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1
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Pérez-Torres Lobato M, Benitez-Carabante MI, Alonso L, Torrents S, Castillo Flores N, Uria Oficialdegui ML, Panesso M, Alonso-Martínez C, Oliveras M, Renedo-Miró B, Vives J, Diaz-de-Heredia C. Mesenchymal stromal cells in the treatment of pediatric hematopoietic cell transplantation-related complications (graft vs. host disease, hemorrhagic cystitis, graft failure and poor graft function): a single center experience. Front Pediatr 2024; 12:1375493. [PMID: 38783918 PMCID: PMC11112085 DOI: 10.3389/fped.2024.1375493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/28/2024] [Indexed: 05/25/2024] Open
Abstract
Objectives To describe mesenchymal stromal cells (MSCs) in the treatment of hematopoietic stem cell transplantation (HSCT) complications and to assess its safety and efficacy. Methods Single-center retrospective study (2016-2023). Patients under 20 years who received MSCs for the treatment of HSCT-related complications were included. Results Thirty patients (53.7% boys), median age at transplant 11 years (range 2-19) were included. MSCs indications were: graft-vs.-host disease (GVHD) in 18 patients (60%), of them 13 had acute GVHD (43.3%) and 5 chronic GVHD (16.7%); Grade 3-4 hemorrhagic cystitis (HC) in 4 (13.3%); poor graft function (PGF) in 6 (20%), 5 of them receiving MSCs with a CD34 stem cell-boost coinfusion; graft failure (GF) in 2 (6.7%), to enhance engraftment after a subsequent HSCT. Infusion-related-adverse-events were not reported. Overall response (OR) was 83% (25/30); 44% of responders (11/25) showed complete response (CR). OR for GVHD, HC, PGF and GF was 83.3%, 100%, 66.7% and 100% respectively. Response rate was 40% (95% CI: 20-55) and 79% (95% CI: 57-89) at 15 and 30 days. With a median follow-up of 21 months (IQR11-52.5), overall survival (OS) was 86% (95% CI: 74-100) and 79% (95% CI: 65-95) at 6 and 12 months post-MSCs infusion. Conclusion In our study, the most frequent indication of MSCs was refractory aGVHD (43.3%). Response rates were high (OR 83%) and safety profile was good.
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Affiliation(s)
- Maria Pérez-Torres Lobato
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Maria Isabel Benitez-Carabante
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Laura Alonso
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | | | | | - Maria Luz Uria Oficialdegui
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Melissa Panesso
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | | | - Maria Oliveras
- Department of Pharmacy, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Berta Renedo-Miró
- Department of Pharmacy, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Joaquim Vives
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
- Banc de Sang I Teixits, Barcelona, Spain
- Department of Medicine, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Cristina Diaz-de-Heredia
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
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2
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Keshavarz Shahbaz S, Mansourabadi AH, Jafari D. Genetically engineered mesenchymal stromal cells as a new trend for treatment of severe acute graft-versus-host disease. Clin Exp Immunol 2022; 208:12-24. [PMID: 35274673 PMCID: PMC9113247 DOI: 10.1093/cei/uxac016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/25/2021] [Accepted: 02/07/2022] [Indexed: 01/12/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a population of non-hematopoietic and self-renewing cells characterized by the potential to differentiate into different cell subtypes. MSCs have interesting features which have attracted a lot of attention in various clinical investigations. Some basic features of MSCs are including the weak immunogenicity (absence of MHC-II and costimulatory ligands accompanied by the low expression of MHC-I) and the potential of plasticity and multi-organ homing via expressing related surface molecules. MSCs by immunomodulatory effects could also ameliorate several immune-pathological conditions like graft-versus-host diseases (GVHD). The efficacy and potency of MSCs are the main objections of MSCs therapeutic applications. It suggested that improving the MSC immunosuppressive characteristic via genetic engineering to produce therapeutic molecules consider as one of the best options for this purpose. In this review, we explain the functions, immunologic properties, and clinical applications of MSCs to discuss the beneficial application of genetically modified MSCs in GVHD.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-communicable Disease, Qazvin University of Medical Science, Qazvin, Iran
| | - Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Immunogenetics Research Network (IgReN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Immunogenetics Research Network (IgReN), Universal Scientific Education and Research Network (USERN), Zanjan, Iran
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3
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Forbes S, Bond AR, Thirlwell KL, Burgoyne P, Samuel K, Noble J, Borthwick G, Colligan D, McGowan NWA, Lewis PS, Fraser AR, Mountford JC, Carter RN, Morton NM, Turner ML, Graham GJ, Campbell JDM. Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization. Sci Transl Med 2021; 12:12/526/eaan5907. [PMID: 31941825 DOI: 10.1126/scitranslmed.aan5907] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 06/24/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.
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Affiliation(s)
- Shareen Forbes
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. .,Clinical Islet Transplantation Programme, Royal Infirmary of Edinburgh, Edinburgh EH16 4SU, UK
| | - Andrew R Bond
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Kayleigh L Thirlwell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Paul Burgoyne
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.,Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Kay Samuel
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - June Noble
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Gary Borthwick
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - David Colligan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Neil W A McGowan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Philip Starkey Lewis
- Medical Research Council (MRC) Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alasdair R Fraser
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Joanne C Mountford
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Roderick N Carter
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Nicholas M Morton
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Marc L Turner
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Gerard J Graham
- Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - John D M Campbell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK. .,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
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4
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Ringdén O, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease. Front Immunol 2020; 11:567210. [PMID: 33193339 PMCID: PMC7604265 DOI: 10.3389/fimmu.2020.567210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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5
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Willis GR, Fernandez-Gonzalez A, Reis M, Mitsialis SA, Kourembanas S. Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension? Int J Mol Sci 2018; 19:ijms19092534. [PMID: 30150544 PMCID: PMC6164282 DOI: 10.3390/ijms19092534] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.
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Affiliation(s)
- Gareth R Willis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Monica Reis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - S Alex Mitsialis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Stella Kourembanas
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
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6
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Abstract
With the advancements in antenatal steroid therapies and surfactant replacement, current clinical practices in neonatal intensive care units allow the survival of infants at very low gestational age. Despite these advances, there continues to be significant morbidity associated with extreme preterm birth that includes both short-term and long-term cardiorespiratory impairment. With no effective single therapy in preventing or treating developmental lung injuries, the need for new tools to treat and reduce risk of complications associated with extreme preterm birth is urgent. Stem cell-based therapies, in particular therapies utilizing mesenchymal stem (stromal) cells (MSCs), have shown promise in a number of animal models of lung pathologies relevant to neonatology. Recent studies in this field have consolidated the concept that the therapeutic mechanism of MSC action is paracrine, and this led to wide acceptance of the concept that the delivery of the MSC secretome rather than live cells may provide an alternative therapeutic approach for many complex diseases. Here, we summarize the significance and application of cell-free based therapies in preclinical models of neonatal lung injury. We emphasize the development of extracellular vesicle (EV)-based therapeutics and focus on the challenges that remain to be addressed before their application to clinical practice.
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7
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Kuçi Z, Bönig H, Kreyenberg H, Bunos M, Jauch A, Janssen JWG, Škifić M, Michel K, Eising B, Lucchini G, Bakhtiar S, Greil J, Lang P, Basu O, von Luettichau I, Schulz A, Sykora KW, Jarisch A, Soerensen J, Salzmann-Manrique E, Seifried E, Klingebiel T, Bader P, Kuçi S. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey. Haematologica 2016; 101:985-94. [PMID: 27175026 DOI: 10.3324/haematol.2015.140368] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 05/04/2016] [Indexed: 12/25/2022] Open
Abstract
To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy "3(rd)-party" donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease.
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Affiliation(s)
- Zyrafete Kuçi
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Halvard Bönig
- Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany
| | - Hermann Kreyenberg
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Milica Bunos
- Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany
| | - Anna Jauch
- Institute of Human Genetics, University of Heidelberg, Germany
| | | | - Marijana Škifić
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany University Hospital Centre Zagreb, Clinical Department of Transfusion and Transplantation Biology, Division of Cellular Therapy, Zagreb, Croatia
| | - Kristina Michel
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Ben Eising
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Giovanna Lucchini
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany Great Ormond Street Hospital, Department of Hematology/Oncology, London, United Kingdom
| | - Shahrzad Bakhtiar
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Johann Greil
- University Children's Hospital Heidelberg, Germany
| | - Peter Lang
- University Children's Hospital Tübingen, Germany
| | - Oliver Basu
- University Children's Hospital Essen, Germany
| | | | | | | | - Andrea Jarisch
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Jan Soerensen
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Emilia Salzmann-Manrique
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Erhard Seifried
- Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany
| | - Thomas Klingebiel
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Peter Bader
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
| | - Selim Kuçi
- University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany
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8
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Gardner J, Webster A. The social management of biomedical novelty: Facilitating translation in regenerative medicine. Soc Sci Med 2016; 156:90-7. [DOI: 10.1016/j.socscimed.2016.03.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 03/15/2016] [Accepted: 03/16/2016] [Indexed: 11/25/2022]
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9
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Lysák D, Koutová L, Holubová M, Vlas T, Miklíková M, Jindra P. The Quality Control of Mesenchymal Stromal Cells by in Vitro Testing of Their Immunomodulatory Effect on Allogeneic Lymphocytes. Folia Biol (Praha) 2016; 62:120-30. [PMID: 27516191 DOI: 10.14712/fb2016062030120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Mesenchymal stromal cells (MSC) represent a promising treatment of graft-versus-host disease (GVHD) in patients after allogeneic haematopoietic stem cell transplantation. We performed co-cultivation experiments with non-specifically stimulated lymphocytes to characterize the immunosuppressive activity of MSC. MSC influenced expression of some activation antigens. CD25 expression was lower with MSC and reached 55.2 % vs. 84.9 % (CD4+, P = 0.0006) and 38.8 % vs. 86.6 % (CD8+, P = 0.0003) on day +4. Conversely, CD69 antigen expression remained higher with MSC (73.3 % vs. 56.8 %, P = 0.0009; 59.5 % vs. 49.7 %, ns) and its down-regulation along with the culture time was less pronounced. MSC reduced proliferation of the stimulated lymphocytes. The cell percentages detected in daughter generations were decreased (32.82 % vs. 10.68 % in generation 4, P = 0.0004 and 29.85 % vs. 10.09 % in generation 5, P = 0.0008), resulting in a lower proliferation index with MSC (1.84 vs. 3.65, P < 0.0001). The addition of MSC affected expression of some cytokines. Production of pro-inflammatory cytokines was decreased: IL-6 (19.5 vs. 16.3 MFI; P < 0.0001 in CD3+/CD4+ and 14.5 vs. 13.2 MFI; P = 0.0128 in CD3+/CD8+), IFN-γ (13.5 vs. 12.0 MFI; P = 0.0096 in CD3+/CD4+). Expression of anti-inflammatory IL-10 was only slightly increased after the addition of MSC (ns). The analysis confirmed the immunomodulatory activity of MSC. The functional tests have proved to be an important part of the quality control of the advanced therapy cellular product intended for GVHD treatment. Future research should focus on the interaction between MSC and the patient immune environment more closely.
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Affiliation(s)
- D Lysák
- Department of Haematology and Oncology, Charles University in Prague, Faculty of Medicine in Pilsen and University Hospital in Pilsen, Pilsen, Czech Republic
| | - L Koutová
- Department of Haematology and Oncology, Charles University in Prague, Faculty of Medicine in Pilsen and University Hospital in Pilsen, Pilsen, Czech Republic
| | - M Holubová
- Department of Haematology and Oncology, Charles University in Prague, Faculty of Medicine in Pilsen and University Hospital in Pilsen, Pilsen, Czech Republic
| | - T Vlas
- Institute of Immunology and Allergology, Charles University in Prague, Faculty of Medicine in Pilsen and University Hospital in Pilsen, Pilsen, Czech Republic
| | - M Miklíková
- Biomedical Centre, Charles University in Prague, Faculty of Medicine in Pilsen, Pilsen, Czech Republic
| | - P Jindra
- Czech National Marrow Donor Registry (CS-2), Pilsen, Czech Republic
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10
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Chan KH, Zhuo S, Ni M. Priming the Surface of Orthopedic Implants for Osteoblast Attachment in Bone Tissue Engineering. Int J Med Sci 2015; 12:701-7. [PMID: 26392807 PMCID: PMC4571547 DOI: 10.7150/ijms.12658] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 07/14/2015] [Indexed: 01/04/2023] Open
Abstract
The development of better orthopedic implants is incessant. While current implants can function reliably in the human body for a long period of time, there are still a significant number of cases for which the implants can fail prematurely due to poor osseointegration of the implant with native bone. Increasingly, it is recognized that it is extremely important to facilitate the attachment of osteoblasts on the implant so that a proper foundation of extracellular matrix (ECM) can be laid down for the growth of new bone tissue. In order to facilitate the osseointegration of the implant, both the physical nanotopography and chemical functionalization of the implant surface have to be optimized. In this short review, however, we explore how simple chemistry procedures can be used to functionalize the surfaces of three major classes of orthopedic implants, i.e. ceramics, metals, and polymers, so that the attachment of osteoblasts on implants can be facilitated in order to promote implant osseointegration.
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Affiliation(s)
- Kiat Hwa Chan
- 2. Institute of Bioengineering and Nanotechnology, Nanos, Singapore 138669, Singapore
| | - Shuangmu Zhuo
- 1. Institute of Laser and Optoelectronics Technology, Fujian Normal University, Fuzhou 350007, China
| | - Ming Ni
- 3. Institute of Bioengineering and Nanotechnology, Nanos, Singapore 138669, Singapore
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11
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Vertès AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter II: emerging transformational cytotherapies. Regen Med 2015; 10:345-73. [DOI: 10.2217/rme.15.13] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for inherited anemias, immunodeficiencies or hematologic malignancies. A major complication of allo-HSCT associated with high transplant-related mortality rates is graft-versus-host disease (GvHD). Current and future clinical benefits in HSCT enabled by advances in hematopoietic stem cells, mesenchymal stem cells, Tregs and natural killer cells technologies are reviewed here and discussed. Among these evolutions, based on the need for mesenchymal stem cells to be recruited by an inflammatory environment, the development and use of novel GvHD biomarkers could be explored further to deliver the right pharmaceutical to the right patient at the right time. The successful commercialization of cytotherapeutics to efficiently manage GvHD will create a virtuous ‘halo’ effect for regenerative medicine.
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Affiliation(s)
- Alain A Vertès
- Sloan Fellow, London Business School, London, UK
- NxR Biotechnologies GmbH, Basel, Switzerland
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Lankford L, Selby T, Becker J, Ryzhuk V, Long C, Farmer D, Wang A. Early gestation chorionic villi-derived stromal cells for fetal tissue engineering. World J Stem Cells 2015; 7:195-207. [PMID: 25621120 PMCID: PMC4300931 DOI: 10.4252/wjsc.v7.i1.195] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/04/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering.
METHODS: PMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis.
RESULTS: We determined that an average of 2.09 × 106 (SD ± 8.59 × 105) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 103. Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation.
CONCLUSION: Our findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.
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van den Berk LCJ, Jansen BJH, Snowden S, Siebers-Vermeulen KGC, Gilissen C, Kögler G, Figdor CG, Wheelock CE, Torensma R. Cord blood mesenchymal stem cells suppress DC-T Cell proliferation via prostaglandin B2. Stem Cells Dev 2014; 23:1582-93. [PMID: 24649980 DOI: 10.1089/scd.2013.0433] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Immune suppression is a very stable property of multipotent stromal cells also known as mesenchymal stem cells (MSCs). All cell lines tested showed robust immune suppression not affected by a long culture history. Several mechanisms were described to account for this capability. Since several of the described mechanisms were not causing the immune suppression, the expression pattern of cord-blood-derived MSCs by microarray experiments was determined. Dendritic cells cocultured with cord blood MSCs were compared with cord blood MSCs. Putative immune suppressive candidates were tested to explain this inhibition. We find that cord blood MSCs themselves are hardly immunogenic as tested with allogeneic T-cells. Dendritic cells cocultured with second-party T-cells evoked abundant proliferation that was inhibited by third-party cord blood MSCs. Optimal inhibition was seen with one cord blood MSC for every dendritic cell. Blocking human leukocyte antigen G only saw partial recovery of proliferation. Several cytokines, gangliosides, enzymes like arginase, NO synthase, and indole amine 2,3-dioxygenase as well as the induction of Treg were not involved in the inhibition. The inhibiting moiety was identified as prostaglandin B2 by lipid metabolite analysis of the culture supernatant and confirmed with purified prostaglandin B2.
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Affiliation(s)
- Lieke C J van den Berk
- 1 Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands
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Kaipe H, Erkers T, Sadeghi B, Ringdén O. Stromal cells–are they really useful for GVHD? Bone Marrow Transplant 2014; 49:737-43. [DOI: 10.1038/bmt.2013.237] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 12/19/2013] [Indexed: 12/29/2022]
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Fierabracci A, Del Fattore A, Luciano R, Muraca M, Teti A, Muraca M. Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles. Cell Transplant 2013; 24:133-49. [PMID: 24268069 DOI: 10.3727/096368913x675728] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cells are the most widely used cell phenotype for therapeutic applications, the main reasons being their well-established abilities to promote regeneration of injured tissues and to modulate immune responses. Efficacy was reported in the treatment of several animal models of inflammatory and autoimmune diseases and, in clinical settings, for the management of disorders such as GVHD, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease. The effects of mesenchymal stem cells are believed to be largely mediated by paracrine signals, and several secreted molecules have been identified as contributors to the net biological effect. Recently, it has been recognized that bioactive molecules can be shuttled from cell to cell packed in microvesicles, tiny portions of cytoplasm surrounded by a membrane. Coding and noncoding RNAs are also carried in such microvesicles, transferring relevant biological activity to target cells. Several reports indicate that the regenerative effect of mesenchymal stem cells can be reproduced by microvesicles isolated from their culture medium. More recent evidence suggests that the immunomodulatory effects of mesenchymal stem cells are also at least partially mediated by secreted microvesicles. These findings allow better understanding of the mechanisms involved in cell-to-cell interaction and may have interesting implications for the development of novel therapeutic tools in place of the parent cells.
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Bernardi M, Albiero E, Alghisi A, Chieregato K, Lievore C, Madeo D, Rodeghiero F, Astori G. Production of human platelet lysate by use of ultrasound for ex vivo expansion of human bone marrow-derived mesenchymal stromal cells. Cytotherapy 2013; 15:920-9. [PMID: 23623274 DOI: 10.1016/j.jcyt.2013.01.219] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 01/08/2013] [Accepted: 01/23/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND AIMS A medium supplemented with fetal bovine serum (FBS) is of common use for the expansion of human mesenchymal stromal cells (MSCs). However, its use is discouraged by regulatory authorities because of the risk of zoonoses and immune reactions. Human platelet lysate (PL) obtained by freezing/thawing disruption of platelets has been proposed as a possible substitute of FBS. The process is time-consuming and not well standardized. A new method for obtaining PL that is based on the use of ultrasound is proposed. METHODS Platelet sonication was performed by submerging platelet-containing plastic bags in an ultrasonic bath. To evaluate platelet lysis we measured platelet-derived growth factor-AB release. PL efficiency was tested by expanding bone marrow (BM)-MSCs, measuring population doubling time, differentiation capacity and immunogenic properties. Safety was evaluated by karyotyping expanded cells. RESULTS After 30 minutes of sonication, 74% of platelet derived growth factor-AB was released. PL enhanced BM-MSC proliferation rate compared with FBS. The mean cumulative population doubling (cPD) of cells growth in PL at 10%, 7.5% and 5% was better compared with cPD obtained with 10% FBS. PD time (hours) of MSCs with PL obtained by sonication was shorter than for cPD with PL obtained by freezing/thawing (18.9 versus 17.4, P < 0.01). BM mononucleated cells expressed MSC markers and were able to differentiate into adipogenic, osteogenic and chondrogenic lineages. When BM-MSCs and T cells were co-cultured in close contact, immunosuppressive activity of BM-MSCs was maintained. Cell karyotype showed no genetic alterations. CONCLUSIONS The proposed method for the production of PL by sonication could be a safe, efficient and fast substitute of FBS, without the potential risks of FBS.
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Affiliation(s)
- Martina Bernardi
- Advanced Cellular Therapy Laboratory, Department of Cellular Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
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Chu PPY, Bari S, Fan X, Gay FPH, Ang JML, Chiu GNC, Lim SK, Hwang WYK. Intercellular cytosolic transfer correlates with mesenchymal stromal cell rescue of umbilical cord blood cell viability during ex vivo expansion. Cytotherapy 2012; 14:1064-79. [PMID: 22775077 PMCID: PMC3484967 DOI: 10.3109/14653249.2012.697146] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background aims. Mesenchymal stromal cells (MSC) have been observed to participate in tissue repair and to have growth-promoting effects on ex vivo co-culture with other stem cells. Methods. In order to evaluate the mechanism of MSC support on ex vivo cultures, we performed co-culture of MSC with umbilical cord blood (UCB) mononuclear cells (MNC) (UCB-MNC). Results. Significant enhancement in cell growth correlating with cell viability was noted with MSC co-culture (defined by double-negative staining for Annexin-V and 7-AAD; P<0.01). This was associated with significant enhancement of mitochondrial membrane potential (P<0.01). We postulated that intercellular transfer of cytosolic substances between MSC and UCB-MNC could be one mechanism mediating the support. Using MSC endogenously expressing green fluorescent protein (GFP) or labeled with quantum dots (QD), we performed co-culture of UCB-MNC with these MSC. Transfer of these GFP and QD was observed from MSC to UCB-MNC as early as 24 h post co-culture. Transwell experiments revealed that direct contact between MSC and UCB-MNC was necessary for both transfer and viability support. UCB-MNC tightly adherent to the MSC layer exhibited the most optimal transfer and rescue of cell viability. DNA analysis of the viable, GFP transfer-positive UCB-MNC ruled out MSC transdifferentiation or MSC-UCB fusion. In addition, there was statistical correlation between higher levels of cytosolic transfer and enhanced UCB-MNC viability (P< 0.0001). Conclusions. Collectively, the data suggest that intercellular transfer of cytosolic materials could be one novel mechanism for preventing UCB cell death in MSC co-culture.
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Affiliation(s)
- Pat P Y Chu
- Department of Hematology, Singapore General Hospital, Singapore
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Davies LC, Lönnies H, Locke M, Sundberg B, Rosendahl K, Götherström C, Le Blanc K, Stephens P. Oral mucosal progenitor cells are potently immunosuppressive in a dose-independent manner. Stem Cells Dev 2012; 21:1478-87. [PMID: 21988324 DOI: 10.1089/scd.2011.0434] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Oral mucosal lamina propria progenitor cells (OMLP-PCs) are a novel, clonally derived PC population of neural crest origin with the potential to differentiate down both mesenchymal and neuronal cell lineages. In this study we aimed to determine the immunological properties of OMLP-PCs and to establish whether they would be suitable candidates for allogeneic tissue engineering and in the treatment of immune-related diseases. OMLP-PCs demonstrated no inherent immunogenicity with insignificant expression of costimulatory molecules (CD40, CD80, CD86, CD154, and CD178) or human leukocyte antigen (HLA) class II. OMLP-PCs required 7 days of stimulation with interferon-γ (IFN-γ) to induce cell surface expression of HLA II. Mixed lymphocyte cultures and mitogen stimulation demonstrated the potent immunosuppressive capability of OMLP-PCs in a contact-independent manner. Complete inhibition of lymphocyte proliferation was seen at doses as low as 0.001% OMLP-PCs to responder lymphocytes, while annexin V staining confirmed that this immunosuppressive effect was not due to the induction of lymphocyte apoptosis. These data demonstrate, for the first time, that OMLP-PC immunomodulation, unlike that for mesenchymal stem cells, occurs via a dose- and HLA II-independent mechanism by the release of immunosuppressive soluble factors and suggests these cells may have wide ranging potential in future immune-related therapies.
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Affiliation(s)
- Lindsay C Davies
- Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry, School of Dentistry, Cardiff University, Cardiff, United Kingdom
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