiation Syndrome. Int J Mol Sci 2025; 26:4804. [PMID: 40429945 PMCID: PMC12111928 DOI: 10.3390/ijms26104804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Acute radiation syndrome (ARS) results from high-dose ionizing radiation (IR) exposure, with bone marrow (BM) being highly susceptible due to its proliferative activity. BM injury causes pancytopenia, leading to infections, anemia, and bleeding. Mesenchymal stem cells (MSCs) hold promise for ARS treatment because of their immunomodulatory, anti-inflammatory, and regenerative properties. However, challenges such as replicative senescence, poor survival, and engraftment in irradiated microenvironments limit their efficacy. This study evaluated rapamycin-preconditioned placenta-derived MSCs (rPD-MSCs) in a mouse ARS model. Rapamycin was selected for preconditioning due to its ability to induce autophagy and modulate cytokine secretion. We assessed rapamycin-dependent modulation of autophagy-related genes and proteins, as well as hematopoietic cytokines secretion in PD-MSCs, and evaluated morphological changes in blood and BM at 7 and 21 days post-irradiation in ICR/CD1 mice. Preconditioning with rapamycin alters the secretion of granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), and Fms-related tyrosine kinase 3 ligand (Flt3LG) in PD-MSCs without affecting cell viability. rPD-MSCs better enhance hematopoietic recovery, restore bone marrow cellularity, and increase peripheral blood cell counts by elevating the secretion of hematopoietic cytokines compared to non-preconditioned cells. These results highlight rapamycin preconditioning as a promising strategy to enhance MSCs therapeutic potential for ARS, supporting further preclinical and clinical exploration.
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Affiliation(s)
- Vasilii Slautin
- Laboratory of Enteric Viral Infections, Federal Scientific Research Institute of Viral Infections «Virome», Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Yekaterinburg 620030, Russia
| | - Vladislav Ivanov
- Department of Pathophysiology, Ural State Medical University, Yekaterinburg 620014, Russia; (V.I.); (A.B.); (D.G.); (O.K.)
| | - Alexandr Bugakov
- Department of Pathophysiology, Ural State Medical University, Yekaterinburg 620014, Russia; (V.I.); (A.B.); (D.G.); (O.K.)
| | - Anna Chernysheva
- Laboratory of Respiratory Viral Infections, Federal Scientific Research Institute of Viral Infections «Virome», Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Yekaterinburg 620030, Russia;
| | - Ilya Gavrilov
- Department of Pathophysiology, Ural State Medical University, Yekaterinburg 620014, Russia; (V.I.); (A.B.); (D.G.); (O.K.)
- Laboratory of Anti-Aging Technologies, Institute of Medical Cell Technologies, Yekaterinburg 620026, Russia;
| | - Irina Maklakova
- Laboratory of Anti-Aging Technologies, Institute of Medical Cell Technologies, Yekaterinburg 620026, Russia;
- Department of Physiology, Ural State Medical University, Yekaterinburg 620014, Russia
| | - Vladimir Bazarnyi
- Department of Medical Microbiology and Clinical Laboratory Diagnostics, Ural State Medical University, Yekaterinburg 620014, Russia;
| | - Dmitry Grebnev
- Department of Pathophysiology, Ural State Medical University, Yekaterinburg 620014, Russia; (V.I.); (A.B.); (D.G.); (O.K.)
- Laboratory of Anti-Aging Technologies, Institute of Medical Cell Technologies, Yekaterinburg 620026, Russia;
| | - Olga Kovtun
- Department of Pathophysiology, Ural State Medical University, Yekaterinburg 620014, Russia; (V.I.); (A.B.); (D.G.); (O.K.)
- Department of Physiology, Ural State Medical University, Yekaterinburg 620014, Russia
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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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Christy BA, Herzig MC, Wu X, Mohammadipoor A, McDaniel JS, Bynum JA. Cell Therapies for Acute Radiation Syndrome. Int J Mol Sci 2024; 25:6973. [PMID: 39000080 PMCID: PMC11241804 DOI: 10.3390/ijms25136973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/14/2024] [Accepted: 06/21/2024] [Indexed: 07/16/2024] Open
Abstract
The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in H-ARS (hematopoietic acute radiation syndrome), which is characterized by damage to the hematopoietic system; higher doses result in further damage to the gastrointestinal and nervous systems. Only a few medical countermeasures for ARS are currently available and approved for use, although others are in development. Cell therapies (cells or products produced by cells) are complex therapeutics that show promise for the treatment of radiation injury and have been shown to reduce mortality and morbidity in animal models. Since clinical trials for ARS cannot be ethically conducted, animal testing is extremely important. Here, we describe cell therapies that have been tested in animal models. Both cells and cell products appear to promote survival and lessen tissue damage after whole-body irradiation, although the mechanisms are not clear. Because radiation exposure often occurs in conjunction with other traumatic injuries, animal models of combined injury involving radiation and future countermeasure testing for these complex medical problems are also discussed.
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Affiliation(s)
- Barbara A Christy
- Blood and Shock Resuscitation, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Maryanne C Herzig
- Blood and Shock Resuscitation, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
| | - Xiaowu Wu
- Blood and Shock Resuscitation, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
| | - Arezoo Mohammadipoor
- Hemorrhage and Vascular Dysfunction, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
| | - Jennifer S McDaniel
- Blood and Shock Resuscitation, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
| | - James A Bynum
- Blood and Shock Resuscitation, US Army Institute of Surgical Research, Joint Base San Antonio, Fort Sam Houston, TX 78234, USA
- Department of Surgery, UT Health San Antonio, San Antonio, TX 78229, USA
- Trauma Research and Combat Casualty Care Collaborative, UT Health San Antonio, San Antonio, TX 78229, USA
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Habata S, Mamillapalli R, Ucar A, Taylor HS. Donor Mesenchymal Stem Cells Program Bone Marrow, Altering Macrophages, and Suppressing Endometriosis in Mice. Stem Cells Int 2023; 2023:1598127. [PMID: 37545483 PMCID: PMC10403325 DOI: 10.1155/2023/1598127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 08/08/2023] Open
Abstract
Endometriosis is a chronic inflammatory gynecological disorder regulated by estrogen and characterized by the growth of endometrial tissue outside the uterus. We have previously demonstrated that mesenchymal stem cells (MSCs) contribute directly to endometriosis. Here, we investigated an indirect effect; we hypothesized that MSCs may also impact the bone marrow (BM) by regulating bone marrow-derived inflammatory cells. Endometriosis was induced in mice by transplanting uterine tissue into recipient mice followed by BM transplant. Control or MSC conditioned BM was injected retro-orbitally. Direct administration of MSCs outside of the setting of BM conditioning did not alter endometriosis. Coculture of an undifferentiated macrophage cell line with MSCs in vitro led to a reduction of M1 and increased M2 macrophages as determined by fluorescence-activated cell sorting and western blot. Conditioning of BM with MSCs and transplantation into a mouse model inhibited endometriotic lesion development and reduced lesion volume by sevenfold compared to BM transplant without MSCs conditioning. Immunohistochemistry and immunofluorescence showed that MSC conditioned BM reduced the infiltration of macrophages and neutrophils into endometriotic lesions by twofold and decreased the proportion of M1 compared to M2 macrophages, reducing inflammation and likely promoting tissue repair. Expression of several inflammatory markers measured by quantitative real-time polymerase chain reaction, including tumor necrosis factor alpha and CXCR4, was decreased in the conditioned BM. Donor MSCs were not detected in recipient BM or endometriotic lesions, suggesting that MSCs actively program the transplanted BM. Taken together, these data show that individual characteristics of BM have an unexpected role in the development of endometriosis. BM remodeling and alterations in the inflammatory response are also potential treatments for endometriosis. Identification of the molecular basis for BM programing by MSCs will lead to a better understanding of the immune system contribution to this disease and may lead to new therapeutic targets for endometriosis.
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Affiliation(s)
- Shutaro Habata
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA
| | - Abdullah Ucar
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA
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Pre-Administration of PLX-R18 Cells Protects Mice from Radiation-Induced Hematopoietic Failure and Lethality. Genes (Basel) 2022; 13:genes13101756. [PMID: 36292639 PMCID: PMC9601513 DOI: 10.3390/genes13101756] [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: 09/02/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/23/2022] Open
Abstract
Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded (PLX)-R18 is a 3D-expanded placenta-derived stromal cell product designated for the treatment of hematological disorders. These cells have been shown in vitro to secrete hematopoietic proteins, to stimulate colony formation, and to induce bone marrow migration. Previous studies in mice showed that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting hematopoiesis related proteins to enhance reconstitution of the hematopoietic system. We assessed the potential effect of prophylactic PLX-R18 treatment on H-ARS. PLX-R18 cells were administered intramuscularly to C57BL/6 mice, −1 and 3 days after (LD70/30) total body irradiation. PLX R18 treatment significantly increased survival after irradiation (p < 0.0005). In addition, peripheral blood and bone marrow (BM) cellularity were monitored at several time points up to 30 days. PLX-R18 treatment significantly increased the number of colony-forming hematopoietic progenitors in the femoral BM and significantly raised peripheral blood cellularity. PLX-R18 administration attenuated biomarkers of bone marrow aplasia (EPO, FLT3L), sepsis (SAA), and systemic inflammation (sP-selectin and E-selectin) and attenuated radiation-induced inflammatory cytokines/chemokines and growth factors, including G-CSF, MIP-1a, MIP-1b, IL-2, IL-6 and MCP-1, In addition, PLX-R18 also ameliorated radiation-induced upregulation of pAKT. Taken together, prophylactic PLX-R18 administration may serve as a protection measure, mitigating bone marrow failure symptoms and systemic inflammation in the H-ARS model.
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Maurya DK, Bandekar M, Sandur SK. Soluble factors secreted by human Wharton’s jelly mesenchymal stromal/stem cells exhibit therapeutic radioprotection: A mechanistic study with integrating network biology. World J Stem Cells 2022; 14:347-361. [PMID: 35722198 PMCID: PMC9157603 DOI: 10.4252/wjsc.v14.i5.347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/25/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells (hWJ-MSCs) have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them. Recently, we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential. This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.
AIM To understand the radioprotective mechanism of soluble factors secreted by hWJ-MSCs and identification of their unique genes.
METHODS Propidium iodide staining, endogenous spleen colony-forming assay, and survival study were carried out for radioprotection studies. Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation. Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells, embryonic stem cells, and human fibroblasts. Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.
RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes. WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes. Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection. Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin (IL)1-α, IL1-β, IL-6, CXCL3, CXCL5, CXCL8, CXCL2, CCL2, FLT-1, and IL-33. It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources. Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.
CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims.
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Affiliation(s)
- Dharmendra Kumar Maurya
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Mayuri Bandekar
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India
- University of Mumbai, Kalina, Mumbai 400098, India
| | - Santosh Kumar Sandur
- Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
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7
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Teli P, Kale V, Vaidya A. Mesenchymal stromal cells-derived secretome protects Neuro-2a cells from oxidative stress-induced loss of neurogenesis. Exp Neurol 2022; 354:114107. [PMID: 35551901 DOI: 10.1016/j.expneurol.2022.114107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/20/2022] [Accepted: 05/02/2022] [Indexed: 12/01/2022]
Abstract
Neurodegenerative diseases (ND) are characterized by debilitating medical conditions that principally affect the neuronal cells in the human brain. One of the major reasons that there are no effective drugs for the treatment of ND is because researchers face technical challenges while conducting studies to understand the molecular mechanism behind ND. Although various studies have established in vitro neurodegenerative model systems, we feel that these model systems are not physiologically relevant, as they do not mimic the in vivo situation of chronic insult. Therefore, the primary aim of this study was to establish an in vitro neurodegenerative model system by inducing oxidative stress in such a way that the neuronal cells remain viable, but lose their structural and functional characteristics. Using a murine neuroblastoma cell line, Neuro-2a, we demonstrate that induction of oxidative stress significantly affects various neurite outgrowth parameters and reduces the expression of neuronal and autophagy markers without causing apoptosis in them. Previously, we have discussed the possible therapeutic applications of mesenchymal stromal cells (MSCs) and their secretome in the treatment of ND. Here, using two distinct approaches, we show that when Neuro-2a cells subjected to oxidative stress are exposed to MSC-derived conditioned medium (secretome), they exhibit a significant improvement in various neuronal parameters and in the expression of neuronal markers. Overall, our findings support the salutary role of MSC-derived secretome in rescuing the oxidative stress-induced loss of neurogenesis using a physiologically relevant in vitro model system. Our data underscore the propensity of the MSC-secretome in reversing ND.
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Affiliation(s)
- Prajakta Teli
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune 412115, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 412115, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune 412115, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 412115, India
| | - Anuradha Vaidya
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune 412115, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 412115, India.
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Gotzhein F, Aranyossy T, Thielecke L, Sonntag T, Thaden V, Fehse B, Müller I, Glauche I, Cornils K. The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age. Int J Mol Sci 2022; 23:ijms23063160. [PMID: 35328579 PMCID: PMC8948791 DOI: 10.3390/ijms23063160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 12/10/2022] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopulations contribute to the dynamics of the reconstitution process and on whether and how these contributions are altered with age. In a murine model of HSCT, we therefore simultaneously tracked different cultivated and transduced hematopoietic stem and progenitor cell (HSPC) populations using a multicolor-coded barcode system (BC32). We studied a series of age-matched and age-mismatched transplantations and compared the influence of age on the reconstitution dynamics. We show that reconstitution from these cultured and assembled grafts was substantially driven by hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) independent of age. The reconstitution patterns were polyclonal and stable in all age groups independently of the variability between individual animals, with higher output rates from MPPs than from HSCs. Our experiments suggest that the dynamics of reconstitution and the contribution of cultured and individually transduced HSPC subpopulations are largely independent of age. Our findings support ongoing efforts to expand the application of HSCT in older individuals as a promising strategy to combat hematological diseases, including gene therapy applications.
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Affiliation(s)
- Frauke Gotzhein
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (F.G.); (V.T.); (I.M.)
- Research Institute Children’s Cancer Center Hamburg, 20251 Hamburg, Germany
| | - Tim Aranyossy
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (T.A.); (T.S.); (B.F.)
| | - Lars Thielecke
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.T.); (I.G.)
| | - Tanja Sonntag
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (T.A.); (T.S.); (B.F.)
| | - Vanessa Thaden
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (F.G.); (V.T.); (I.M.)
- Research Institute Children’s Cancer Center Hamburg, 20251 Hamburg, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (T.A.); (T.S.); (B.F.)
| | - Ingo Müller
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (F.G.); (V.T.); (I.M.)
- Research Institute Children’s Cancer Center Hamburg, 20251 Hamburg, Germany
| | - Ingmar Glauche
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.T.); (I.G.)
| | - Kerstin Cornils
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (F.G.); (V.T.); (I.M.)
- Research Institute Children’s Cancer Center Hamburg, 20251 Hamburg, Germany
- Correspondence: ; Tel.: +49-40-7410-52721
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Chinnadurai R, Bates PD, Kunugi KA, Nickel KP, DeWerd LA, Capitini CM, Galipeau J, Kimple RJ. Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease. Front Immunol 2021; 12:708950. [PMID: 34386012 PMCID: PMC8352793 DOI: 10.3389/fimmu.2021.708950] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/01/2021] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are being tested as a cell therapy in clinical trials for dozens of inflammatory disorders, with varying levels of efficacy reported. Suitable and robust preclinical animal models for testing the safety and efficacy of different types of MSC products before use in clinical trials are rare. We here introduce two highly robust animal models of immune pathology: 1) acute radiation syndrome (ARS) and 2) graft versus host disease (GvHD), in conjunction with studying the immunomodulatory effect of well-characterized Interferon gamma (IFNγ) primed bone marrow derived MSCs. The animal model of ARS is based on clinical grade dosimetry precision and bioluminescence imaging. We found that allogeneic MSCs exhibit lower persistence in naïve compared to irradiated animals, and that intraperitoneal infusion of IFNγ prelicensed allogeneic MSCs protected animals from radiation induced lethality by day 30. In direct comparison, we also investigated the effect of IFNγ prelicensed allogeneic MSCs in modulating acute GvHD in an animal model of MHC major mismatched bone marrow transplantation. Infusion of IFNγ prelicensed allogeneic MSCs failed to mitigate acute GvHD. Altogether our results demonstrate that infused IFNγ prelicensed allogeneic MSCs protect against lethality from ARS, but not GvHD, thus providing important insights on the dichotomy of IFNγ prelicensed allogenic MSCs in well characterized and robust animal models of acute tissue injury.
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Affiliation(s)
- Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
| | - Paul D Bates
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Keith A Kunugi
- Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Kwangok P Nickel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Larry A DeWerd
- Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Christian M Capitini
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.,University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jacques Galipeau
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.,Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Randall J Kimple
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.,University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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10
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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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11
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Gorodetsky R, Aicher WK. Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies. Int J Mol Sci 2021; 22:5302. [PMID: 34069909 PMCID: PMC8157571 DOI: 10.3390/ijms22105302] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.
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Affiliation(s)
- Raphael Gorodetsky
- Biotechnology and Radiobiology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Wilhelm K. Aicher
- Center of Medical Research, Department of Urology at UKT, Eberhard-Karls-University, 72076 Tuebingen, Germany
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12
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Extracellular vesicles isolated from mesenchymal stromal cells primed with neurotrophic factors and signaling modifiers as potential therapeutics for neurodegenerative diseases. Curr Res Transl Med 2021; 69:103286. [DOI: 10.1016/j.retram.2021.103286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022]
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13
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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: 7] [Impact Index Per Article: 1.8] [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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14
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Therapeutic Applications of Stem Cells and Extracellular Vesicles in Emergency Care: Futuristic Perspectives. Stem Cell Rev Rep 2021; 17:390-410. [PMID: 32839921 PMCID: PMC7444453 DOI: 10.1007/s12015-020-10029-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Regenerative medicine (RM) is an interdisciplinary field that aims to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. Stem cells, which are undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered as an important part of the RM approaches. They have been widely investigated in preclinical and clinical studies for therapeutic purposes. Extracellular vesicles (EVs) are the vital mediators that regulate the therapeutic effects of stem cells. Besides, they carry various types of cargo between cells which make them a significant contributor of intercellular communication. Given their role in physiological and pathological conditions in living cells, EVs are considered as a new therapeutic alternative solution for a variety of diseases in which there is a high unmet clinical need. This review aims to summarize and identify therapeutic potential of stem cells and EVs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, acute respiratory distress syndrome and burn injury. Diseases that affect militaries or societies including acute radiation syndrome, sepsis and viral pandemics such as novel coronavirus disease 2019 are also discussed. Additionally, featuring and problematic issues that hamper clinical translation of stem cells and EVs are debated in a comparative manner with a futuristic perspective. Graphical Abstract.
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15
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Rühle A, Grosu AL, Nicolay NH. The Particle Radiobiology of Multipotent Mesenchymal Stromal Cells: A Key to Mitigating Radiation-Induced Tissue Toxicities in Cancer Treatment and Beyond? Front Oncol 2021; 11:616831. [PMID: 33912447 PMCID: PMC8071947 DOI: 10.3389/fonc.2021.616831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent stromal cells that have gained attention for the treatment of irradiation-induced normal tissue toxicities due to their regenerative abilities. As the vast majority of studies focused on the effects of MSCs for photon irradiation-induced toxicities, little is known about the regenerative abilities of MSCs for particle irradiation-induced tissue damage or the effects of particle irradiation on the stem cell characteristics of MSCs themselves. MSC-based therapies may help treat particle irradiation-related tissue lesions in the context of cancer radiotherapy. As the number of clinical proton therapy centers is increasing, there is a need to decidedly investigate MSC-based treatments for particle irradiation-induced sequelae. Furthermore, therapies with MSCs or MSC-derived exosomes may also become a useful tool for manned space exploration or after radiation accidents and nuclear terrorism. However, such treatments require an in-depth knowledge about the effects of particle radiation on MSCs and the effects of MSCs on particle radiation-injured tissues. Here, the existing body of evidence regarding the particle radiobiology of MSCs as well as regarding MSC-based treatments for some typical particle irradiation-induced toxicities is presented and critically discussed.
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Affiliation(s)
- Alexander Rühle
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany.,Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany
| | - Nils H Nicolay
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany.,Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
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16
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Chinnadurai R, Forsberg MH, Kink JA, Hematti P, Capitini CM. Use of MSCs and MSC-educated macrophages to mitigate hematopoietic acute radiation syndrome. CURRENT STEM CELL REPORTS 2020; 6:77-85. [PMID: 32944493 DOI: 10.1007/s40778-020-00176-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Innovative and minimally toxic treatment approaches are sorely needed for the prevention and treatment of hematopoietic acute radiation syndrome (H-ARS). Cell therapies have been increasingly studied for their potential use as countermeasures for accidental and intentional ionizing radiation exposures which can lead to fatal ARS. Mesenchymal stem/stromal cells (MSCs) are a cell therapy that have shown promising results in preclinical studies of ARS, and are being developed in clinical trials specifically for H-ARS. MSCs, MSC-educated macrophages (MEMs) and MSC-exosome educated macrophages (EEMs) all have the potential to be used as adoptive cell therapies for H-ARS. Here we review how MSCs have been reported to mitigate inflammation from radiation injury while also stimulating hematopoiesis during ARS. Recent findings We discuss emerging work with immune cell subsets educated by MSCs, including MEMs and EEMs, in promoting hematopoiesis in xenogeneic models of ARS. We also discuss the first placental-derived MSC product to enter phase I trials, PLX-R18, and the challenges faced by bringing MSC and other cell therapies into the clinic for treating ARS. Summary Although MSCs, MEMs and EEMs are potential cell therapy candidates in promoting hematopoietic HRS, challenges persist in translational clinical development of these products to the clinic. Whether any of these cellular therapies will be sufficient as stand-alone therapies to mitigate H-ARS or if they will be a bridging therapy that insures survival until a curative allogeneic hematopoietic stem cell transplant can be performed are the key questions that will have to be answered.
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Affiliation(s)
- Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA
| | - Matthew H Forsberg
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - John A Kink
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Christian M Capitini
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
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17
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Abstract
Radiation therapy can cause haematopoietic damage, and mesenchymal stem cells (MSCs) derived extracellular vesicles (EVs) have been shown to reverse this damage. Our previous research showed that dental pulp stem cells (DPSCs) have a strong proliferation capacity and can produce abundant amounts of EVs to meet the requirements for use in vitro and in vivo. DPSCs derived EVs (DPSCs-EVs) are evaluated for their effect on reducing haematopoietic damage. Haematopoietic stem cell (HSC) numbers and function were assessed by flow cytometry, peripheral blood cell counts, histology and bone marrow transplantation. Epidermal growth factor (EGF) was used as a reference for evaluating the efficiency of EVs. miRNA microarray was employed to find out the changes of miRNA expression after cells being irradiated in vivo and the role they may play in mitigation the radiation caused injury. We observed the effect of DPSCs-EVs on promoting proliferation and inhibiting apoptosis of human umbilical vein endothelial cells (HUVECs) and FDC-P1 cells in vitro. We found that DPSCs-EVs and EGF could comparably inhibit the decrease in WBC, CFU count and KSL cells in vivo. We also verified that EVs could accelerate the recovery of long-term HSCs. In summary, DPSCs-EVs showed an apoptosis resistant effect on HUVECs and FDC-P1 cells after radiation injury in vitro. EVs from DPSCs were comparable to EGF in their ability to regulate haematopoietic regeneration after radiation injury in vivo. Radiation could alter the expression of some miRNAs in bone marrow cells, and EVs could correct these changes to some extent.
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18
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Forsberg MH, Kink JA, Hematti P, Capitini CM. Mesenchymal Stromal Cells and Exosomes: Progress and Challenges. Front Cell Dev Biol 2020; 8:665. [PMID: 32766255 PMCID: PMC7379234 DOI: 10.3389/fcell.2020.00665] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022] Open
Abstract
Due to their robust immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) have been used as a cellular therapy for a number of human diseases. Part of the mechanism of action of MSCs is the production of extracellular vesicles (EVs) that contain proteins, nucleic acids, and lipids that transmit signals to recipient cells that change their biologic behavior. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our present understanding of exosomes; how they exert their effects on target cells, and how they are differentiated from other EVs. The current treatment paradigm for acute radiation syndrome (ARS) is discussed, and how MSCs and MSC derived exosomes are emerging as treatment options for treating patients after radiation exposure. Other conditions such as graft-versus-host disease and cardiovascular disease/stroke are discussed as examples to highlight the immunomodulatory and regenerative capacity of MSC-exosomes. Finally, a consideration is given to how these cell-based therapies could possibly be deployed in the event of a catastrophic radiation exposure event.
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Affiliation(s)
- Matthew H Forsberg
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - John A Kink
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Peiman Hematti
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Christian M Capitini
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
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19
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Cavallero S, Riccobono D, Drouet M, François S. MSC-Derived Extracellular Vesicles: New Emergency Treatment to Limit the Development of Radiation-Induced Hematopoietic Syndrome? HEALTH PHYSICS 2020; 119:21-36. [PMID: 32384375 DOI: 10.1097/hp.0000000000001264] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Nuclear accidents or acts of terrorism involving radioactive sources might lead to mass casualties irradiation. The hematopoietic system is one of the most critical and radiation-sensitive tissues because the limited life span of blood cells requires the continuous division of hematopoietic stem cells (HSCs) into the bone marrow. The radiation-induced hematopoietic syndrome, RI-HS, is an impairment of the hematopoiesis that will result in pancytopenia of various degrees. In fact, treatment with granulocyte-colony stimulating factor (G-CSF) is considered as a valuable adjunct to treatment controls in some irradiated patients. Nevertheless, these overexposed patients with bone marrow suppression have minimal medullary territories that do not allow complete recovery of hematopoiesis but lead to significant immunoreactivity following allogeneic hematopoietic stem cell transplantation (HSCT). The high morbidity and mortality of these overexposed patients is a reminder of the lack of effective treatment for hematopoietic syndrome. During the last 20 y, a therapeutic approach for mesenchymal stem cells (MSC) has been proposed for the management of accidentally irradiated victims. Many preclinical animal studies have shown that MSC, mainly by their secretory activity, in particular extracellular vesicles (EVs), contribute to the control of inflammation and promote regeneration of tissues by accelerating angiogenesis and re-epithelialization processes. Therefore, we investigated the potential effect of EVs on the reduction of early bone marrow ionization toxicity, early anti-apoptotic therapy, and vascular protection in the RI-HS model. The main purpose is to propose an innovative treatment of non-patient-specific RI-HS emergency treatment in order to limit allogeneic HSC.
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Affiliation(s)
- Sophie Cavallero
- DEBR/Rad Unit/ Biomedical Research Institute of the Armed Forces, 1 place du général Valérie André, 91223 Brétigny sur orge, France
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20
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Budgude P, Kale V, Vaidya A. Mesenchymal stromal cell‐derived extracellular vesicles as cell‐free biologics for the ex vivo expansion of hematopoietic stem cells. Cell Biol Int 2020; 44:1078-1102. [DOI: 10.1002/cbin.11313] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 01/31/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Pallavi Budgude
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
| | - Anuradha Vaidya
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
- Symbiosis School of Biological SciencesSymbiosis International (Deemed University) Pune 412115 India
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21
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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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22
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Kink JA, Forsberg MH, Reshetylo S, Besharat S, Childs CJ, Pederson JD, Gendron-Fitzpatrick A, Graham M, Bates PD, Schmuck EG, Raval A, Hematti P, Capitini CM. Macrophages Educated with Exosomes from Primed Mesenchymal Stem Cells Treat Acute Radiation Syndrome by Promoting Hematopoietic Recovery. Biol Blood Marrow Transplant 2019; 25:2124-2133. [PMID: 31394269 DOI: 10.1016/j.bbmt.2019.07.026] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 07/17/2019] [Accepted: 07/23/2019] [Indexed: 12/28/2022]
Abstract
In the setting of radiation-induced trauma, exposure to high levels of radiation can cause an acute radiation syndrome (ARS) causing bone marrow (BM) failure, leading to life-threatening infections, anemia, and thrombocytopenia. We have previously shown that human macrophages educated with human mesenchymal stem cells (MSCs) by coculture can significantly enhance survival of mice exposed to lethal irradiation. In this study, we investigated whether exosomes isolated from MSCs could replace direct coculture with MSCs to generate exosome educated macrophages (EEMs). Functionally unique phenotypes were observed by educating macrophages with exosomes from MSCs (EEMs) primed with bacterial lipopolysaccharide (LPS) at different concentrations (LPS-low EEMs or LPS-high EEMs). LPS-high EEMs were significantly more effective than uneducated macrophages, MSCs, EEMs, or LPS-low EEMs in extending survival after lethal ARS in vivo. Moreover, LPS-high EEMs significantly reduced clinical signs of radiation injury and restored hematopoietic tissue in the BM and spleen as determined by complete blood counts and histology. LPS-high EEMs showed significant increases in gene expression of STAT3, secretion of cytokines like IL-10 and IL-15, and production of growth factors like FLT-3L. LPS-EEMs also showed increased phagocytic activity, which may aid with tissue remodeling. LPS-high EEMs have the potential to be an effective cellular therapy for the management of ARS.
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Affiliation(s)
- John A Kink
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Matthew H Forsberg
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sofiya Reshetylo
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Soroush Besharat
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Charlie J Childs
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jessica D Pederson
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Annette Gendron-Fitzpatrick
- The Comparative Pathology Laboratory, Research Animal Resource Center, University of Wisconsin, Madison, Wisconsin
| | - Melissa Graham
- The Comparative Pathology Laboratory, Research Animal Resource Center, University of Wisconsin, Madison, Wisconsin
| | - Paul D Bates
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Eric G Schmuck
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Amish Raval
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
| | - Christian M Capitini
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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23
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Caplan H, Olson SD, Kumar A, George M, Prabhakara KS, Wenzel P, Bedi S, Toledano-Furman NE, Triolo F, Kamhieh-Milz J, Moll G, Cox CS. Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application. Front Immunol 2019; 10:1645. [PMID: 31417542 PMCID: PMC6685059 DOI: 10.3389/fimmu.2019.01645] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022] Open
Abstract
For several decades, multipotent mesenchymal stromal cells (MSCs) have been extensively studied for their therapeutic potential across a wide range of diseases. In the preclinical setting, MSCs demonstrate consistent ability to promote tissue healing, down-regulate excessive inflammation and improve outcomes in animal models. Several proposed mechanisms of action have been posited and demonstrated across an array of in vitro models. However, translation into clinical practice has proven considerably more difficult. A number of prominent well-funded late-phase clinical trials have failed, thus calling out for new efforts to optimize product delivery in the clinical setting. In this review, we discuss novel topics critical to the successful translation of MSCs from pre-clinical to clinical applications. In particular, we focus on the major routes of cell delivery, aspects related to hemocompatibility, and potential safety concerns associated with MSC therapy in the different settings.
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Affiliation(s)
- Henry Caplan
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Scott D. Olson
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Akshita Kumar
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Mitchell George
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Karthik S. Prabhakara
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Pamela Wenzel
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Supinder Bedi
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Naama E. Toledano-Furman
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Fabio Triolo
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Julian Kamhieh-Milz
- Department of Transfusion Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Guido Moll
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Charles S. Cox
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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24
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Yamaguchi M, Hirouchi T, Yoshioka H, Watanabe J, Kashiwakura I. Diverse functions of the thrombopoietin receptor agonist romiplostim rescue individuals exposed to lethal radiation. Free Radic Biol Med 2019; 136:60-75. [PMID: 30926566 DOI: 10.1016/j.freeradbiomed.2019.03.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 01/03/2023]
Abstract
In cases of radiological accidents, especially victims exposed to high-dose ionizing radiation, the administration of appropriate approved pharmaceutical drugs is the most rapid medical treatment. However, currently, there are no suitable candidates. The thrombopoietin receptor (TPOR) agonist romiplostim (RP) is a therapeutic agent for immune thrombocytopenia and has potential to respond to such victims. Here, we show that RP administration in mice exposed to lethal-dose radiation leads not only to the promotion of haematopoiesis in multiple organs, including the lungs but also a reduction in damage to organs and cells. RP also causes a rapid increase in the number of mesenchymal stem cells in the spleen. In addition, RP suppresses the expression of several miRNAs involved in radiation-induced leukemogenesis, suggesting the presence of targets other than TPOR. Among the currently approved pharmaceutical drugs, RP is the most suitable candidate for victims exposed to high-dose ionizing radiation.
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Affiliation(s)
- Masaru Yamaguchi
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan
| | - Tokuhisa Hirouchi
- Department of Radiobiology, Institute for Environmental Sciences, 2-121 Hacchazawa, Takahoko, Rokkasho-vil. Kamikita-gun, Aomori, 039-3213, Japan
| | - Haruhiko Yoshioka
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan
| | - Jun Watanabe
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan
| | - Ikuo Kashiwakura
- Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan.
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25
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Kim MM, Schlussel L, Zhao L, Himburg HA. Dickkopf-1 Treatment Stimulates Hematopoietic Regenerative Function in Infused Endothelial Progenitor Cells. Radiat Res 2019; 192:53-62. [PMID: 31081743 DOI: 10.1667/rr15361.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Acute high-dose radiation injury damages the bone marrow hematopoietic stem and progenitor cell compartment. This damage compromises the functional ability of the bone marrow to produce mature blood cells and results in an increased risk of death due to hematopoietic complications. Past work has shown that the bone marrow endothelium provides critical cues, which promote hematopoietic stem cell regeneration after injury. Additionally, transfusion of endothelial cells after radiation injury has been shown to promote recovery of both the bone marrow vasculature and hematopoietic systems. In this work, we examined the regenerative capacity of intravenous infusion of umbilical cord-blood derived endothelial progenitor cells (EPCs) since this is a cell source which is easy to obtain, expand and cryopreserve. We show that pre-treatment with the Wnt-antagonist Dickkopf1 (Dkk1) augments EPC regenerative function in an allogeneic mouse transplant model. Here, hematopoietic recovery was assessed in Balb/c mice after 5 Gy total-body irradiation and transplantation with C57/BL6-derived EPCs either with or without Dkk1 pre-treatment. The Dkk1-treated EPC group had significantly faster recovery of peripheral white blood cells, total bone marrow cellularity, bone marrow progenitors and BM endothelial cells compared to EPC treatment alone or saline controls. Importantly, after an LD50/30 dose of 8 Gy in the Balb/c mouse, Dkk1-treated EPCs were able to rescue 100% of irradiated mice versus 80% in the EPC control group and only 33% in the saline-treated group. To understand how Dkk1 induces regenerative function in the EPCs, we screened for pro-regenerative factors secreted by the EPC in response to Dkk1. Dkk1-treated EPCs were observed to secrete high levels of the anti-fibrotic protein follistatin as well as several proteins known to promote regeneration including EGF, VEGF and G-CSF. This work demonstrates the potential for Dkk1-treated EPCs as a rescue therapeutic for victims of acute radiation injury.
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Affiliation(s)
- Mindy M Kim
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Lauren Schlussel
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Liman Zhao
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Heather A Himburg
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
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26
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Atkinson SP. A Preview of Selected Articles. Stem Cells Transl Med 2019. [PMCID: PMC6476998 DOI: 10.1002/sctm.19-0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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27
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Alchinova IB, Polyakova MV, Yakovenko EN, Medvedeva YS, Saburina IN, Karganov MY. Effect of Extracellular Vesicles Formed by Multipotent Mesenchymal Stromal Cells on Irradiated Animals. Bull Exp Biol Med 2019; 166:574-579. [PMID: 30783847 DOI: 10.1007/s10517-019-04394-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Indexed: 11/30/2022]
Abstract
C57Bl/6J mice were exposed to γ-radiation in a dose of 7.5 Gy. A week later, the experimental group received intravenous injection of extracellular vesicles isolated from the culture medium of human bone marrow multipotent mesenchymal stromal cells. Changes in the physiological parameters of animals were assessed by laser correlation spectroscopy, histological examination, cytometry, and by differential leukocyte count. In 3 and 6 weeks, the parameters of the experimental group occupied an intermediate position between the intact and irradiated groups or did not differ significantly from the parameters of the intact group. The rate and efficiency of recovery varied at different levels of organization. Reduction of damage caused by irradiation in a sublethal dose at different levels of organization of experimental animals was shown.
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Affiliation(s)
- I B Alchinova
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia.,Research Institute for Space Medicine, Federal Research Center of Specialized Health Care and Medical Technologies, Federal Medical-Biological Agency, Ministry of Health of the Russian Federation, Moscow, Russia
| | - M V Polyakova
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - E N Yakovenko
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yu S Medvedeva
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I N Saburina
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia.,Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow, Russia
| | - M Yu Karganov
- Research Institute of General Pathology and Pathophysiology, Ministry of Health of the Russian Federation, Moscow, Russia
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28
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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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29
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Fu Y, Karbaat L, Wu L, Leijten J, Both SK, Karperien M. Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2018; 23:515-528. [PMID: 28490258 DOI: 10.1089/ten.teb.2016.0365] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) are considered to hold great therapeutic value for cell-based therapy and for tissue regeneration in particular. Recent evidence indicates that the main underlying mechanism for MSCs' beneficial effects in tissue regeneration is based on their capability to produce a large variety of bioactive trophic factors that stimulate neighboring parenchymal cells to start repairing damaged tissues. These new findings could potentially replace the classical paradigm of MSC differentiation and cell replacement. These bioactive factors have diverse actions like modulating the local immune system, enhancing angiogenesis, preventing cell apoptosis, and stimulating survival, proliferation, and differentiation of resident tissue specific cells. Therefore, MSCs are referred to as conductors of tissue repair and regeneration by secreting trophic mediators. In this review article, we have summarized the studies that focused on the trophic effects of MSC within the context of tissue regeneration. We will also highlight the various underlying mechanisms used by MSCs to act as trophic mediators. Besides the secretion of growth factors, we discuss two additional mechanisms that are likely to mediate MSC's beneficial effects in tissue regeneration, namely the production of extracellular vesicles and the formation of membrane nanotubes, which can both connect different cells and transfer a variety of trophic factors varying from proteins to mRNAs and miRNAs. Furthermore, we postulate that apoptosis of the MSCs is an integral part of the trophic effect during tissue repair.
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Affiliation(s)
- Yao Fu
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Lisanne Karbaat
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Ling Wu
- 2 Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, Los Angeles, California
| | - Jeroen Leijten
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Sanne K Both
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Marcel Karperien
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
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30
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Mesenchymal stem cell-mediated Notch2 activation overcomes radiation-induced injury of the hematopoietic system. Sci Rep 2018; 8:9277. [PMID: 29915190 PMCID: PMC6006282 DOI: 10.1038/s41598-018-27666-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 05/16/2018] [Indexed: 12/12/2022] Open
Abstract
Radiation exposure severely damages the hematopoietic system. Although several radio-protectors have been proposed to prevent radiation-induced damage, most agents have limited efficacy. In the present study, we investigated whether mesenchymal stem cells (MSCs) could contribute to the expansion of hematopoietic cells and mitigate radiation-induced hematopoietic injury in vitro and in vivo. We found that co-culture with MSCs promoted hematopoietic progenitor/stem cell (HPSCs) maintenance by providing a bone marrow-like microenvironment. In addition, we showed that MSCs prevented radiation-induced damage to HPSCs, as evidenced by the lack of DNA damage and apoptosis. Intravenously injected MSCs rapidly migrated to the bone marrow (BM) and prevented loss of BM cellularity, which reduced lethality and ameliorated pancytopenia in the BM of whole body-irradiated mice. We demonstrated that MSC-derived Jagged1 attenuated radiation-induced cytotoxicity of HPSCs, and that this was mediated by Notch signaling and expression of downstream proteins Bcl2 and p63 in HPSCs. In addition, Notch2 depletion significantly reduced the MSC-mediated radio-protective effect in human- and mouse-derived HPSCs. Collectively, our data show that activation of Notch and its associated downstream signaling pathways prevent radiation-induced hematopoietic injury. Therefore, enhancing Jagged1-Notch2 signaling could provide therapeutic benefit by protecting the hematopoietic system against damage after radiation.
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31
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Roobrouck VD, Wolfs E, Delforge M, Broekaert D, Chakraborty S, Sels K, Vanwelden T, Holvoet B, Lhoest L, Khurana S, Pandey S, Hoornaert C, Ponsaerts P, Struys T, Boeckx N, Vandenberghe P, Deroose CM, Verfaillie CM. Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia. Cytotherapy 2017; 19:744-755. [PMID: 28499585 DOI: 10.1016/j.jcyt.2017.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 03/09/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND AIMS Myelodysplastic syndromes (MDS) are a group of clonal stem cell disorders affecting the normal hematopoietic differentiation process and leading to abnormal maturation and differentiation of all blood cell lineages. Treatment options are limited, and there is an unmet medical need for effective therapies for patients with severe cytopenias. METHODS We demonstrate that multipotent adult progenitor cells (MAPC) improve the function of hematopoietic progenitors derived from human MDS bone marrow (BM) by significantly increasing the frequency of primitive progenitors as well as the number of myeloid colonies. RESULTS This effect was more pronounced in a non-contact culture, indicating the importance of soluble factors produced by the MAPC cells. Moreover, the cells did not stimulate the growth of the abnormal MDS clone, as shown by fluorescent in situ hybridization analysis on BM cells from patients with a known genetic abnormality. We also demonstrate that MAPC cells can provide stromal support for patient-derived hematopoietic cells. When MAPC cells were intravenously injected into a mouse model of MDS, they migrated to the site of injury and increased the hematopoietic function in diseased mice. DISCUSSION The preclinical studies undertaken here indicate an initial proof of concept for the use of MAPC cell therapy in patients with MDS-related severe and symptomatic cytopenias and should pave the way for further investigation in clinical trials.
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Affiliation(s)
- Valerie D Roobrouck
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Esther Wolfs
- Nuclear Medicine & Molecular Imaging and Molecular Small Animal Imaging Center, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Morphology Research Group, Biomedical Research Institute, Universiteit Hasselt, Diepenbeek, Belgium
| | - Michel Delforge
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium; Department of Hematology, University Hospitals Leuven, Belgium
| | - Dorien Broekaert
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Soumen Chakraborty
- Department of Gene Function and Regulation, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Kathleen Sels
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Thomas Vanwelden
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Bryan Holvoet
- Nuclear Medicine & Molecular Imaging and Molecular Small Animal Imaging Center, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Larissa Lhoest
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Satish Khurana
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Shubham Pandey
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium
| | - Chloé Hoornaert
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Peter Ponsaerts
- Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Tom Struys
- Morphology Research Group, Biomedical Research Institute, Universiteit Hasselt, Diepenbeek, Belgium
| | - Nancy Boeckx
- Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium
| | - Peter Vandenberghe
- Department of Hematology, University Hospitals Leuven, Belgium; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Christophe M Deroose
- Nuclear Medicine & Molecular Imaging and Molecular Small Animal Imaging Center, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Catherine M Verfaillie
- Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium.
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32
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Mesenchymal Stromal Cell-Derived Extracellular Vesicles Provide Long-Term Survival After Total Body Irradiation Without Additional Hematopoietic Stem Cell Support. Stem Cells 2017; 35:2379-2389. [DOI: 10.1002/stem.2716] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 09/11/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022]
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33
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Chang PY, Zhang BY, Cui S, Qu C, Shao LH, Xu TK, Qu YQ, Dong LH, Wang J. MSC-derived cytokines repair radiation-induced intra-villi microvascular injury. Oncotarget 2017; 8:87821-87836. [PMID: 29152123 PMCID: PMC5675675 DOI: 10.18632/oncotarget.21236] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/26/2017] [Indexed: 02/06/2023] Open
Abstract
Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose-derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro. Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6 and TNF-α, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1α and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1α and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine.
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Affiliation(s)
- Peng-Yu Chang
- State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, Changchun Jilin 130022, P.R. China.,Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Bo-Yin Zhang
- Department of Orthopedic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Shuang Cui
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Chao Qu
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Li-Hong Shao
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Tian-Kai Xu
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Ya-Qin Qu
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Li-Hua Dong
- Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China
| | - Jin Wang
- State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, Changchun Jilin 130022, P.R. China.,Department of Chemistry and Physics, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
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34
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Bouchlaka MN, Moffitt AB, Kim J, Kink JA, Bloom DD, Love C, Dave S, Hematti P, Capitini CM. Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models. Biol Blood Marrow Transplant 2017; 23:897-905. [PMID: 28257800 DOI: 10.1016/j.bbmt.2017.02.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 02/27/2017] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated MØs [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated MØs: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-β, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.
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Affiliation(s)
- Myriam N Bouchlaka
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Andrea B Moffitt
- Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina
| | - Jaehyup Kim
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - John A Kink
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Debra D Bloom
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Cassandra Love
- Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina
| | - Sandeep Dave
- Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
| | - Christian M Capitini
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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Aghamir SMR, Mehrabani D, Amini M, Mosleh-Shirazi MA, Nematolahi S, Shekoohi-Shooli F, Mortazavi SMJ, Razeghian Jahromi I. The Regenerative Effect of Bone Marrow-Derived Stem Cells on Cell Count and Survival in Acute Radiation Syndrome. World J Plast Surg 2017; 6:111-113. [PMID: 28289623 PMCID: PMC5339619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/30/2016] [Accepted: 05/10/2016] [Indexed: 11/24/2022] Open
Affiliation(s)
- Seyed Mahmood Reza Aghamir
- Department of Radiology and Radiotherapy, School of paramedical, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Davood Mehrabani
- Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoud Amini
- Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Samaneh Nematolahi
- Department of Biostatistics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Shekoohi-Shooli
- Department of Radiology and Radiotherapy, School of paramedical, Shahid Beheshti University of Medical Science, Tehran, Iran
| | | | - Iman Razeghian Jahromi
- Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Vitacolonna M, Belharazem D, Hohenberger P, Roessner ED. In-vivo quantification of the revascularization of a human acellular dermis seeded with EPCs and MSCs in co-culture with fibroblasts and pericytes in the dorsal chamber model in pre-irradiated tissue. Cell Tissue Bank 2016; 18:27-43. [PMID: 28004288 DOI: 10.1007/s10561-016-9606-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/08/2016] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Transplantation of a cell-seeded graft may improve wound healing after radiotherapy. However, the survival of the seeded cells depends on a rapid vascularization of the graft. Co-culturing of adult stem cells may be a promising strategy to accelerate the vessel formation inside the graft. Thus, we compared the in vivo angiogenic potency of mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) using dorsal skinfold chambers and intravital microscopy. MATERIALS AND METHODS Cells were isolated from rat bone marrow and adipose tissue and characterized by immunostaining and flow cytometry. Forty-eight rats received a dorsal skinfold chamber and were divided into 2 main groups, irradiated and non-irradiated. Each of these 2 groups were further subdivided into 4 groups: unseeded matrices, matrices + fibroblasts + pericytes, matrices + fibroblasts + pericytes + MSCs and matrices + fibroblasts + pericytes + EPCs. Vessel densities were quantified semi-automatically using FIJI. RESULTS Fibroblasts + pericytes - seeded matrices showed a significantly higher vascular density in all groups with an exception of non-irradiated rats at day 12 compared to unseeded matrices. Co-seeding of MSCs increased vessel densities in both, irradiated and non-irradiated groups. Co-seeding with EPCs did not result in an increase of vascularization in none of the groups. DISCUSSION We demonstrated that the pre-radiation treatment led to a significant decreased vascularization of the implanted grafts. The augmentation of the matrices with fibroblasts and pericytes in co-culture increased the vascularization compared to the non-seeded matrices. A further significant enhancement of vessel ingrowth into the matrices could be achieved by the co-seeding with MSCs in both, irradiated and non-irradiated groups.
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Affiliation(s)
- M Vitacolonna
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
| | - D Belharazem
- Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - P Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - E D Roessner
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Fischer S, Cornils K, Speiseder T, Badbaran A, Reimer R, Indenbirken D, Grundhoff A, Brunswig-Spickenheier B, Alawi M, Lange C. Indication of Horizontal DNA Gene Transfer by Extracellular Vesicles. PLoS One 2016; 11:e0163665. [PMID: 27684368 PMCID: PMC5042424 DOI: 10.1371/journal.pone.0163665] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 09/12/2016] [Indexed: 12/27/2022] Open
Abstract
The biological relevance of extracellular vesicles (EV) in intercellular communication has been well established. Thus far, proteins and RNA were described as main cargo. Here, we show that EV released from human bone marrow derived mesenchymal stromal cells (BM-hMSC) also carry high-molecular DNA in addition. Extensive EV characterization revealed this DNA mainly associated with the outer EV membrane and to a smaller degree also inside the EV. Our EV purification protocol secured that DNA is not derived from apoptotic or necrotic cells. To analyze the relevance of EV-associated DNA we lentivirally transduced Arabidopsis thaliana-DNA (A.t.-DNA) as indicator into BM-hMSC and generated EV. Using quantitative polymerase chain reaction (qPCR) techniques we detected high copy numbers of A.t.-DNA in EV. In recipient hMSC incubated with tagged EV for two weeks we identified A.t.-DNA transferred to recipient cells. Investigation of recipient cell DNA using quantitative PCR and verification of PCR-products by sequencing suggested stable integration of A.t.-DNA. In conclusion, for the first time our proof-of-principle experiments point to horizontal DNA transfer into recipient cells via EV. Based on our results we assume that eukaryotic cells are able to exchange genetic information in form of DNA extending the known cargo of EV by genomic DNA. This mechanism might be of relevance in cancer but also during cell evolution and development.
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Affiliation(s)
- Stefanie Fischer
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kerstin Cornils
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Speiseder
- Research Unit Viral Transformation, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Anita Badbaran
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rudolph Reimer
- Dept. Electron Microscopy, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Daniela Indenbirken
- Research Group Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Adam Grundhoff
- Research Group Virus Genomics, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Bärbel Brunswig-Spickenheier
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malik Alawi
- Bioinformatic Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Lange
- Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. Ann ICRP 2016; 44:7-357. [PMID: 26637346 DOI: 10.1177/0146645315595585] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure.
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Apoptosis of the Tracheal Epithelium Can Increase the Number of Recipient Bone Marrow–Derived Myofibroblasts in Allografts and Exacerbate Obliterative Bronchiolitis After Tracheal Transplantation in Mice. Transplantation 2016; 100:1880-8. [DOI: 10.1097/tp.0000000000001230] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Abramowski P, Krasemann S, Ernst T, Lange C, Ittrich H, Schweizer M, Zander AR, Martin R, Fehse B. Mesenchymal Stromal/Stem Cells Do Not Ameliorate Experimental Autoimmune Encephalomyelitis and Are Not Detectable in the Central Nervous System of Transplanted Mice. Stem Cells Dev 2016; 25:1134-48. [PMID: 27250994 DOI: 10.1089/scd.2016.0020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) constitute progenitor cells that can be isolated from different tissues. Based on their immunomodulatory and neuroprotective functions, MSC-based cell-therapy approaches have been suggested to antagonize inflammatory activity and neuronal damage associated with autoimmune disease of the central nervous system (CNS), for example, multiple sclerosis (MS). Intravenous MSC transplantation was reported to ameliorate experimental autoimmune encephalomyelitis (EAE), the murine model of MS, within days after transplantation. However, systemic distribution patterns and fate of MSCs after administration, especially their potential to migrate into inflammatory lesions within the CNS, remain to be elucidated. This question has of recent become particularly important, since therapeutic infusion of MSCs is now being tested in clinical trials with MS-affected patients. Here, we made use of the established EAE mouse model to investigate migration and therapeutic efficacy of murine bone marrow-derived MSCs. Applying a variety of techniques, including magnetic resonance imaging, immunohistochemistry, fluorescence in-situ hybridization, and quantitative polymerase chain reaction we found no evidence for immediate migration of infused MSC into the CNS of treated mice. Moreover, in contrast to other studies, transplanted MSCs did not ameliorate EAE. In conclusion, our data does not provide substantiation for a relevant migration of infused MSCs into the CNS of EAE mice supporting the hypothesis that potential therapeutic efficacy could be based on systemic effects. Evaluation of possible mechanisms underlying the observed discrepancies in MSC treatment outcomes between different EAE models demands further studies.
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Affiliation(s)
- Pierre Abramowski
- 1 Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf , Hamburg, Germany .,2 Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (INIMS), ZMNH, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Susanne Krasemann
- 3 Institute for Neuropathology, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Thomas Ernst
- 4 Diagnostic and Interventional Radiology Department and Clinic, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Claudia Lange
- 1 Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Harald Ittrich
- 4 Diagnostic and Interventional Radiology Department and Clinic, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Michaela Schweizer
- 5 Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Axel R Zander
- 6 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
| | - Roland Martin
- 2 Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (INIMS), ZMNH, University Medical Center Hamburg-Eppendorf , Hamburg, Germany .,7 Neuroimmunology and MS Research, Department of Neurology, University Hospital Zurich , Zurich, Switzerland
| | - Boris Fehse
- 1 Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf , Hamburg, Germany
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Mortazavi SMJ, Shekoohi-Shooli F, Aghamir SMR, Mehrabani D, Dehghanian A, Zare S, Mosleh-Shirazi MA. The healing effect of bone marrow-derived stem cells in acute radiation syndrome. Pak J Med Sci 2016; 32:646-51. [PMID: 27375707 PMCID: PMC4928416 DOI: 10.12669/pjms.323.9895] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Objectives: To determine the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on regeneration of bone marrow and intestinal tissue and survival rate in experimental mice with acute radiation syndrome (ARS). Methods: Forty mice were randomly divided into two equal groups of A receiving no BMSC transplantation and B receiving BMSCs. BMSCs were isolated from the bone marrow and cultured in DMEM media. Both groups were irradiated with 10 Gy (dose rate 0.28 Gy/ min) 60CO during 35 minutes with a field size of 35×35 for all the body area. Twenty-four hours after γ irradiation, 150×103 cells of passage 5 in 150 µl medium were injected intravenously into the tail. Animals were euthanized one and two weeks after cell transplantation. They were evaluated histologically for any changes in bone marrow and intestinal tissues. The survival rate in mice were also determined. Results: A significant increase for bone marrow cell count and survival rate were observed in group B in comparison to group A. Histological findings denoted to a healing in sample tissues. Conclusion: BMSCs could significantly reduce the side effects of ARS and increase the survival rate and healing in injured tissue. As such their transplantation may open a window in treatment of patients with ARS.
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Affiliation(s)
- Seyed Mohammad Javad Mortazavi
- Seyed Mohammad Javad Mortazavi, Ionizing and Non-ionizing Radiation Protection Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Shekoohi-Shooli
- Fatemeh Shekoohi-Shooli , Radiology and Radiotherapy Department, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Seyed Mahmood Reza Aghamir
- Seyed Mahmood Reza Aghamir, Radiology and Radiotherapy Department, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Davood Mehrabani
- Davood Mehrabani, Regenerative Medicine Department, University of Manitoba, Winnipeg, Manitoba, Canada. Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirreza Dehghanian
- Amirreza Dehghanian, Trauma Research Center, Shahid Rajayee Hospital, Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahrokh Zare
- Shahrokh Zare, Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Amin Mosleh-Shirazi
- Mohammad Amin Mosleh-Shirazi, Ionizing and Non-ionizing Radiation Protection Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Wen S, Dooner M, Cheng Y, Papa E, Del Tatto M, Pereira M, Deng Y, Goldberg L, Aliotta J, Chatterjee D, Stewart C, Carpanetto A, Collino F, Bruno S, Camussi G, Quesenberry P. Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia 2016; 30:2221-2231. [PMID: 27150009 PMCID: PMC5093052 DOI: 10.1038/leu.2016.107] [Citation(s) in RCA: 171] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/05/2016] [Accepted: 04/11/2016] [Indexed: 12/20/2022]
Abstract
Mesenchymal stromal cells (MSCs) have been shown to reverse radiation damage to marrow stem cells. We have evaluated the capacity of MSC-derived extracellular vesicles (MSC-EVs) to mitigate radiation injury to marrow stem cells at 4 h to 7 days after irradiation. Significant restoration of marrow stem cell engraftment at 4, 24 and 168 h post irradiation by exposure to MSC-EVs was observed at 3 weeks to 9 months after transplant and further confirmed by secondary engraftment. Intravenous injection of MSC-EVs to 500cGy exposed mice led to partial recovery of peripheral blood counts and restoration of the engraftment of marrow. The murine hematopoietic cell line, FDC-P1 exposed to 500cGy, showed reversal of growth inhibition, DNA damage and apoptosis on exposure to murine or human MSC-EVs. Both murine and human MSC-EVs reverse radiation damage to murine marrow cells and stimulate normal murine marrow stem cell/progenitors to proliferate. A preparation with both exosomes and microvesicles was found to be superior to either microvesicles or exosomes alone. Biologic activity was seen in freshly isolated vesicles and in vesicles stored for up to 6 months in 10% dimethyl sulfoxide at -80 °C. These studies indicate that MSC-EVs can reverse radiation damage to bone marrow stem cells.
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Affiliation(s)
- S Wen
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - M Dooner
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - Y Cheng
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - E Papa
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - M Del Tatto
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - M Pereira
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - Y Deng
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - L Goldberg
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - J Aliotta
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - D Chatterjee
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - C Stewart
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
| | - A Carpanetto
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - F Collino
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - S Bruno
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - G Camussi
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - P Quesenberry
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, USA
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Hynes K, Bright R, Proudman S, Haynes D, Gronthos S, Bartold M. Immunomodulatory properties of mesenchymal stem cell in experimental arthritis in rat and mouse models: A systematic review. Semin Arthritis Rheum 2016; 46:1-19. [PMID: 27105756 DOI: 10.1016/j.semarthrit.2016.02.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 02/18/2016] [Accepted: 02/29/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite recent advances in the treatment of arthritis with the development of disease-modifying antirheumatic drugs, 30% of patients still fail to respond to treatment. Given the potent anti-inflammatory and immunomodulatory properties of mesenchymal stem cells (MSC) and their ability to repair damaged cartilage, bone, and tendons, it has been proposed that MSC could be ideal for cell-based treatment of arthritis. OBJECTIVE This systematic review investigates evidence from studies on the therapeutic efficacy of MSC in rodent models of arthritis. METHODS PubMed, Embase, MEDLINE, and Wed of Science were searched to June 2015 for quantitative studies examining the outcome of treating animal models of arthritis with MSC. Inclusion criteria were as follows: administration of mesenchymal stem as a treatment approach for arthritis; animal models only; and published in English. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS The literature search identified 30 studies which met the inclusion criteria. A range of MSC populations were assessed in various rodent models of arthritis. Of these, 19 demonstrated positive outcomes while 11 studies failed to demonstrate positive effects. Owing to the extensive variation in the experimental design, cells investigated and the outcome measures described in the manuscripts, no meta-analysis was possible. Furthermore, the numerical values for the primary outcome measure of clinical paw score were frequently not published in the manuscripts analyzed, as they were only illustrated in graphical form. CONCLUSIONS Numerous studies have investigated the utility of a range of MSC populations in the treatment of experimental arthritis. The results obtained from these studies have been highly inconsistent, with multiple studies identifying a statistically significant improvement in arthritis scores after treatment with MSC, while other studies identified a statistically significant deterioration in arthritis scores and thirdly some studies showed no effect. Further studies using standardized protocols and outcome measures are needed to determine fully the potential of MSC populations in the treatment of experimental arthritis.
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Affiliation(s)
- Kim Hynes
- Colgate Australian Dental Research Centre, Dental School, University of Adelaide, Adelaide, SA, Australia; School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
| | - Richard Bright
- Colgate Australian Dental Research Centre, Dental School, University of Adelaide, Adelaide, SA, Australia
| | - Susanna Proudman
- Rheumatology Unit, Royal Adelaide Hospital and Discipline of Medicine, University of Adelaide, SA, Australia
| | - David Haynes
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stan Gronthos
- School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Mark Bartold
- Colgate Australian Dental Research Centre, Dental School, University of Adelaide, Adelaide, SA, Australia
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Dai T, Chen Z, Tan L, Shi C. Radioresistance of granulation tissue-derived cells from skin wounds combined with total body irradiation. Mol Med Rep 2016; 13:3377-83. [PMID: 26936439 DOI: 10.3892/mmr.2016.4939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 02/02/2016] [Indexed: 11/06/2022] Open
Abstract
Combined radiation and wound injury (CRWI) occurs following nuclear explosions and accidents, radiological or nuclear terrorism, and radiation therapy combined with surgery. CRWI is complicated and more difficult to heal than single injuries. Stem cell‑based therapy is a promising treatment strategy for CRWI, however, sourcing stem cells remains a challenge. In the present study, the granulation tissue-derived cells (GTCs) from the skin wounds (SWs) of CRWI mice (C‑GTCs) demonstrated a higher radioresistance to the damage caused by combined injury, and were easier to isolate and harvest when compared with bone marrow‑derived mesenchymal stromal cells (BMSCs). Furthermore, the C-GTCs exhibited similar stem cell-associated properties, such as self-renewal and multilineage differentiation capacity, when compared with neonatal dermal stromal cells (DSCs) and GTCs from unirradiated SWs. Granulation tissue, which is easy to access, may present as an optimal autologous source of stem/progenitor cells for therapeutic applications in CRWI.
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Affiliation(s)
- Tingyu Dai
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, P.R. China
| | - Zelin Chen
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, P.R. China
| | - Li Tan
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, P.R. China
| | - Chunmeng Shi
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, P.R. China
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Peris P, Roforth MM, Nicks KM, Fraser D, Fujita K, Jilka RL, Khosla S, McGregor U. Ability of circulating human hematopoietic lineage negative cells to support hematopoiesis. J Cell Biochem 2016; 116:58-66. [PMID: 25145595 DOI: 10.1002/jcb.24942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 08/15/2014] [Indexed: 12/24/2022]
Abstract
Hematopoietic stem cell (HSC) self-renewal is regulated by osteoblast and/or endothelial cells within the hematopoietic niche. However, the true identity of the supporting cells and the nature of the secreted factors remain uncertain. We developed a novel mouse model and analyzed whether circulating human peripheral hematopoietic lineage negative/AP+ (lin-/AP+) cells support hematopoiesis in vivo. Thus, immunocompromised (Rag) mice expressing thymidine kinase (Tk) under the control of the 3.6Col1α1 promoter (Tk-Rag) were treated with ganciclovir, resulting in osteoblast progenitor cell ablation and subsequent loss of hematopoiesis (evaluated by measuring mouse Ter119+ erythroid cells). Following hematopoietic cell depletion, human bone marrow-derived marrow stromal cells (MSCs) or lin-/AP+ cells were infused into Tk-Rag mice and compared with saline infusions. Ganciclovir significantly reduced (7.4-fold) Ter119+ cells in the bone marrow of Tk-Rag mice compared to saline injections. Infusion of either MSCs or lin-/AP+ cells into ganciclovir-treated mice resulted in a 3.3-fold and 2.7-fold increase (P < 0.01), respectively, in Ter119+ cells compared to mice receiving saline. Relative to lin-/AP- cells, lin-/AP+ cells expressed high levels of mesenchymal, endothelial, and hematopoiesis supporting genes. Thus, human peripheral blood lin-/AP+ cells represent a novel cell type capable of supporting hematopoiesis in a manner comparable to MSCs.
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Affiliation(s)
- Pilar Peris
- Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, Minnesota; Rheumatology Department, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
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Abstract
Acute radiation syndrome affects military personnel and civilians following the uncontrolled dispersal of radiation, such as that caused by detonation of nuclear devices and inappropriate medical treatments. Therefore, there is a growing need for medical interventions that facilitate the improved recovery of victims and patients. One promising approach may be cell therapy, which, when appropriately implemented, may facilitate recovery from whole body injuries. This editorial highlights the current knowledge regarding the use of mesenchymal stem cells for the treatment of acute radiation syndrome, the benefits and limitations of which are under investigation. Establishing successful therapies for acute radiation syndrome may require using such a therapeutic approach in addition to conventional approaches.
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Affiliation(s)
- Risaku Fukumoto
- Educational-Scientific Center, Faculty of Health Sciences, Medical University of Białystok, ul. Szpitalna 37, 15-295 Białystok, Poland
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Cao Y, Cai J, Zhang S, Yuan N, Fang Y, Wang Z, Li X, Cao D, Xu F, Lin W, Song L, Wang Z, Wang J, Xu X, Zhang Y, Zhao W, Hu S, Zhang X, Wang J. Autophagy Sustains Hematopoiesis Through Targeting Notch. Stem Cells Dev 2015; 24:2660-73. [PMID: 26178296 DOI: 10.1089/scd.2015.0176] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Yan Cao
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Jinyang Cai
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Suping Zhang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Na Yuan
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Yixuan Fang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Zhijian Wang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Xin Li
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Dan Cao
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Fei Xu
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Weiwei Lin
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Lin Song
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Zhen Wang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Jian Wang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Xiaoxiao Xu
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Yi Zhang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Wenli Zhao
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Shaoyan Hu
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Xueguang Zhang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
| | - Jianrong Wang
- Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, First Affiliated Hospital, Soochow University School of Medicine, Suzhou, China
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Association between in vivo bone formation and ex vivo migratory capacity of human bone marrow stromal cells. Stem Cell Res Ther 2015; 6:196. [PMID: 26450135 PMCID: PMC4599318 DOI: 10.1186/s13287-015-0188-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 09/02/2015] [Accepted: 09/21/2015] [Indexed: 12/13/2022] Open
Abstract
Introduction There is a clinical need for developing systemic transplantation protocols for use of human skeletal stem cells (also known bone marrow stromal stem cells) (hBMSC) in tissue regeneration. In systemic transplantation studies, only a limited number of hBMSC home to injured tissues suggesting that only a subpopulation of hBMSC possesses “homing” capacity. Thus, we tested the hypothesis that a subpopulation of hBMSC defined by ability to form heterotopic bone in vivo, is capable of homing to injured bone. Methods We tested ex vivo and in vivo homing capacity of a number of clonal cell populations derived from telomerized hBMSC (hBMSC-TERT) with variable ability to form heterotopic bone when implanted subcutaneously in immune deficient mice. In vitro transwell migration assay was used and the in vivo homing ability of transplanted hBMSC to bone fractures in mice was visualized by bioluminescence imaging (BLI). In order to identify the molecular phenotype associated with enhanced migration, we carried out comparative DNA microarray analysis of gene expression of hBMSC-derived high bone forming (HBF) clones versus low bone forming (LBF) clones. Results HBF clones were exhibited higher ex vivo transwell migration and following intravenous injection, better in vivo homing ability to bone fracture when compared to LBF clones. Comparative microarray analysis of HBF versus LBF clones identified enrichment of gene categories of chemo-attraction, adhesion and migration associated genes. Among these, platelet-derived growth factor receptor (PDGFR) α and β were highly expressed in HBF clones. Follow up studies showed that the chemoattractant effects of PDGF in vitro was more enhanced in HBF compared to LBF clones and this effect was reduced in presence of a PDGFRβ-specific inhibitor: SU-16 f. Also, PDGF exerted greater chemoattractant effect on PDGFRβ+ cells sorted from LBF clones compared to PDGFRβ- cells. Conclusion Our data demonstrate phenotypic and molecular association between in vivo bone forming ability and migratory capacity of hBMSC. PDGFRβ can be used as a potential marker for the prospective selection of hBMSC populations with high migration and bone formation capacities suitable for clinical trials for enhancing bone regeneration. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0188-9) contains supplementary material, which is available to authorized users.
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Nicolay NH, Lopez Perez R, Debus J, Huber PE. Mesenchymal stem cells – A new hope for radiotherapy-induced tissue damage? Cancer Lett 2015; 366:133-40. [DOI: 10.1016/j.canlet.2015.06.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 06/17/2015] [Accepted: 06/18/2015] [Indexed: 12/11/2022]
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50
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Kuehn SC, Koehne T, Cornils K, Markmann S, Riedel C, Pestka JM, Schweizer M, Baldauf C, Yorgan TA, Krause M, Keller J, Neven M, Breyer S, Stuecker R, Muschol N, Busse B, Braulke T, Fehse B, Amling M, Schinke T. Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I. Hum Mol Genet 2015; 24:7075-86. [PMID: 26427607 DOI: 10.1093/hmg/ddv407] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/22/2015] [Indexed: 01/21/2023] Open
Abstract
Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.
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Affiliation(s)
| | - Till Koehne
- Department of Osteology and Biomechanics, Department of Orthodontics
| | - Kerstin Cornils
- Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy
| | | | | | | | - Michaela Schweizer
- Center of Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany and
| | | | | | | | | | - Mona Neven
- Department of Osteology and Biomechanics
| | - Sandra Breyer
- Children's Hospital Hamburg-Altona, Department of Orthopedics, University Clinic Hamburg, Hamburg 22763, Germany
| | - Ralf Stuecker
- Children's Hospital Hamburg-Altona, Department of Orthopedics, University Clinic Hamburg, Hamburg 22763, Germany
| | | | | | | | - Boris Fehse
- Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy
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