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Chae HK, Suh N, Jang MJ, Kim YS, Kim BH, Aum J, Shin HC, You D, Hong B, Park HK, Kim CS. Efficacy and Safety of Human Bone Marrow-Derived Mesenchymal Stem Cells according to Injection Route and Dose in a Chronic Kidney Disease Rat Model. Int J Stem Cells 2022; 16:66-77. [PMID: 35483715 PMCID: PMC9978839 DOI: 10.15283/ijsc21146] [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: 08/26/2021] [Revised: 02/21/2022] [Accepted: 03/20/2022] [Indexed: 11/09/2022] Open
Abstract
Background and Objectives We compared the efficacy and safety of human bone marrow-derived mesenchymal stem cells (hBMSC), delivered at different doses and via different injection routes in an animal model of chronic kidney disease. Methods and Results A total of ninety 12-week-old rats underwent 5/6 nephrectomy and randomized among nine groups: sham, renal artery control (RA-C), tail vein control (TV-C), renal artery low dose (RA-LD) (0.5×106 cells), renal artery moderate dose (RA-MD) (1.0×106 cells), renal artery high dose (RA-HD) (2.0×106 cells), tail vein low dose (TV-LD) (0.5×106 cells), tail vein moderate dose (TV-MD) (1.0×106 cells), and tail vein high dose (TV-HD) (2.0×106 cells). Renal function and mortality of rats were evaluated after hBMSC injection. Serum blood urea nitrogen was significantly lower in the TV-HD group at 2 weeks (p<0.01), 16 weeks (p<0.05), and 24 weeks (p<0.01) than in the TV-C group, as determined by one-way ANOVA. Serum creatinine was significantly lower in the TV-HD group at 24 weeks (p<0.05). At 8 weeks, creatinine clearance was significantly higher in the TV-MD and TV-HD groups (p<0.01, p<0.05) than in the TV-C group. In the safety evaluation, we observed no significant difference among the groups. Conclusions Our findings confirm the efficacy and safety of high dose (2×106 cells) injection of hBMSC via the tail vein.
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Affiliation(s)
- Han Kyu Chae
- Department of Urology, Gangneung Asan Medical Center, University of Ulsan College of Medicine, Gangneung, Korea
| | - Nayoung Suh
- Department of Pharmaceutical Engineering, College of Medical Sciences and Department of Medical Sciences, General Graduate School, Soon Chun Hyang University, Asan, Korea
| | - Myong Jin Jang
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
| | - Yu Seon Kim
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bo Hyun Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joomin Aum
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Dalsan You
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bumsik Hong
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung Keun Park
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Choung-Soo Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Correspondence to Choung-Soo Kim, Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea, Tel: +82-2-3010-3734, Fax: +82-2-477-8928, E-mail:
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2
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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3
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Wang F, Chen X, Li J, Wang D, Huang H, Li X, Bi Z, Peng Y, Zhang X, Li G, Wang J, Wang C, Fu Q, Liu L. Dose- and Time-Dependent Effects of Human Mesenchymal Stromal Cell Infusion on Cardiac Allograft Rejection in Mice. Stem Cells Dev 2021; 30:203-213. [PMID: 33371825 DOI: 10.1089/scd.2019.0300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Heart transplantation is the final life-saving therapeutic strategy for many end-stage heart diseases. Long-term immunosuppressive regimens are needed to prevent allograft rejection. Mesenchymal stromal cells (MSCs) have been shown as immunomodulatory therapy for organ transplantation. However, the effect of dose and timing of MSC treatment on heart transplantation has not yet been examined. In this study, we infused three doses (1 × 106, 2 × 106, or 5 × 106 cells) of human MSCs (hMSCs) to the recipient BALB/c mice before (7 days or 24 h) or after (24 h) receiving C57BL/6 cardiac transplants. We found that infusion of high dose hMSCs (5 × 106) at 24 h post-transplantation significantly prolonged the survival time of cardiac grafts. To delineate the underlying mechanism, grafts, spleens, and draining lymph nodes were harvested for analysis. Dose-dependent effect of hMSC treatment was shown in: (1) alleviation of International Society of Heart and Lung Transplantation (ISHLT) score in grafts; (2) reduction of the population of CD4+ and CD8+ T cells; (3) increase of regulatory T (Treg) cells; (4) and decrease of serum levels of inflammatory cytokines and donor-specific antibodies. Taken together, we showed timing critical and dose-dependent immunomodulatory effects of hMSC treatment against acute allograft rejection in a mouse model of heart transplantation.
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Affiliation(s)
- Feng Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Organ Transplant Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, SunYat-sen University, Guangzhou, China
| | - Huiting Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xirui Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zirong Bi
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanwen Peng
- The Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jiali Wang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changxi Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology, Guangzhou, China
| | - Qian Fu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology, Guangzhou, China
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4
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Will cell therapies provide the solution for the shortage of transplantable organs? Curr Opin Organ Transplant 2020; 24:568-573. [PMID: 31389811 DOI: 10.1097/mot.0000000000000686] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW The potential to regenerate ischemically damaged kidneys while being perfused ex-vivo offers the best near-term solution to increasing kidney allografts for transplantation. RECENT FINDINGS There are a number of stem-cell sources including: stromal mesenchymal cells (MSC), induced adult pluripotent stem cells, fetal stem cells from placenta, membranes, amniotic fluid and umbilical cord and hematopoietic cells. MSC are increasingly the stem cell of choice and studies are primarily focused on novel induction immunosuppression to prevent rejection. Stem-cell therapies applied in vivo may be of limited benefit because the nonintegrating cells do not remain in the kidney and are not detectable in the body after several days. MSC therapies for transplantation have demonstrated early safety and feasibility. However, efficacy has not been clearly established. A more feasible application of a stem-cell therapy in transplantation is the administration of MSC to treat damaged renal allografts directly while being perfused ex vivo. Initial feasibility has been established demonstrating MSC-treatment results in statistically significant reduction of inflammatory responses, increased ATP and growth factor synthesis and mitosis. SUMMARY The ability to regenerate renal tissue ex-vivo sufficiently to result in immediate function could revolutionize transplantation by solving the chronic organ shortage.
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Hoogduijn MJ, Montserrat N, van der Laan LJW, Dazzi F, Perico N, Kastrup J, Gilbo N, Ploeg RJ, Roobrouck V, Casiraghi F, Johnson CL, Franquesa M, Dahlke MH, Massey E, Hosgood S, Reinders MEJ. The emergence of regenerative medicine in organ transplantation: 1st European Cell Therapy and Organ Regeneration Section meeting. Transpl Int 2020; 33:833-840. [PMID: 32237237 PMCID: PMC7497223 DOI: 10.1111/tri.13608] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/06/2020] [Accepted: 03/20/2020] [Indexed: 12/19/2022]
Abstract
Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state‐of‐the‐art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation.
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Affiliation(s)
- Martin J Hoogduijn
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Nuria Montserrat
- Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain.,Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.,Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Francesco Dazzi
- School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Norberto Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Jens Kastrup
- Cardiology Stem Cell Center, Rigshospitalet University Hospital Copenhagen, Copenhagen, Denmark
| | - Nicholas Gilbo
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Rutger J Ploeg
- Nuffield Department of Surgical Sciences and Oxford Transplant Centre, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, UK
| | | | | | - Christian L Johnson
- Institute for Clinical Chemistry and Laboratory Medicine, Transfusion Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Marcella Franquesa
- REMAR-IVECAT Group, Germans Trias i Pujol Health Science Research Institute, Badalona, Spain
| | - Marc H Dahlke
- Department of Surgery, Robert-Bosch-Health-Campus, Stuttgart, Germany
| | - Emma Massey
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Sarah Hosgood
- Department of Surgery, University of Cambridge, Cambridge, UK
| | - Marlies E J Reinders
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
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Stem cells out of the bag: characterization of ex vivo expanded mesenchymal stromal cells for possible clinical use. Future Sci OA 2020; 6:FSO449. [PMID: 32140248 PMCID: PMC7050601 DOI: 10.2144/fsoa-2019-0129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in establishing a MSC expansion protocol is the large volume of bone marrow (BM) required. We studied whether cells trapped within a collection bag and filter system could be considered as a source of MSC. Results: From the 20 BM collection bag and filter systems, we recovered an average of 1.68 × 108 mononuclear cells, which is the equivalent to 60 ml of filtered BM. Mononuclear cells were expanded ex vivo to 17 × 106 MSC, with purity shown by a CD44+, CD105+, CD90+ and CD73+ immunophenotype, a reduction of 20% proliferating cells in a mixed lymphocyte reaction and also the ability of adipocyte differentiation. Conclusion: Long-term MSC cultures were established from the usually discarded BM collection bag and filter, maintaining an appropriate phenotype and function, being suitable for both investigation and clinical settings. Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in obtaining MSC is the large volume of bone marrow (BM) required from a healthy donor. From usually discarded collection bags of BM collected for transplant, we recovered a number of cells equivalent to 60 ml of BM and expanded functional MSC with high purity. We believe that those recovered cells are an alternative to BM for obtaining MSC. The routinely recovery of such cells in reference centers, in a way similar to a public cord-blood bank, could benefit the scientific community, once further research is conducted to confirm results.
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7
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Rangel ÉB, Gomes SA, Kanashiro-Takeuchi R, Hare JM. Progenitor/Stem Cell Delivery by Suprarenal Aorta Route in Acute Kidney Injury. Cell Transplant 2019; 28:1390-1403. [PMID: 31409111 PMCID: PMC6802150 DOI: 10.1177/0963689719860826] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/14/2019] [Accepted: 06/03/2019] [Indexed: 02/06/2023] Open
Abstract
Progenitor/stem cell-based kidney regenerative strategies are a key step towards the development of novel therapeutic regimens for kidney disease treatment. However, the route of cell delivery, e.g., intravenous, intra-arterial, or intra-parenchymal, may affect the efficiency for kidney repair in different models of acute and chronic injury. Here, we describe a protocol of intra-aorta progenitor/stem cell injection in rats following either acute ischemia-reperfusion injury or acute proteinuria induced by puromycin aminonucleoside (PAN) - the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. Vascular clips were applied across both renal pedicles for 35 min, or a single dose of PAN was injected via intra-peritoneal route, respectively. Subsequently, 2 x 106 stem cells [green fluorescent protein (GFP)-labeled c-Kit+ progenitor/stem cells or GFP-mesenchymal stem cells] or saline were injected into the suprarenal aorta, above the renal arteries, after application of a vascular clip to the abdominal aorta below the renal arteries. This approach contributed to engraftment rates of ∼10% at day 8 post ischemia-reperfusion injury, when c-Kit+ progenitor/stem cells were injected, which accelerated kidney recovery. Similar rates of engraftment were found after PAN-induced podocyte damage at day 21. With practice and gentle surgical technique, 100% of the rats could be injected successfully, and, in the week following injection, ∼ 85% of the injected rats will recover completely. Given the similarities in mammals, much of the data obtained from intra-arterial delivery of progenitor/stem cells in rodents can be tested in translational research and clinical trials with endovascular catheters in humans.
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Affiliation(s)
- Érika B. Rangel
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Hospital Israelita Albert Einstein, São Paulo, Brazil
- Federal University of São Paulo, Brazil
| | - Samirah A. Gomes
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Laboratory of Cellular, Genetic, and Molecular Nephrology, Renal
Division, University of São Paulo, Brazil
| | - Rosemeire Kanashiro-Takeuchi
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Department of Molecular and Cellular Pharmacology, Leonard M Miller
School of Medicine, University of Miami, USA
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Department of Molecular and Cellular Pharmacology, Leonard M Miller
School of Medicine, University of Miami, USA
- Division of Cardiology, Leonard M Miller School of Medicine,
University of Miami, USA
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8
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Manzia TM, Gazia C, Baiocchi L, Lenci I, Milana M, Santopaolo F, Angelico R, Tisone G. Clinical Operational Tolerance and Immunosuppression Minimization in Kidney Transplantation: Where Do We Stand? Rev Recent Clin Trials 2019; 14:189-202. [PMID: 30868959 DOI: 10.2174/1574887114666190313170205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 02/27/2019] [Accepted: 03/05/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND The 20th century represents a breakthrough in the transplantation era, since the first kidney transplantation between identical twins was performed. This was the first case of tolerance, since the recipient did not need immunosuppression. However, as transplantation became possible, an immunosuppression-free status became the ultimate goal, since the first tolerance case was a clear exception from the hard reality nowadays represented by rejection. METHODS A plethora of studies was described over the past decades to understand the molecular mechanisms responsible for rejection. This review focuses on the most relevant studies found in the literature where renal tolerance cases are claimed. Contrasting, and at the same time, encouraging outcomes are herein discussed and a glimpse on the main renal biomarkers analyzed in this field is provided. RESULTS The activation of the immune system has been shown to play a central role in organ failure, but also it seems to induce a tolerance status when an allograft is performed, despite tolerance is still rare to register. Although there are still overwhelming challenges to overcome and various immune pathways remain arcane; the immunosuppression minimization might be more attainable than previously believed. CONCLUSION . Multiple biomarkers and tolerance mechanisms suspected to be involved in renal transplantation have been investigated to understand their real role, with still no clear answers on the topic. Thus, the actual knowledge provided necessarily leads to more in-depth investigations, although many questions in the past have been answered, there are still many issues on renal tolerance that need to be addressed.
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Affiliation(s)
- Tommaso Maria Manzia
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Gazia
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
- Department of Surgery, Abdominal Organ Transplant Program, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
- Wake Forest Institute for Regenerative Medicine, Department of Surgery, Winston-Salem, NC, United States
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | - Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome, Italy
| | | | - Roberta Angelico
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Giuseppe Tisone
- Transplant and Hepatobiliary Unit, Department of Surgery, University of Rome Tor Vergata, Rome, Italy
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9
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Hua F, Chen Y, Yang Z, Teng X, Huang H, Shen Z. Protective action of bone marrow mesenchymal stem cells in immune tolerance of allogeneic heart transplantation by regulating CD45RB + dendritic cells. Clin Transplant 2018; 32:e13231. [PMID: 29488658 DOI: 10.1111/ctr.13231] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Bone marrow-derived mesenchymal stem cells (BMSCs) could exert a potent immunosuppressive effect and therefore may have a therapeutic potential in T-cell-dependent pathologies. We aimed to examine the effects of BMSCs on immune tolerance of allogeneic heart transplantation and the involvement of CD45RB+ dendritic cells (DCs). METHODS Bone marrow-derived DCs and BMSCs were co-cultured, with CD45RB expression on the surface of DCs measured by flow cytometry. qRT-PCR and Western blotting were used to detect mRNA and protein levels. Cytometric bead array was performed to determine the serum level of IL-10. Survival time of transplanted heart and expression of CD4+ , CD8+ , IL-2, IL-4, IL-10, IFN-γ were determined. Immunofluorescence assay was employed to determine intensity of C3d and C4d. RESULTS DCs co-cultured with BMSCs showed increased CD45RB and Foxp3 levels. CD45RB+ DCs co-cultured with T-cells CD4+ displayed increased T-cell CD4+ Foxp3 ratio and IL-10 than DCs. Both of them extended survival time of transplanted heart, decreased histopathological classification and score, intensity of C3d, C4d, proportion of CD4+ , expression levels of IL-2 and IFN-γ, and increased the CD4+ Foxp3 ratio and levels of IL-4 and IL-10. CD45RB+ DCs achieved better protective effects than DCs. CONCLUSION BMSCs increased the expression of CD45RB in the bone marrow-derived DCs, thereby strengthening immunosuppression capacity of T cells and immune tolerance of allogeneic heart transplantation.
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Affiliation(s)
- Fei Hua
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Yueqiu Chen
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Ziying Yang
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Xiaomei Teng
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Haoyue Huang
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Zhenya Shen
- Department of Cardiac Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
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10
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Sasajima H, Miyagi S, Kakizaki Y, Kamei T, Unno M, Satomi S, Goto M. Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation from Donors After Cardiac Death in Rats. Transplant Proc 2018; 50:2815-2820. [PMID: 30401403 DOI: 10.1016/j.transproceed.2018.02.180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 02/19/2018] [Indexed: 02/09/2023]
Abstract
BACKGROUND Liver transplantation from donors after cardiac death (DCD) might increase the pool of available organs. Recently, some investigators reported the potential use of mesenchymal stem cells (MSCs) to improve the outcome of liver transplantation from DCD. The aim of this study was to evaluate the cytoprotective effects and safety of MSC transplantation on liver grafts from DCD. METHODS Rats were divided into 4 groups (n = 5) as follows: 1. the heart-beating group, in which liver grafts were retrieved from heart-beating donors; 2. the DCD group, in which liver grafts were retrieved from DCD that had experienced apnea-induced agonal conditions; 3. the MSC-1 group, and 4. the MSC-2 group, in which liver grafts were retrieved as with the DCD group, but were infused MSCs (2.0 × 105 or 1.0 × 106, respectively). The retrieved livers were perfused with oxygenated Krebs-Henseleit bicarbonate buffer (37°C) through the portal vein for 2 hours after 6 hours of cold preservation. Perfusate, bile, and liver tissues were then investigated. RESULTS Bile production in the MSC-2 group was significantly improved compared with that in the DCD group. Based on histologic findings, narrowing of the sinusoidal space in the both MSC groups was improved compared with that in the DCD group. CONCLUSIONS MSCs could protect the function of liver grafts from warm ischemia-reperfusion injury and improve the viability of DCD liver grafts. In addition, we found that the infusion of 1.0 × 106 MSCs does not obstruct the hepatic sinusoids of grafts from DCD.
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Affiliation(s)
- H Sasajima
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - S Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Y Kakizaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - T Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - M Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - S Satomi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - M Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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11
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Schnapper A, Christmann A, Knudsen L, Rahmanian P, Choi YH, Zeriouh M, Karavidic S, Neef K, Sterner-Kock A, Guschlbauer M, Hofmaier F, Maul AC, Wittwer T, Wahlers T, Mühlfeld C, Ochs M. Stereological assessment of the blood-air barrier and the surfactant system after mesenchymal stem cell pretreatment in a porcine non-heart-beating donor model for lung transplantation. J Anat 2017; 232:283-295. [PMID: 29193065 DOI: 10.1111/joa.12747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2017] [Indexed: 01/09/2023] Open
Abstract
More frequent utilization of non-heart-beating donor (NHBD) organs for lung transplantation has the potential to relieve the shortage of donor organs. In particular with respect to uncontrolled NHBD, concerns exist regarding the risk of ischaemia/reperfusion (IR) injury-related graft damage or dysfunction. Due to their immunomodulating and tissue-remodelling properties, bone-marrow-derived mesenchymal stem cells (MSCs) have been suspected of playing a beneficial role regarding short- and long-term survival and function of the allograft. Thus, MSC administration might represent a promising pretreatment strategy for NHBD organs. To study the initial effects of warm ischaemia and MSC application, a large animal lung transplantation model was generated, and the structural organ composition of the transplanted lungs was analysed stereologically with particular respect to the blood-gas barrier and the surfactant system. In this study, porcine lungs (n = 5/group) were analysed. Group 1 was the sham-operated control group. In pigs of groups 2-4, cardiac arrest was induced, followed by a period of 3 h of ventilated ischaemia at room temperature. In groups 3 and 4, 50 × 106 MSCs were administered intravascularly via the pulmonary artery and endobronchially, respectively, during the last 10 min of ischaemia. The left lungs were transplanted, followed by a reperfusion period of 4 h. Then, lungs were perfusion-fixed and processed for light and electron microscopy. Samples were analysed stereologically for IR injury-related structural parameters, including volume densities and absolute volumes of parenchyma components, alveolar septum components, intra-alveolar oedema, and the intracellular and intra-alveolar surfactant pool. Additionally, the volume-weighted mean volume of lamellar bodies (lbs) and their profile size distribution were determined. Three hours of ventilated warm ischaemia was tolerated without eliciting histological or ultrastructural signs of IR injury, as revealed by qualitative and quantitative assessment. However, warm ischaemia influenced the surfactant system. The volume-weighted mean volume of lbs was reduced significantly (P = 0.024) in groups subjected to ischaemia (group medians of groups 2-4: 0.180-0.373 μm³) compared with the sham control group (median 0.814 μm³). This was due to a lower number of large lb profiles (size classes 5-15). In contrast, the intra-alveolar surfactant system was not altered significantly. No significant differences were encountered comparing ischaemia alone (group 2) or ischaemia plus application of MSCs (groups 3 and 4) in this short-term model.
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Affiliation(s)
- Anke Schnapper
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,REBIRTH (From Regenerative Biology to Reconstructive Therapy), Cluster of Excellence, Hannover, Germany
| | - Astrid Christmann
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,REBIRTH (From Regenerative Biology to Reconstructive Therapy), Cluster of Excellence, Hannover, Germany
| | - Lars Knudsen
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,REBIRTH (From Regenerative Biology to Reconstructive Therapy), Cluster of Excellence, Hannover, Germany
| | - Parwis Rahmanian
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Yeong-Hoon Choi
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany.,Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Mohamed Zeriouh
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Samira Karavidic
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Klaus Neef
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany.,Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Anja Sterner-Kock
- Center for Experimental Medicine, University of Cologne, Cologne, Germany
| | - Maria Guschlbauer
- Center for Experimental Medicine, University of Cologne, Cologne, Germany.,Decentral Animal Facility, University of Cologne, Cologne, Germany
| | - Florian Hofmaier
- Center for Experimental Medicine, University of Cologne, Cologne, Germany
| | - Alexandra C Maul
- Center for Experimental Medicine, University of Cologne, Cologne, Germany
| | - Thorsten Wittwer
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany.,Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany.,Center of Molecular Medicine, University of Cologne, Cologne, Germany
| | - Christian Mühlfeld
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,REBIRTH (From Regenerative Biology to Reconstructive Therapy), Cluster of Excellence, Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Matthias Ochs
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,REBIRTH (From Regenerative Biology to Reconstructive Therapy), Cluster of Excellence, Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
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Sierra-Parraga JM, Eijken M, Hunter J, Moers C, Leuvenink H, Møller B, Ploeg RJ, Baan CC, Jespersen B, Hoogduijn MJ. Mesenchymal Stromal Cells as Anti-Inflammatory and Regenerative Mediators for Donor Kidneys During Normothermic Machine Perfusion. Stem Cells Dev 2017; 26:1162-1170. [PMID: 28557562 DOI: 10.1089/scd.2017.0030] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There is great demand for transplant kidneys for the treatment of end-stage kidney disease patients. To expand the donor pool, organs from older and comorbid brain death donors, so-called expanded criteria donors (ECD), as well as donation after circulatory death donors, are considered for transplantation. However, the quality of these organs may be inferior to standard donor organs. A major issue affecting graft function and survival is ischemia/reperfusion injury, which particularly affects kidneys from deceased donors. The development of hypothermic machine perfusion has been introduced in kidney transplantation as a preservation technique and has improved outcomes in ECD and marginal organs compared to static cold storage. Normothermic machine perfusion (NMP) is the most recent evolution of perfusion technology and allows assessment of the donor organ before transplantation. The possibility to control the content of the perfusion fluid offers opportunities for damage control and reparative therapies during machine perfusion. Mesenchymal stromal cells (MSC) have been demonstrated to possess potent regenerative properties via the release of paracrine effectors. The combination of NMP and MSC administration at the same time is a promising procedure in the field of transplantation. Therefore, the MePEP consortium has been created to study this novel modality of treatment in preparation for human trials. MePEP aims to assess the therapeutic effects of MSC administered ex vivo by NMP in the mechanisms of injury and repair in a porcine kidney autotransplantation model.
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Affiliation(s)
- Jesus Maria Sierra-Parraga
- 1 Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center , Rotterdam, the Netherlands
| | - Marco Eijken
- 2 Institute of Clinical Medicine, Department of Medicine and Nephrology C, Aarhus University , Aarhus, Denmark
| | - James Hunter
- 3 Nuffield Department of Surgical Sciences, Oxford Biomedical Research Centre, University of Oxford , Oxford, United Kingdom
| | - Cyril Moers
- 4 Department of Surgery-Organ Donation and Transplantation, University of Medical Center Groningen , Groningen, the Netherlands
| | - Henri Leuvenink
- 4 Department of Surgery-Organ Donation and Transplantation, University of Medical Center Groningen , Groningen, the Netherlands
| | - Bjarne Møller
- 5 Department of Clinical Immunology, Aarhus University Hospital , Aarhus, Denmark
| | - Rutger J Ploeg
- 3 Nuffield Department of Surgical Sciences, Oxford Biomedical Research Centre, University of Oxford , Oxford, United Kingdom
| | - Carla C Baan
- 1 Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center , Rotterdam, the Netherlands
| | - Bente Jespersen
- 6 Department of Renal Medicine, Aarhus University Hospital , Aarhus, Denmark
| | - Martin J Hoogduijn
- 1 Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center , Rotterdam, the Netherlands
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Indoleamine 2, 3-Dioxgenase Transfected Mesenchymal Stem Cells Induce Kidney Allograft Tolerance by Increasing the Production and Function of Regulatory T Cells. Transplantation 2015; 99:1829-38. [DOI: 10.1097/tp.0000000000000856] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury. J Immunol Res 2015; 2015:202975. [PMID: 26380314 PMCID: PMC4561317 DOI: 10.1155/2015/202975] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 05/27/2015] [Indexed: 12/21/2022] Open
Abstract
Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI.
C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment. Conclusion. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure.
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Mudrabettu C, Kumar V, Rakha A, Yadav AK, Ramachandran R, Kanwar DB, Nada R, Minz M, Sakhuja V, Marwaha N, Jha V. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study. Nephrology (Carlton) 2015; 20:25-33. [PMID: 25230334 DOI: 10.1111/nep.12338] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2014] [Indexed: 01/12/2023]
Abstract
AIM This pilot study assesses the safety and feasibility of autologous mesenchymal stromal cell (MSC) transplantation in four patients that underwent living donor renal transplantation, and the effect on the immunophenotype and functionality of peripheral T lymphocytes following transplantation. METHODS All patients received low dose ATG induction followed by calcineurin inhibitor-based triple drug maintenance immunosuppression. Autologous MSCs were administered intravenously pre transplant and day 30 post-transplant. Patients were followed up for 6 months. The frequency of regulatory T cells and T cell proliferation was assessed at different time points. RESULTS None of the four patients developed any immediate or delayed adverse effects following MSC infusion. All had excellent graft function, and none developed graft dysfunction. Protocol biopsies at 1 and 3 months did not reveal any abnormality. Compared to baseline, there was an increase in the CD4 + CD25+FOXP3+ regulatory T cells and reduction in CD4 T cell proliferation. CONCLUSION We conclude that autologous MSCs can be used safely in patients undergoing living donor renal transplantation, lead to expansion of regulatory T cells and decrease in T cell proliferation. Larger randomized trials studies are needed to confirm these findings and evaluate whether this will have any impact on immunosuppressive therapy.
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Affiliation(s)
- Chetan Mudrabettu
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Lejmi E, Perriraz N, Clément S, Morel P, Baertschiger R, Christofilopoulos P, Meier R, Bosco D, Bühler LH, Gonelle-Gispert C. Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells. Stem Cells Dev 2015; 24:1223-35. [PMID: 25579056 DOI: 10.1089/scd.2014.0176] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate to areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated the migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time polymerase chain reaction, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5, and CCR6 in MSC. Expression of these chemokine receptors was not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblasts. In conclusion, we report that two inflammatory cytokines, MIP-1δ and MIP-3α, are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts around tumors.
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Affiliation(s)
- Esma Lejmi
- 1 Surgical Research Unit, University Hospitals of Geneva , Geneva, Switzerland
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18
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Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology 2014; 121:1099-121. [PMID: 25211170 DOI: 10.1097/aln.0000000000000446] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Critically ill patients often suffer from multiple organ failures involving lung, kidney, liver, or brain. Genomic, proteomic, and metabolomic approaches highlight common injury mechanisms leading to acute organ failure. This underlines the need to focus on therapeutic strategies affecting multiple injury pathways. The use of adult stem cells such as mesenchymal stem or stromal cells (MSC) may represent a promising new therapeutic approach as increasing evidence shows that MSC can exert protective effects following injury through the release of promitotic, antiapoptotic, antiinflammatory, and immunomodulatory soluble factors. Furthermore, they can mitigate metabolomic and oxidative stress imbalance. In this work, the authors review the biological capabilities of MSC and the results of clinical trials using MSC as therapy in acute organ injuries. Although preliminary results are encouraging, more studies concerning safety and efficacy of MSC therapy are needed to determine their optimal clinical use. (ANESTHESIOLOGY 2014; 121:1099-121).
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Takahashi T, Tibell A, Ljung K, Saito Y, Gronlund A, Osterholm C, Holgersson J, Lundgren T, Ericzon BG, Corbascio M, Kumagai-Braesch M. Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of Foxp3+ regulatory T cells. Stem Cells Transl Med 2014; 3:1484-94. [PMID: 25313200 DOI: 10.5966/sctm.2014-0012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2b) mice were infused together with fully major histocompatibility complex-mismatched Balb/c (H2d) allogeneic islets into the portal vein of diabetic C57BL/6 (H2b) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3+ regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naïve nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-γ production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3+ regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine.
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Affiliation(s)
- Tohru Takahashi
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Annika Tibell
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Karin Ljung
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Yu Saito
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Anna Gronlund
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Cecilia Osterholm
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Jan Holgersson
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Torbjörn Lundgren
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Bo-Göran Ericzon
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Matthias Corbascio
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
| | - Makiko Kumagai-Braesch
- Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden
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Wittwer T, Rahmanian P, Choi YH, Zeriouh M, Karavidic S, Neef K, Christmann A, Piatkowski T, Schnapper A, Ochs M, Mühlfeld C, Wahlers T. Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation. J Cardiothorac Surg 2014; 9:151. [PMID: 25179441 PMCID: PMC4169637 DOI: 10.1186/s13019-014-0151-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 08/18/2014] [Indexed: 12/30/2022] Open
Abstract
Background Lung transplantation (LTx) is still limited by organ shortage. To expand the donor pool, lung retrieval from non-heart-beating donors (NHBD) was introduced into clinical practice recently. However, primary graft dysfunction with inactivation of endogenous surfactant due to ischemia/reperfusion-injury is a major cause of early mortality. Furthermore, donor-derived human mesenchymal stem cell (hMSC) expansion and fibrotic differentiation in the allograft results in bronchiolitis obliterans syndrome (BOS), a leading cause of post-LTx long-term mortality. Therefore, pretreatment of NHBD with recipient-specific bone-marrow-(BM)-derived hMSC might have the potential to both improve the postischemic allograft function and influence the long-term development of BOS by the numerous paracrine, immunomodulating and tissue-remodeling properties especially on type-II-pneumocytes of hMSC. Methods Asystolic pigs (n = 5/group) were ventilated for 3 h of warm ischemia (groups 2–4). 50x106 mesenchymal-stem-cells (MSC) were administered in the pulmonary artery (group 3) or nebulized endobronchially (group 4) before lung preservation. Following left-lung-transplantation, grafts were reperfused, pulmonary-vascular-resistance (PVR), oxygenation and dynamic-lung-compliance (DLC) were monitored and compared to control-lungs (group 2) and sham-controls (group 1). To prove and localize hMSC in the lung, cryosections were counter-stained. Intra-alveolar edema was determined stereologically. Statistics comprised ANOVA with repeated measurements. Results Oxygenation (p = 0.001) and PVR (p = 0.009) following endovascular application of hMSC were significantly inferior compared to Sham controls, whereas DLC was significantly higher in endobronchially pretreated lungs (p = 0.045) with overall sham-comparable outcome regarding oxygenation and PVR. Stereology revealed low intrapulmonary edema in all groups (p > 0.05). In cryosections of both unreperfused and reperfused grafts, hMSC were localized in vessels of alveolar septa (endovascular application) and alveolar lumen (endobronchial application), respectively. Conclusions Preischemic deposition of hMSC in donor lungs is feasible and effective, and endobronchial application is associated with significantly better DLC as compared to sham controls. In contrast, transvascular hMSC delivery results in inferior oxygenation and PVR. In the long term perspective, due to immunomodulatory, paracrine and tissue-remodeling effects on epithelial and endothelial restitution, an endobronchial NHBD allograft-pretreatment with autologous mesenchymal-stem-cells to attenuate limiting bronchiolitis-obliterans-syndrome in the long-term perspective might be promising in clinical lung transplantation. Subsequent work with chronic experiments is initiated to further elucidate this important field. Electronic supplementary material The online version of this article (doi:10.1186/s13019-014-0151-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Thorsten Wittwer
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Kerpener Strasse 61, Cologne, 50924, Germany.
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Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: lessons learned from first clinical trials. Transplantation 2014; 96:234-8. [PMID: 23759879 DOI: 10.1097/tp.0b013e318298f9fa] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies.
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Hackl C, Schlitt HJ, Kirchner GI, Knoppke B, Loss M. Liver transplantation for malignancy: Current treatment strategies and future perspectives. World J Gastroenterol 2014; 20:5331-5344. [PMID: 24833863 PMCID: PMC4017048 DOI: 10.3748/wjg.v20.i18.5331] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In 1967, Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma. In the following, liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies. Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed. In 1996, Mazzaferro et al introduced the Milan criteria, offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma. Since then, liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research. In this context, several aspects must be considered: (1) Given the shortage of deceased-donor organs, long-term overall and disease free survival should be comparable with results obtained in patients transplanted for non-malignant disease; (2) In this regard, living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice; and (3) Ongoing research focusing on perioperative therapy and anti-proliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival. The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.
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Immunomodulatory effects of mesenchymal stromal cells in solid organ transplantation. Curr Opin Organ Transplant 2014; 15:731-7. [PMID: 20881495 DOI: 10.1097/mot.0b013e328340172c] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW Multipotent mesenchymal stromal cells (MSCs) possess powerful immunomodulatory activity highlighting the potential for their clinical translation in solid organ transplantation. In this review, we summarize recent advances in understanding MSC immunomodulatory effect in vitro and in experimental transplant models and discuss topics of crucial importance for the future clinical use of MSCs as immunotherapy in solid organ transplantation. RECENT FINDINGS MSCs strongly inhibited T-cell activity in vitro and exerted similar inhibitory effects on other cells of the immune system. MSC-mediated immune suppression has been attributed mainly to the secretion of soluble factors; however, cell-contact mechanisms cannot be excluded. Available studies in animal transplant models raised variable results, but overall indicate that MSCs could be useful to modulate recipient immune cells. The timing of cell application and the origin of MSCs (autologous or allogeneic) seem to be the most crucial factors impacting the in-vivo efficacy of MSCs. SUMMARY A better understanding of the mechanisms underlying the immunomodulatory effects of MSCs in vitro and in vivo is needed to define the optimal condition for the use of MSCs as immunotherapy in solid organ transplantation.
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Overview of the indications and contraindications for liver transplantation. Cold Spring Harb Perspect Med 2014; 4:4/5/a015602. [PMID: 24789874 DOI: 10.1101/cshperspect.a015602] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver transplantation is the only definitive treatment option for patients with irrevocable acute or chronic liver failure. In the last four decades, liver transplantation has developed from an experimental approach with a very high mortality to an almost routine procedure with good short- and long-term survival rates. Here, we present an up-to-date overview of the indications and contraindications for liver transplantation. It is shown how the evaluation of a candidate and finally listing for transplantation has to be performed in a multidisciplinary setting. Meticulous listing, timing, and organ allocation are the crucial factors to achieve an optimal outcome for the individual patient on the one hand, and reasonably using the limited deceased donor pool on the other hand. Living-donor liver transplantation is demanding but necessarily increasing. Because patients after liver transplantation need lifelong aftercare, it is important for primary care clinicians to understand the basic medical problems and risks.
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25
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Rationale and prospects of mesenchymal stem cell therapy for liver transplantation. Curr Opin Organ Transplant 2014; 19:60-4. [DOI: 10.1097/mot.0000000000000031] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169-1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107-111, 2013; Perico et al. in Transpl Int 26:867-878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412-422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.
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Salisbury EM, Game DS, Lechler RI. Transplantation tolerance. Pediatr Nephrol 2014; 29:2263-72. [PMID: 24213880 PMCID: PMC4212135 DOI: 10.1007/s00467-013-2659-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 10/01/2013] [Accepted: 10/04/2013] [Indexed: 01/26/2023]
Abstract
Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.
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Affiliation(s)
- Emma M. Salisbury
- Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, Exhibition Road, London, SW7 2AZ UK
| | - David S. Game
- Department of Renal Medicine, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, Great Maze Pond, London, SE1 9RT UK
| | - Robert I. Lechler
- King’s Health Partners Academic Health Sciences Centre, King’s College London, London, WC2R 2LS UK
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Pileggi A, Xu X, Tan J, Ricordi C. Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant 2013; 18:672-81. [PMID: 24220050 PMCID: PMC4391704 DOI: 10.1097/mot.0000000000000029] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Discuss the recent progress on the clinical use of mesenchymal stromal (stem) cells (MSC) in solid organ transplantation (SOT). RECENT FINDINGS Tissue repair and immunomodulatory properties have been recognized for MSC obtained from different human tissues. MSC-based therapy has been proposed to reduce ischemia-reperfusion injury and to promote immune tolerance. The results of recent clinical trial support the safety and promising effects of autologous and allogeneic MSC in SOT. Collectively, the use of MSC in recipients of living donor kidney transplantation was associated with improved graft function, reduced rejection, ability to omit induction and/or lower maintenance immunosuppression regimen, as well as to treat rejection episodes. SUMMARY We are living in very exciting times with the implementation of novel clinical trials aimed at establishing safety, feasibility and efficacy of cellular therapies including MSC to improve SOT outcomes. The results of the initial clinical trials support the safety of MSC-based therapy and justifying cautious optimism for the immediate future.
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Affiliation(s)
- Antonello Pileggi
- Cell Transplant Center, Diabetes Research Institute, Miami, FL 33136, USA
- The DeWitt-Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33136, USA
| | - Xiumin Xu
- Cell Transplant Center, Diabetes Research Institute, Miami, FL 33136, USA
| | - Jianming Tan
- Cell and Stem Cell Institute of Xiamen University, Fuzhou, Fujian 350025, P.R. China
- Affiliated Fuzhou General Hospital of Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute, Miami, FL 33136, USA
- The DeWitt-Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33136, USA
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Stubbendorff M, Deuse T, Hua X, Phan TT, Bieback K, Atkinson K, Eiermann TH, Velden J, Schröder C, Reichenspurner H, Robbins RC, Volk HD, Schrepfer S. Immunological properties of extraembryonic human mesenchymal stromal cells derived from gestational tissue. Stem Cells Dev 2013; 22:2619-29. [PMID: 23711207 DOI: 10.1089/scd.2013.0043] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been isolated from many tissues, including gestational tissue. To date, a study comparing the properties and suitability of these cells in cell-based therapies is lacking. In this study, we compared the phenotype, proliferation rate, migration, immunogenicity, and immunomodulatory capabilities of human MSCs derived from umbilical cord lining (CL-MSCs), umbilical cord blood (CB-MSCs), placenta (P-MSCs), and Wharton's jelly (WJ-MSCs). Differences were noted in differentiation, proliferation, and migration, with CL-MSCs showing the highest proliferation and migration rates resulting in prolonged survival in immunodeficient mice. Moreover, CL-MSCs showed a prolongation in survival in xenogeneic BALB/c mice, which was attributed to their ability to dampen TH1 and TH2 responses. Weaker human cellular immune responses were detected against CL-MSCs and P-MSCs, which were correlated with their lower HLA I expression. Furthermore, HLA II was upregulated less substantially by CL-MSCs and CB-MSCs after IFN-γ stimulation. MSC types did not differ in indolamine 2,3-dioxygenase (IDO) expression after IFN-γ stimulation. Despite their lower IDO, HLA-G, and TGF-β1 expression, only CL-MSCs were able to reduce the release of IFN-γ by lymphocytes in a mixed lymphocyte reaction. In summary, CL-MSCs showed the best characteristics for cell-based strategies, as they are hypo-immunogenic and show high proliferation and migration rates. In addition, these studies show for the first time that although immunomodulatory molecules HLA-G, HLA-E, and TGF-β play an important role in MSC immune evasion, basal and induced HLA expression seems to be decisive in determining the immunogenicity of MSCs.
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Affiliation(s)
- Mandy Stubbendorff
- 1 Transplant and Stem Cell Immunobiology Lab, University Heart Center Hamburg , Hamburg, Germany
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Eggenhofer E, Popp FC, Mendicino M, Silber P, Van't Hof W, Renner P, Hoogduijn MJ, Pinxteren J, van Rooijen N, Geissler EK, Deans R, Schlitt HJ, Dahlke MH. Heart grafts tolerized through third-party multipotent adult progenitor cells can be retransplanted to secondary hosts with no immunosuppression. Stem Cells Transl Med 2013; 2:595-606. [PMID: 23836805 DOI: 10.5966/sctm.2012-0166] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Multipotent adult progenitor cells (MAPCs) are an adherent stem cell population that belongs to the mesenchymal-type progenitor cell family. Although MAPCs are emerging as candidate agents for immunomodulation after solid organ transplantation, their value requires further validation in a clinically relevant cell therapy model using an organ donor- and organ recipient-independent, third-party cell product. We report that stable allograft survival can be achieved following third-party MAPC infusion in a rat model of fully allogeneic, heterotopic heart transplantation. Furthermore, long-term accepted heart grafts recovered from MAPC-treated animals can be successfully retransplanted to naïve animals without additional immunosuppression. This prolongation of MAPC-mediated allograft acceptance depends upon a myeloid cell population since depletion of macrophages by clodronate abrogates the tolerogenic MAPC effect. We also show that MAPC-mediated allograft acceptance differs mechanistically from drug-induced tolerance regarding marker gene expression, T regulatory cell induction, retransplantability, and macrophage dependence. MAPC-based immunomodulation represents a promising pathway for clinical immunotherapy that has led us to initiate a phase I clinical trial for testing safety and feasibility of third-party MAPC therapy after liver transplantation.
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Affiliation(s)
- Elke Eggenhofer
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
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31
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The generation of hepatocytes from mesenchymal stem cells and engraftment into the liver. Curr Opin Organ Transplant 2013; 16:69-75. [PMID: 21150616 DOI: 10.1097/mot.0b013e3283424f5b] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation is the ultimate therapeutic option for the treatment of end-stage liver diseases, which, however, is restricted by the shortage of donor organs. Instead hepatocyte transplantation seemed to be a way out, but again marginal donor livers for the isolation of primary human hepatocytes are scarce. The hepatocyte differentiation capacity of mesenchymal stem cells might open a new cell resource to generate hepatocyte-like cells for therapeutical use. RECENT FINDINGS Apart from their potency of hepatocyte differentiation mesenchymal stem cells display pleiotropic biological features including modulation of immunogenicity, anti-inflammatory and anti-apoptotic as well as pro-proliferative impact at the site of tissue or organ lesions. They are mobilized from the bone marrow and migrate to the liver along chemoattractive gradients thus contributing to the humoral and cellular response in tissue repair. The cause of different liver diseases is varying depending on, for example, viral, toxic, nutritional, neoplastic challenges. As known from animal studies mesenchymal stem cells seem to have a beneficial impact on liver regeneration and tissue repair under a variety of liver disease conditions. SUMMARY Their versatile biological features render mesenchymal stem cells an alternate cell resource for the treatment of liver diseases. It is important to know the mechanisms of integration of transplanted cells into the recipient tissue and to understand the communication between donor cells and the host tissue on the molecular level in order to support efficacy of cell transplantation and thus optimize the therapeutical outcome.
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32
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Lee S, Szilagyi E, Chen L, Premanand K, DiPietro LA, Ennis W, Bartholomew AM. Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages. J Surg Res 2013; 181:20-4. [DOI: 10.1016/j.jss.2012.05.040] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 05/02/2012] [Accepted: 05/10/2012] [Indexed: 01/09/2023]
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Selleri S, Dieng MM, Nicoletti S, Louis I, Beausejour C, Le Deist F, Haddad E. Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells. Stem Cells Dev 2013; 22:1063-75. [PMID: 23167734 PMCID: PMC3608091 DOI: 10.1089/scd.2012.0315] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 11/19/2012] [Indexed: 12/14/2022] Open
Abstract
The mechanisms by which mesenchymal stromal cells (MSCs) induce immunomodulation are still poorly understood. In the current work, we show by a combination of polymerase chain reaction (PCR) array, flow cytometry, and multiplex cytokine data analysis that during the inhibition of an alloantigen-driven CD4+ T-cell response, MSCs induce a fraction of CD4+ T-cells to coexpress interferon-γ (IFNγ) and interleukin-10 (IL-10). This CD4+ IFNγ+ IL-10+ cell population shares properties with recently described T-cells originating from switched Th1 cells that start producing IL-10 and acquire a regulatory function. Here we report that IL-10-producing Th1 cells accumulated with time during T-cell stimulation in the presence of MSCs. Moreover, MSCs caused stimulated T-cells to downregulate the IFNγ receptor (IFNγR) without affecting IL-10 receptor expression. Further, the inhibitory effect of MSCs could be reversed by an anti-IFNγR-blocking antibody, indicating that IFNγ is one of the major players in MSC-induced T-cell suppression. Stimulated (and, to a lesser extent, resting) CD4+ T-cells treated with MSCs were able to inhibit the proliferation of autologous CD4+ T-cells, demonstrating their acquired regulatory properties. Altogether, our results suggest that the generation of IL-10-producing Th1 cells is one of the mechanisms by which MSCs can downmodulate an immune response.
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Affiliation(s)
- Silvia Selleri
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
- Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | | | - Simon Nicoletti
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
- Faculté de Médecine, Université Paris Descartes, Paris, France
| | - Isabelle Louis
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
| | - Christian Beausejour
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
- Department of Pharmacology, Université de Montréal, Montréal, Quebec, Canada
| | - Françoise Le Deist
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
- Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
- Department of Microbiology and Immunology, Université de Montréal, Montréal, Quebec, Canada
| | - Elie Haddad
- CHU Sainte-Justine Research Center, Montréal, Quebec, Canada
- Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
- Department of Microbiology and Immunology, Université de Montréal, Montréal, Quebec, Canada
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34
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Gruttadauria S, Grosso G, Pagano D, Biondi A, Echeverri G, Seria E, Pietrosi G, Liotta R, Basile F, Gridelli B. Marrow-Derived Mesenchymal Stem Cells Restore Biochemical Markers of Acute Liver Injury in Experimental Model. Transplant Proc 2013; 45:480-6. [DOI: 10.1016/j.transproceed.2012.06.087] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 04/20/2012] [Accepted: 06/06/2012] [Indexed: 01/02/2023]
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Abstract
As has been true with many emerging technologies, successful clinical development and recruitment of capital sufficient to reach market approval is measured as an industry platform. Risk, failure and achievement by individual companies are shared by all in the context of access to enthusiastic capital markets and codevelopment partnerships.
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Affiliation(s)
- Robert Deans
- Athersys Inc., 3201 Carnegie Avenue, Cleveland, OH 44115-2634, USA
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36
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The impact of mesenchymal stem cell therapy in transplant rejection and tolerance. Curr Opin Organ Transplant 2012; 17:355-61. [DOI: 10.1097/mot.0b013e328355a886] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Xia X, Chen W, Ma T, Xu G, Liu H, Liang C, Bai X, Zhang Y, He Y, Liang T. Mesenchymal stem cells administered after liver transplantation prevent acute graft-versus-host disease in rats. Liver Transpl 2012; 18:696-706. [PMID: 22344929 DOI: 10.1002/lt.23414] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute graft-versus-host disease is a serious and life-threatening complication of liver transplantation (LT) that occurs in 1% to 2% of liver allograft recipients. It is associated with a high mortality rate, and effective therapies are lacking. In our established rat model, a relative decrease in regulatory T cells (Tregs) was previously shown to be associated with acute graft-versus-host disease after liver transplantation (LT-aGVHD). Mesenchymal stem cells (MSCs) have been used to treat graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, and they have been shown to induce Tregs, which have immunomodulatory effects. In this study, when a treatment with donor- or recipient-derived MSCs was administered from day 8 to day 14 after the typical symptoms of LT-aGVHD started, the recipients were not cured, and their survival time was not prolonged. However, when MSCs of different origins were administered from day 0 to day 6 after LT, the recipients survived significantly longer than the control group, and the surviving MSC-treated rats did not show typical LT-aGVHD symptoms. In vivo tracings of carboxyfluorescein diacetate succinimidyl ester-stained MSCs did not show significant accumulations in the target organs after administration. Flow cytometry analysis showed that the Treg ratios in peripheral blood were more higher for the MSC-treated groups versus the control group. More immunohistochemically stained forkhead box P3-positive cells were also found in the intestines of the MSC-treated groups versus the control group. Further investigations of the function of MSCs showed that they could increase the Treg ratio in a mixed lymphocyte reaction (MLR) and lead to a greater reduction in MLR proliferation in vitro. In conclusion, the post-LT administration of MSCs of either donor or recipient origin could prevent the onset of LT-aGVHD in our rat model.
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Affiliation(s)
- Xuefeng Xia
- Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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38
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Jui HY, Lin CH, Hsu WT, Liu YR, Hsu RB, Chiang BL, Tseng WYI, Chen MF, Wu KK, Lee CM. Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase. Cell Transplant 2012; 21:971-84. [PMID: 22449499 DOI: 10.3727/096368911x627525] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Transplant arteriosclerosis (TA) remains the major limitation of long-term graft survival in heart transplantation despite the advances in immunosuppressants. Mesenchymal stem cells (MSCs) have been demonstrated to suppress allogeneic immune responses by numerous in vitro studies. However, the immunomodulatory effects of MSCs in vivo are controversial and the underlying molecular mechanisms are not conclusive. In this study, we investigated the therapeutic potential of autologous bone marrow-derived MSCs on TA in a porcine model of femoral artery transplantation. MSCs or saline were injected into the soft tissue surrounding the arterial grafts immediately postanastomosis. Four weeks after transplantation, neointimal formation increased significantly in untreated allografts compared with the MSC-treated grafts as assessed by intravascular ultrasound (maximum luminal area stenosis: 40 ± 12% vs. 18 ± 6%, p < 0.001). Grafts harvested at 4 weeks showed dense perivascular lymphocyte infiltration accompanied by significant intimal hyperplasia in the untreated but not in the MSC-treated allografts. Serial angiographic examination showed that all of the untreated allografts became occluded at the 8th week whereas the majority of the MSC-treated grafts remained patent at the 12th week posttransplantation (n = 12 each group, p < 0.001). Quantitative PCR analysis revealed that Foxp3 expression was comparable between the untreated and the MSC-treated groups. However, expression of interleukin-10 (IL-10), interferon-γ (IFN-γ), and indoleamine 2,3-dioxygenase (IDO) was increased significantly in the MSC-treated allografts compared with that in the allograft controls (p = 0.021 for IL-10, p = 0.003 for IFN-γ, and p = 0.008 for IDO). In conclusion, local delivery of autologous MSCs alleviates TA by inducing allograft tolerance via enhanced expression of IL-10, IFN-γ, and IDO but not Foxp3-positive cells in the vessel wall. These results suggest that MSCs induce immune tolerance by activating the type 1 regulatory T-like cells.
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Affiliation(s)
- Hsiang-Yiang Jui
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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39
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Charles R, Lu L, Qian S, Fung JJ. Stromal cell-based immunotherapy in transplantation. Immunotherapy 2012; 3:1471-85. [PMID: 22091683 DOI: 10.2217/imt.11.132] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Organs are composed of parenchymal cells that characterize organ function and nonparenchymal cells that are composed of cells in transit, as well as tissue connective tissue, also referred to as tissue stromal cells. It was originally thought that these tissue stromal cells provided only structural and functional support for parenchymal cells and were relatively inert. However, we have come to realize that tissue stromal cells, not restricted to in the thymus and lymphoid organs, also play an active role in modulating the immune system and its response to antigens. The recognition of these elements and the elucidation of their mechanisms of action have provided valuable insight into peripheral immune regulation. Extrapolation of these principles may allow us to utilize their potential for clinical application. In this article, we will summarize a number of tissue stromal elements/cell types that have been shown to induce hyporesponsiveness to transplants. We will also discuss the mechanisms by which these stromal cells create a tolerogenic environment, which in turn results in long-term allograft survival.
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Affiliation(s)
- Ronald Charles
- Department of General Surgery, Transplantation Center, Digestive Disease Institute, Cleveland, OH, USA
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40
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41
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Hoogduijn MJ, Dor FJ. Mesenchymal stem cells in transplantation and tissue regeneration. Front Immunol 2011; 2:84. [PMID: 22566873 PMCID: PMC3342393 DOI: 10.3389/fimmu.2011.00084] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 12/12/2011] [Indexed: 01/09/2023] Open
Affiliation(s)
- Martin J Hoogduijn
- Transplantation Laboratory, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Netherlands.
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42
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O'Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011; 65:263-279. [PMID: 21763562 DOI: 10.1016/j.jaad.2010.11.063] [Citation(s) in RCA: 130] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2010] [Revised: 10/30/2010] [Accepted: 11/20/2010] [Indexed: 12/13/2022]
Abstract
The management of skin cancer in solid organ transplant recipients is a challenge to both the dermatologist and transplant physician. Part II of this continuing medical education review offers an approach to the management of this increasing problem. The importance of specialty dermatology clinics providing access to transplant patients, frequent skin cancer screening, patient education, and multidisciplinary care is discussed. The management of low risk squamous cell carcinoma with topical therapies, photodynamic therapy, systemic retinoids, and capecitabine is reviewed. Revision of immunosuppression in the management of high-risk patients is discussed in association with the potential role of sentinel lymph node biopsy for aggressive disease. Finally, management of in-transit and metastatic squamous cell carcinoma is reviewed, with a discussion of the role of more recent innovative therapies, including epidermal growth factor receptor inhibitors in advanced squamous cell carcinoma in solid organ transplant recipients.
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Affiliation(s)
- Fiona O'Reilly Zwald
- Department of Dermatology and Division of Transplantation, Department of Surgery, Emory University, Atlanta, Georgia.
| | - Marc Brown
- Department of Dermatology and Oncology, University of Rochester, Rochester, New York
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Flemming A, Schallmoser K, Strunk D, Stolk M, Volk HD, Seifert M. Immunomodulative Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells Cultured in Human Platelet Lysate. J Clin Immunol 2011; 31:1143-56. [DOI: 10.1007/s10875-011-9581-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 08/08/2011] [Indexed: 01/04/2023]
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Abstract
This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.
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Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One 2011; 6:e19195. [PMID: 21559442 PMCID: PMC3084802 DOI: 10.1371/journal.pone.0019195] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 03/22/2011] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ischemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS We used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase-expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group. CONCLUSIONS/SIGNIFICANCE These data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration.
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Kanazawa H, Fujimoto Y, Teratani T, Iwasaki J, Kasahara N, Negishi K, Tsuruyama T, Uemoto S, Kobayashi E. Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One 2011. [PMID: 21559442 DOI: 10.1371/journal.pone.00 19195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ischemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS We used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase-expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group. CONCLUSIONS/SIGNIFICANCE These data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration.
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Affiliation(s)
- Hiroyuki Kanazawa
- Division of Development of Advanced Treatment, Center for Development of Advanced Medical Technology, Jichi Medical University, Yakushiji City, Tochigi, Japan.
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47
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Crop MJ, Korevaar SS, de Kuiper R, IJzermans JNM, van Besouw NM, Baan CC, Weimar W, Hoogduijn MJ. Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant 2011; 20:1547-59. [PMID: 21396164 DOI: 10.3727/096368910x564076] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
There is growing interest in the use of mesenchymal stem cells (MSCs) to improve the outcome of organ transplantation. The immunogenicity of MSCs is, however, unclear and is important for the efficacy of MSC therapy and for potential sensitization against donor antigens. We investigated the susceptibility of autologous and allogeneic MSCs for lysis by CD8(+) T-lymphocytes and NK cells in a kidney transplant setting. MSCs were derived from adipose tissue of human kidney donors and were CD90(+), CD105(+), CD166(+), and HLA class I(+). They showed differentiation ability and immunosuppressive capacity. Lysis of MSCs by peripheral blood mononuclear cells (PBMCs), FACS-sorted CD8(+) T cells, and NK cells was measured by europium release assay. Allogeneic MSCs were susceptible for lysis by cytotoxic CD8(+) T cells and NK cells, while autologous MSCs were lysed by NK cells only. NK cell-mediated lysis was inversely correlated with the expression of HLA class I on MSCs. Lysis of autologous MSCs was not dependent on culturing of MSCs in FBS, and MSCs in suspension as well as adherent to plastic were lysed by NK cells. Pretransplant recipient PBMCs did not lyse donor MSCs, but PBMCs isolated 3, 6, and 12 months after transplantation showed increasing lysing ability. After 12 months, CD8(+) T-cell-mediated lysis of donor MSCs persisted, indicating there was no evidence for desensitization against donor MSCs. Lysis of MSCs is important to take into account when MSCs are considered for clinical application. Our results suggest that the HLA background of MSCs and timing of MSC administration are important for the efficacy of MSC therapy.
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Affiliation(s)
- Meindert J Crop
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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Eggenhofer E, Steinmann JF, Renner P, Slowik P, Piso P, Geissler EK, Schlitt HJ, Dahlke MH, Popp FC. Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts. Transpl Immunol 2010; 24:157-63. [PMID: 21194567 DOI: 10.1016/j.trim.2010.12.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 12/12/2010] [Accepted: 12/13/2010] [Indexed: 12/13/2022]
Abstract
Donor-derived mesenchymal stem cells (MSC) can induce long-term acceptance in a rat heart transplantation model when injected prior to transplantation in combination with mycophenolate mofetil (MMF). In contrast, MSC alone cause accelerated graft rejection. To better understand these conflicting data we studied the effects of MSC and MMF on lymphocyte populations in heart allografts and secondary lymphatic organs. Allogeneic MSC injected prior to transplantation are immunogenic in this model because activated CD4+ and CD8+ cells emerged earlier in secondary lymphatic organs of MSC- and MSC/MMF-treated animals, compared to animals not treated with MSC. Consequently T cells infiltrated the grafts of MSC-only treated animals promptly causing accelerated graft rejection. However, few T cells or antigen-presenting cells (APC) infiltrated the grafts of animals treated with MSC and MMF. Consistent with this finding, intercellular adhesion molecule 1 (ICAM-1) and E-selectin was down-regulated exclusively in MSC/MMF-treated grafts, indicating that MSC together with MMF interfere with endothelial activation. Additionally, the presence of interferon-gamma (IFN-γ) enhanced MSC capabilities to suppress T cell proliferation in vitro. Interestingly, MMF did not influence serum IFN-γ levels in vivo. Together, our data indicate that MSC pre-activate T cells, but co-treatment with MMF eliminates these T cells, decreases intragraft APC and T cell trafficking by inhibiting endothelial activation, and allows IFN-γ stimulation of suppressive MSC.
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Affiliation(s)
- E Eggenhofer
- Department of Surgery, University Medical Center Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany
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Orlando G, Hematti P, Stratta RJ, Burke GW, Di Cocco P, Pisani F, Soker S, Wood K. Clinical operational tolerance after renal transplantation: current status and future challenges. Ann Surg 2010; 252:915-928. [PMID: 21107102 PMCID: PMC4547843 DOI: 10.1097/sla.0b013e3181f3efb0] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In solid organ transplantation, the achievement of an immunosuppression (IS)-free state [also referred to as clinical operational tolerance (COT)] represents the ultimate goal. Although COT is feasible and safe in selected cases after liver transplantation, it is an exceptional finding after other types of solid organ transplantation. In the field of renal transplantation (RT), approximately 100 cases of COT have been reported to date, mainly in patients who were not compliant with their immunosuppressive regimens or in individuals who had previously received a bone marrow transplant for hematological disorders. On the basis of promising results obtained in animal models, several tolerogenic protocols have been attempted in humans, but most have failed to achieve robust and stable COT after RT. Molecule-based regimens have been largely ineffective, whereas cell-based regimens have provided some encouraging results. In these latter regimens, apart from standard IS, patients usually receive perioperative infusion of donor bone marrow-derived stem cells, which are able to interact with the immune cells of the host and mitigate their response to engraftment. Unfortunately, most renal transplant patients who developed acute rejection-occurring either during the weaning protocol or after complete withdrawal of IS-eventually lost their grafts. Currently, the immune monitoring necessary for predicting the presence and persistence of donor-specific unresponsiveness is not available. Overall, the present review will provide a conceptual framework for COT and conclude that stable and robust COT after RT remains an elusive goal and that the different strategies attempted to date are not yet reproducibly safe or effective.
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Affiliation(s)
- Giuseppe Orlando
- Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, Oxford, UK.
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Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, Phan TT, Volk HD, Reichenspurner H, Robbins RC, Schrepfer S. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 2010; 20:655-67. [PMID: 21054940 DOI: 10.3727/096368910x536473] [Citation(s) in RCA: 212] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We here present an immunologic head-to-head comparison between human umbilical cord lining mesenchymal stem cells (clMSCs) and adult bone marrow MSCs (bmMSCs) from patients >65 years of age. clMSCs had significantly lower HLA class I expression, higher production of tolerogenic TGF-β and IL-10, and showed significantly faster proliferation. In vitro activation of allogeneic lymphocytes and xenogeneic in vivo immune activation was significantly stronger with bmMSCs, whereas immune recognition of clMSCs was significantly weaker. Thus, bmMSCs were more quickly rejected in immunocompetent mice. IFN-γ at 25 ng/ml increased both immunogenicity by upregulation of HLA class I/ HLA-DR expression and tolerogenicity by increasing intracellular HLA-G and surface HLA-E expression, augmenting TGF-β and IL-10 release, and inducing indoleamine 2,3-dioxygenase (IDO) expression. Higher concentrations of IFN-γ (>50 ng/ml) further enhanced the immunosuppressive phenotype of clMSCs, more strongly downregulating HLA-DR expression and further increasing IDO production (at 500 ng/ml). The net functional immunosuppressive efficacy of MSCs was tested in mixed lymphocyte cultures. Although both clMSCs and bmMSCs significantly reduced in vitro immune activation, clMSCs were significantly more effective than bmMSCs. The veto function of both MSC lines was enhanced in escalating IFN-γ environments. In conclusion, clMSCs show a more beneficial immunogeneic profile and stronger overall immunosuppressive potential than aged bmMSCs.
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Affiliation(s)
- Tobias Deuse
- Cardiovascular Surgery, University Heart Center Hamburg, Germany
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