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Smallbone P, Mehta RS, Alousi A. Steroid Refractory Acute GVHD: The Hope for a Better Tomorrow. Am J Hematol 2025; 100 Suppl 3:14-29. [PMID: 40123554 DOI: 10.1002/ajh.27592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 03/25/2025]
Abstract
Steroid-refractory acute graft-versus-host disease (SR-AGVHD) presents a significant barrier to successful outcomes following allogeneic hematopoietic cell transplantation (HCT), despite advancements in GVHD prophylaxis and management. While ruxolitinib therapy has shown improved response rates, survival benefits remain elusive. This review explores the definitions and proposed distinct pathophysiology and treatment landscape of SR-AGVHD. Emerging therapies offer potential, yet further research is critical to better define steroid-refractory populations, improve treatment precision with biomarkers, and overcome resistance, particularly in ruxolitinib-refractory cases.
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Affiliation(s)
- Portia Smallbone
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Rohtesh S Mehta
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Amin Alousi
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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2
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Smallbone P, Kebriaei P, Mendt M, Shpall EJ, Olson AL, Fingrut WB. Mesenchymal stem cells in hematology: Therapeutic initiatives and future directions. Best Pract Res Clin Haematol 2025; 38:101613. [PMID: 40274341 DOI: 10.1016/j.beha.2025.101613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 03/13/2025] [Accepted: 03/18/2025] [Indexed: 04/26/2025]
Abstract
In recent years, the landscape of hematology has undergone rapid transformation, driven by innovative therapeutic strategies harnessing the properties of novel cellular therapies. Mesenchymal stem cells (MSCs) represent one of these promising therapies, with potential applications across a range of hematologic conditions. These cells are notable for their immunomodulatory properties, key role in supporting the hematopoietic micro-environment and capacity for multi-directional differentiation. This review will focus on the biologic mechanisms underlying MSC therapeutic use, current avenues of clinical investigation, and potential challenges and future directions for MSC derived therapies.
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Affiliation(s)
- Portia Smallbone
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amanda L Olson
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Warren B Fingrut
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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3
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Gorjipour F, Bohloolighashghaei S, Sotoudeheian M, Pazoki Toroudi H. Fetal adnexa-derived allogeneic mesenchymal stem cells for cardiac regeneration: the future trend of cell-based therapy for age-related adverse conditions. Hum Cell 2025; 38:61. [PMID: 39998714 DOI: 10.1007/s13577-025-01190-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/17/2025] [Indexed: 02/27/2025]
Abstract
Heart failure is known as the leading cause of mortality and morbidity in adults, not only in USA but worldwide. Since the world's population is aging, the burden of cardiovascular disorders is increasing. Mesenchymal stem/stromal cells (MSCs) from a patient's bone marrow or other tissues have been widely used as the primary source of stem cells for cellular cardiomyoplasty. The incongruencies that exist between various cell-therapy approaches for cardiac diseases could be attributed to variations in cell processing methods, quality of the process, and cell donors. Off-the-shelf preparations of MSCs, enabled by batch processing of the cells and controlled cell processing factories in regulated facilities, may offer opportunities to overcome these problems. In this study, for the first time, we focused on the fetal membranes and childbirth byproducts as a promising source of cells for regenerative medicine. While many studies have described the advantages of cells derived from these organs, their advantage as a source of younger cells has not been sufficiently covered by the literature. Thus, herein, we highlight challenges that may arise from the impairment of the regenerative capacity of MSCs due to donor age and how allograft cells from fetal adnexa can be a promising substitute for the aged patients' stem cells for myocardial regeneration. Moreover, obstacles to the use of off-the-shelf cell-therapy preparations in regenerative medicine are briefly summarized here.
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Affiliation(s)
- Fazel Gorjipour
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Hamidreza Pazoki Toroudi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Boregowda SV, Booker CN, Strivelli J, Phinney DG. Mesenchymal Stem/Stromal Cells (MSCs) from Mouse Pelvic vs. Long Bones Exhibit Disparate Critical Quality Attributes: Implications for Translational Studies. Cells 2025; 14:274. [PMID: 39996746 PMCID: PMC11853496 DOI: 10.3390/cells14040274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/07/2024] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have been exploited as an experimental cell therapy in a broad array of clinical applications but have underperformed based on results from pre-clinical studies due to gaps in translating pre-clinical findings to human patients. Herein, we isolated mouse MSCs from pelvic bone marrow (BMP), a preferred source for human MSCs, and compared their growth, differentiation, and immuno-modulatory activity to those derived from long bone marrow (BML), the traditional source of mouse MSCs. We report that BMP-MSCs exhibit significantly enhanced growth kinetics in 5% and 21% oxygen saturation and superior bi-lineage differentiation and hematopoiesis-supporting activity as compared to BML-MSCs. Additionally, we show that TNF upregulates inducible nitric oxide synthase (NOS2) in BML- and BMP- MSCs and augments their immune suppressive activity in cell-based assays, while interferon-gamma (INFG) upregulates indoleamine, 2-3, dioxygenase (IDO1) and enhances the immune suppressive activity of only BMP-MSCs. These results indicate that mouse MSCs sourced from different bone compartments exhibit measurable differences in critical quality attributes, and these differences are comparable to those observed across species. Based on these differences, BMP- MSCs represent a useful resource to model the behavior of human BM-derived MSCs.
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Affiliation(s)
| | | | | | - Donald G. Phinney
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA; (S.V.B.); (C.N.B.); (J.S.)
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5
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Sharun K, Banu SA, Alifsha B, Abualigah L, Pawde AM, Dhama K, Pal A. Mesenchymal stem cell therapy in veterinary ophthalmology: clinical evidence and prospects. Vet Res Commun 2024; 48:3517-3531. [PMID: 39212813 DOI: 10.1007/s11259-024-10522-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Mesenchymal stem cell (MSC) therapy presents a promising strategy for treating various ocular conditions in veterinary medicine. This review explores the therapeutic potential of MSCs in managing corneal ulcers, immune-mediated keratitis, chronic superficial keratitis, keratoconjunctivitis sicca, retinal degeneration, and ocular burns in feline, equine, and canine patients. Studies have demonstrated the immunomodulatory and regenerative properties of MSCs, highlighting their ability to mitigate inflammation and promote tissue regeneration. Experimental studies have shown the potential of MSC therapy in reducing corneal opacity and vascularization, indicating significant therapeutic advantages. Delivery methods play a crucial role in optimizing the therapeutic efficacy of MSCs in ocular diseases. Various delivery methods, such as intravitreal injection, subconjunctival injection, topical administration, and scaffold-mediated delivery, are being explored to optimize MSC delivery to the target ocular tissues. Clinical trials have shown significant improvements in clinical signs following MSC therapy, underscoring its efficacy in treating ocular diseases. Additionally, tissue engineering approaches incorporating MSCs, growth factors, and scaffolds offer innovative strategies for corneal regeneration and tissue repair. Despite challenges such as standardization of protocols and long-term safety assessment, ongoing research endeavours seek to unlock the full therapeutic potential of MSC therapy in ocular diseases. Future prospects in MSC therapy involve exploring scaffold and hydrogel-based approaches and cell-free therapies leveraging the bioactive molecules released by MSCs. Continued research and development efforts are essential to unlock the full therapeutic potential of MSCs and realize their transformative impact on ocular diseases in veterinary patients.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan, 32003, Taiwan.
| | - S Amitha Banu
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - B Alifsha
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Laith Abualigah
- Computer Science Department, Al al-Bayt University, Mafraq, 25113, Jordan
- MEU Research Unit, Middle East University, Amman, 11831, Jordan
- Applied Science Research Center, Applied Science Private University, Amman, 11931, Jordan
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
- Artificial Intelligence and Sensing Technologies (AIST) Research Center, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - A M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Amar Pal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
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Phillips B, Morgan J, Walker R, Heggie C, Ali S. Interventions to reduce the risk of side-effects of cancer treatments in childhood. Expert Rev Anticancer Ther 2024; 24:1117-1129. [PMID: 39381913 DOI: 10.1080/14737140.2024.2411255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/27/2024] [Indexed: 10/10/2024]
Abstract
INTRODUCTION Childhood cancers as a group affect around 1 in 500 children but each individual diagnosis is a rare disease. While research largely focuses on improving cure rates, the management of side effects of treatment are high priority for clinicians, families and children and young people. AREAS COVERED The prevention and efficient management of infectious complications, oral mucositis, nausea and vomiting and graft-vs-host disease illustrated with examples of implementation research, translation of engineering to care, advances in statistical methodologies, and traditional bench-to-patient development. The reviews draw from existing systematic reviews and well conducted clinical practice guidelines. EXPERT OPINION The four areas are driven from patient and family priorities. Some of the problems outlined are ready for proven interventions, others require us to develop new technologies. Advancement needs us to make the best use of new methods of applied health research and clinical trial methodologies. Some of the greatest challenges may be those we're not fully aware of, as new therapies move from their use in adult oncological practice into children. This will need us to continue our collaborative, multi-professional, multi-disciplinary and eclectic approach.
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Affiliation(s)
- Bob Phillips
- Centre for Reviews and Dissemination, University of York and Hull-York Medical School, York, UK
- Regional Department of Paediatric Haematology and Oncology, Leeds Children's Hospital, Leeds, UK
| | - Jess Morgan
- Centre for Reviews and Dissemination, University of York and Hull-York Medical School, York, UK
- Regional Department of Paediatric Haematology and Oncology, Leeds Children's Hospital, Leeds, UK
| | - Ruth Walker
- Centre for Reviews and Dissemination, University of York and Hull-York Medical School, York, UK
| | | | - Salah Ali
- Department of Pediatric Haematology/Oncology, Cancer Center of Southeastern Ontario, Queens University, Kingston, Ontario, Canada
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Niu JW, Li Y, Xu C, Sheng H, Tian C, Ning H, Hu J, Chen J, Li B, Wang J, Lou X, Liu N, Su Y, Sun Y, Qiao Z, Wang L, Zhang Y, Lan S, Xie J, Ren J, Peng B, Wang S, Shi Y, Zhao L, Zhang Y, Chen H, Zhang B, Hu L. Human umbilical cord-derived mesenchymal stromal cells for the treatment of steroid refractory grades III-IV acute graft-versus-host disease with long-term follow-up. Front Immunol 2024; 15:1436653. [PMID: 39211037 PMCID: PMC11357908 DOI: 10.3389/fimmu.2024.1436653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Introduction Mesenchymal stromal cells (MSCs) have been extensively studied as a potential treatment for steroid refractory acute graft-versus-host disease (aGVHD). However, the majority of clinical trials have focused on bone marrow-derived MSCs. Methods In this study, we report the outcomes of 86 patients with grade III-IV (82.6% grade IV) steroid refractory aGVHD who were treated with human umbilical cord-derived mesenchymal stromal cells (UC-MSCs). The patient cohort included 17 children and 69 adults. All patients received intravenous infusions of UC-MSCs at a dose of 1 × 106 cells per kg body weight, with a median of 4 infusions (ranging from 1 to 16). Results The median time between the onset of aGVHD and the first infusion of UC-MSCs was 7 days (ranging from 3 to 88 days). At day 28, the overall response (OR) rate was 52.3%. Specifically, 24 patients (27.9%) achieved complete remission, while 21 (24.4%) exhibited partial remission. The estimated survival probability at 100 days was 43.7%. Following a median follow-up of 108 months (ranging from 61 to 159 months), the survival rate was approximately 11.6% (10/86). Patients who developed acute lower GI tract and liver GVHD exhibited poorer OR rates at day 28 compared to those with only acute lower GI tract GVHD (22.2% vs. 58.8%; p= 0.049). No patient experienced serious adverse events. Discussion These finding suggest that UC-MSCs are safe and effective in both children and adults with steroid refractory aGVHD. UC-MSCs could be considered as a feasible treatment option for this challenging conditon. (NCT01754454).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Bin Zhang
- Senior Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Liangding Hu
- Senior Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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Raoufinia R, Rahimi HR, Keyhanvar N, Moghbeli M, Abdyazdani N, Rostami M, Naghipoor K, Forouzanfar F, Foroudi S, Saburi E. Advances in Treatments for Epidermolysis Bullosa (EB): Emphasis on Stem Cell-Based Therapy. Stem Cell Rev Rep 2024; 20:1200-1212. [PMID: 38430362 DOI: 10.1007/s12015-024-10697-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 03/03/2024]
Abstract
Epidermolysis bullosa (EB) is a rare genetic dermatosis characterized by skin fragility and blister formation. With a wide phenotypic spectrum and potential extracutaneous manifestations, EB poses significant morbidity and mortality risks. Currently classified into four main subtypes based on the level of skin cleavage, EB is caused by genetic mutations affecting proteins crucial for maintaining skin integrity. The management of EB primarily focuses on preventing complications and treating symptoms through wound care, pain management, and other supportive measures. However, recent advancements in the fields of stem cell therapy, tissue engineering, and gene therapy have shown promise as potential treatments for EB. Stem cells capable of differentiating into skin cells, have demonstrated positive outcomes in preclinical and early clinical trials by promoting wound healing and reducing inflammation. Gene therapy, on the other hand, aims to correct the underlying genetic defects responsible for EB by introducing functional copies of mutated genes or modifying existing genes to restore protein function. Particularly for severe subtypes like Recessive Dystrophic Epidermolysis Bullosa (RDEB), gene therapy holds significant potential. This review aims to evaluate the role of new therapeutic approaches in the treatment of EB. The review includes findings from studies conducted on humans. While early studies and clinical trials have shown promising results, further research and trials are necessary to establish the safety and efficacy of these innovative approaches for EB treatment.
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Affiliation(s)
- Ramin Raoufinia
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Abdyazdani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of medicine, Mashhad University of medical sciences, Mashhad, Iran
| | - Karim Naghipoor
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Forouzanfar
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sara Foroudi
- Department of Biology, Faculty of Sciences, University of Ferdowsi, Mashhad, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Bicer M. Revolutionizing dermatology: harnessing mesenchymal stem/stromal cells and exosomes in 3D platform for skin regeneration. Arch Dermatol Res 2024; 316:242. [PMID: 38795200 PMCID: PMC11127839 DOI: 10.1007/s00403-024-03055-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/09/2024] [Accepted: 04/26/2024] [Indexed: 05/27/2024]
Abstract
Contemporary trends reveal an escalating interest in regenerative medicine-based interventions for addressing refractory skin defects. Conventional wound healing treatments, characterized by high costs and limited efficacy, necessitate a more efficient therapeutic paradigm to alleviate the economic and psychological burdens associated with chronic wounds. Mesenchymal stem/stromal cells (MSCs) constitute cell-based therapies, whereas cell-free approaches predominantly involve the utilization of MSC-derived extracellular vesicles or exosomes, both purportedly safe and effective. Exploiting the impact of MSCs by paracrine signaling, exosomes have emerged as a novel avenue capable of positively impacting wound healing and skin regeneration. MSC-exosomes confer several advantages, including the facilitation of angiogenesis, augmentation of cell proliferation, elevation of collagen production, and enhancement of tissue regenerative capacity. Despite these merits, challenges persist in clinical applications due to issues such as poor targeting and facile removal of MSC-derived exosomes from skin wounds. Addressing these concerns, a three-dimensional (3D) platform has been implemented to emend exosomes, allowing for elevated levels, and constructing more stable granules possessing distinct therapeutic capabilities. Incorporating biomaterials to encapsulate MSC-exosomes emerges as a favorable approach, concentrating doses, achieving intended therapeutic effectiveness, and ensuring continual release. While the therapeutic potential of MSC-exosomes in skin repair is broadly recognized, their application with 3D biomaterial scenarios remains underexplored. This review synthesizes the therapeutic purposes of MSCs and exosomes in 3D for the skin restoration, underscoring their promising role in diverse dermatological conditions. Further research may establish MSCs and their exosomes in 3D as a viable therapeutic option for various skin conditions.
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Affiliation(s)
- Mesude Bicer
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey.
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Curley GF, O’Kane CM, McAuley DF, Matthay MA, Laffey JG. Cell-based Therapies for Acute Respiratory Distress Syndrome: Where Are We Now? Am J Respir Crit Care Med 2024; 209:789-797. [PMID: 38324017 PMCID: PMC10995569 DOI: 10.1164/rccm.202311-2046cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/07/2024] [Indexed: 02/08/2024] Open
Abstract
There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. Clinical studies indicate that MSCs are safe and well tolerated, with promising therapeutic benefits in specific clinical settings, leading to regulatory approvals of MSCs for specific indications in some countries.This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.
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Affiliation(s)
- Gerard F. Curley
- Department of Anaesthesia, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom
| | - Daniel F. McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom
- Department of Critical Care, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - Michael A. Matthay
- Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
| | - John G. Laffey
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland; and
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
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11
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Teryek M, Jadhav P, Bento R, Parekkadan B. 3D microcapsules for human bone marrow-derived mesenchymal stem cell biomanufacturing in a vertical-wheel bioreactor. BIOTECHNOL BIOPROC E 2024. [DOI: 10.1007/s12257-024-00069-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/01/2023] [Accepted: 05/28/2023] [Indexed: 01/06/2025]
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12
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Bai X, Chen T, Li Y, Ge X, Qiu C, Gou H, Wei S, Liu T, Yang W, Yang L, Liang Y, Jia Z, Lv L, Li T. PD-L1 expression levels in mesenchymal stromal cells predict their therapeutic values for autoimmune hepatitis. Stem Cell Res Ther 2023; 14:370. [PMID: 38111045 PMCID: PMC10729378 DOI: 10.1186/s13287-023-03594-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis is a chronic inflammatory hepatic disorder with no effective treatment. Mesenchymal stromal cells (MSCs) have emerged as a promising treatment owing to their unique advantages. However, their heterogeneity is hampering use in clinical applications. METHODS Wharton's jelly derived MSCs (WJ-MSCs) were isolated from 58 human donors using current good manufacturing practice conditions. Gene expression profiles of the WJ-MSCs were analyzed by transcriptome and single-cell RNA-sequencing (scRNA-seq), and subsequent functional differences were assessed. Expression levels of programmed death-ligand 1 (PD-L1) were used as an indicator to screen WJ-MSCs with varied immunomodulation activities and assessed their corresponding therapeutic effects in a mouse model of concanavalin A-induced autoimmune hepatitis. RESULTS The 58 different donor-derived WJ-MSCs were grouped into six gene expression profile clusters. The gene in different clusters displayed obvious variations in cell proliferation, differentiation bias, trophic factor secretion, and immunoregulation. Data of scRNA-seq revealed four distinct WJ-MSCs subpopulations. Notably, the different immunosuppression capacities of WJ-MSCs were positively correlated with PD-L1 expression. WJ-MSCs with high expression of PD-L1 were therapeutically superior to WJ-MSCs with low PD-L1 expression in treating autoimmune hepatitis. CONCLUSION PD-L1 expression levels of WJ-MSCs could be regarded as an indicator to choose optimal MSCs for treating autoimmune disease. These findings provided novel insights into the quality control of MSCs and will inform improvements in the therapeutic benefits of MSCs.
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Affiliation(s)
- Xilong Bai
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
- Department of Hematology, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Tingwei Chen
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Yuqi Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Xiaofan Ge
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Caie Qiu
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Huili Gou
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Sili Wei
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Tingting Liu
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Wei Yang
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Liting Yang
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Yingmin Liang
- Department of Hematology, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Zhansheng Jia
- Department of Infection and Liver Disease, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Liangshan Lv
- Department of Minimally Invasive Interventional Radiology, Xi'an Gaoxin Hospital, Xi'an, , 710075, Shaanxi, China
| | - Tianqing Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China.
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Negoro T, Okura H, Hayashi S, Arai T, Matsuyama A. Poor Result Reporting Rate in Cell Therapy Trials Registered at ClinicalTrials.gov. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:623-633. [PMID: 37166388 DOI: 10.1089/ten.teb.2023.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
As research associates in clinical experiments, we have an obligation to disclose clinical methodologies and findings in full transparency in ethics. However, inadequate disclosure in results reporting clinical trials registered on ClinicalTrials.gov has been revealed, with approximately half the trial results not being reported in an applicable manner. Our recent study in clinical trials of regenerative medicine for four kinds of neurological diseases revealed that the rate of result reporting to ClinicalTrials.gov is inadequate for gene and cell therapy (CT) trials. In this path, further curiosity emerged to see what the findings would be if the analysis was conducted for trials in all disease areas, and outcomes if gene therapy (GT) and CT were distinguished in terms. In this study, the scope of analysis was further expanded to include all disease areas, and the drug classification from the AdisInsight database was used for modality classification, with biologic drug trials classified as controls, CT, ex vivo GT, and in vivo GT. To begin, among all interventional clinical trials with registration in the ClinicalTrials.gov registry and with a primary completion between 2010 and 2019, we created a total of 5539 datasets corresponding to trials classified as GT and CT, while biologics (BLG) as controls in the AdisInsight drug classification. The status of reported results of these trials was identified by surveying posting status of ClinicalTrials.gov and publication in journals (PubMed), respectively. Based on the obtained dataset, multivariate analysis was performed on the data on the reporting rate of clinical trial results, aggregated by sponsor, phase, status, and modality (CT, ex vivo GT, in vivo GT, and BLG), respectively. The result shows that CT was identified as an independent factor restraining result reporting ratio in both ClinicalTrials.gov and total disclosures, whereas ex vivo GT as boosting result reporting ratio. Since the result reporting rate of CT results was notably poor, we discussed the causes and solutions in this regard.
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Affiliation(s)
- Takaharu Negoro
- Center for Reverse Translational Research, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Habikino City, Japan
- Institute of Innovative Medical Technology, Osaka, Japan
| | - Hanayuki Okura
- Center for Reverse Translational Research, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Habikino City, Japan
- Institute of Innovative Medical Technology, Osaka, Japan
| | - Shigekazu Hayashi
- Center for Reverse Translational Research, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Habikino City, Japan
| | - Tsutomu Arai
- Center for Reverse Translational Research, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Habikino City, Japan
| | - Akifumi Matsuyama
- Center for Reverse Translational Research, Osaka Habikino Medical Center, Osaka Prefectural Hospital Organization, Habikino City, Japan
- Institute of Innovative Medical Technology, Osaka, Japan
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14
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Lee RH, Boregowda SV, Shigemoto-Kuroda T, Bae E, Haga CL, Abbery CA, Bayless KJ, Haskell A, Gregory CA, Ortiz LA, Phinney DG. TWIST1 and TSG6 are coordinately regulated and function as potency biomarkers in human MSCs. SCIENCE ADVANCES 2023; 9:eadi2387. [PMID: 37948519 PMCID: PMC10637745 DOI: 10.1126/sciadv.adi2387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/11/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) have been evaluated in >1500 clinical trials, but outcomes remain suboptimal because of knowledge gaps in quality attributes that confer potency. We show that TWIST1 directly represses TSG6 expression that TWIST1 and TSG6 are inversely correlated across bone marrow-derived MSC (BM-MSC) donor cohorts and predict interdonor differences in their proangiogenic, anti-inflammatory, and immune suppressive activity in vitro and in sterile inflammation and autoimmune type 1 diabetes preclinical models. Transcript profiling of TWIST1HiTSG6Low versus TWISTLowTSG6Hi BM-MSCs revealed previously unidentified roles for TWIST1/TSG6 in regulating cellular oxidative stress and TGF-β2 in modulating TSG6 expression and anti-inflammatory activity. TWIST1 and TSG6 levels also correlate to donor stature and predict differences in iPSC-derived MSC quality attributes. These results validate TWIST1 and TSG6 as biomarkers that predict interdonor differences in potency across laboratories and assay platforms, thereby providing a means to manufacture MSC products tailored to specific diseases.
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Affiliation(s)
- Ryang Hwa Lee
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Siddaraju V. Boregowda
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, 33458, USA
| | - Taeko Shigemoto-Kuroda
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - EunHye Bae
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Christopher L. Haga
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, 33458, USA
| | - Colette A. Abbery
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Kayla J. Bayless
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Andrew Haskell
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Carl A. Gregory
- Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, TX, 77845, USA
| | - Luis A. Ortiz
- Department of Environmental Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Donald G. Phinney
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, 33458, USA
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15
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Zaripova LN, Midgley A, Christmas SE, Beresford MW, Pain C, Baildam EM, Oldershaw RA. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. Int J Mol Sci 2023; 24:16040. [PMID: 38003230 PMCID: PMC10671211 DOI: 10.3390/ijms242216040] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
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Affiliation(s)
- Lina N. Zaripova
- Institute of Fundamental and Applied Medicine, National Scientific Medical Center, 42 Abylai Khan Avenue, Astana 010000, Kazakhstan;
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Angela Midgley
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
| | - Stephen E. Christmas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, Faculty of Health and Life Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE, UK;
| | - Michael W. Beresford
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Clare Pain
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Eileen M. Baildam
- Department of Paediatric Rheumatology, The Alexandra Hospital, Mill Lane, Cheadle SK8 2PX, UK;
| | - Rachel A. Oldershaw
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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16
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Ding Y, Liu C, Cai Y, Hou C, Chen G, Xu Y, Hu S, Wu D. The efficiency of human umbilical cord mesenchymal stem cells as a salvage treatment for steroid-refractory acute graft-versus-host disease. Clin Exp Med 2023; 23:2561-2570. [PMID: 36598673 DOI: 10.1007/s10238-022-00983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 01/05/2023]
Abstract
Acute graft-versus-host disease (aGVHD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) and is primarily treated with steroids. However, there is no standard treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). Although mesenchymal stem cells (MSCs) have proven effective for SR-aGVHD, few reports have focused on human umbilical cord blood-derived MSCs (hUCB-MSCs). Here, we report on the efficiency of hUCB-MSCs as the salvage therapy for SR-aGVHD in 54 patients. The overall response rate (ORR) reached 59.3% (32/54) 28 days later. Twenty-four patients achieved complete remission (CR), and 8 achieved partial remission (PR). The median follow-up time after the initiation of hUCB-MSC treatment was 19.3 (0.6-59.0) months. The probability of overall survival (OS) and progression-free survival (PFS) was 60.9% (47.4-74.4%, 95% CI) and 58.8% (45.3-72.3%, 95% CI), respectively, while that of GVHD/relapse-free survival (GRFS) was only 30.8% (17.86-43.74%, 95% CI). Multivariate analysis revealed that response on Day 28 was an independent favorable prognostic factor (OS, P < 0.001; PFS, P < 0.001; GRFS, P = 0.001), but an age of ≥ 18 years suggested an unfavorable long-term prognosis (OS, P < 0.001; PFS, P < 0.001; GRFS, P = 0.003). In addition, liver involvement was adversely associated with PFS (P = 0.021) and GRFS (P = 0.009). An infused MNC ≥ 8.66 × 108/kg was also detrimental to GRFS (P = 0.031). Collectively, our results support hUCB-MSCs as an effective treatment for SR-aGVHD.
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Affiliation(s)
- Yihan Ding
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Department of Hematology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Chang Liu
- Department of Hematology, Jiangsu Children's Hematology and Oncology Center, Children's Hospital of Soochow University, Suzhou, China
| | - Yiming Cai
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chang Hou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Guanghua Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Shaoyan Hu
- Department of Hematology, Jiangsu Children's Hematology and Oncology Center, Children's Hospital of Soochow University, Suzhou, China.
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
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17
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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18
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Lin T, Yang Y, Chen X. A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation. Eur J Med Res 2023; 28:268. [PMID: 37550742 PMCID: PMC10405442 DOI: 10.1186/s40001-023-01244-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.
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Affiliation(s)
- Ting Lin
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunfan Yang
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xinchuan Chen
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
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19
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Teryek M, Jadhav P, Bento R, Parekkadan B. High-Throughput Production of Microcapsules for Human Bone Marrow Derived Mesenchymal Stem Cell Biomanufacturing in a Vertical-Wheel Bioreactor. BIOTECHNOL BIOPROC E 2023; 28:528-544. [DOI: 10.1007/s12257-023-0020-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/02/2023] [Accepted: 05/28/2023] [Indexed: 01/06/2025]
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20
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Mattoli S, Schmidt M. Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives. Adv Ther 2023; 40:2626-2692. [PMID: 37069355 PMCID: PMC10109238 DOI: 10.1007/s12325-023-02507-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/24/2023] [Indexed: 04/19/2023]
Abstract
Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.
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Affiliation(s)
- Sabrina Mattoli
- Center of Expertise in Research and Innovation of the International Network for the Advancement of Viable and Applicable Innovations in Life Sciences (InAvail), InAvail at Rosental Nexxt, 4058 Basel, Switzerland
- Avail Biomedical Research Institute, 80539 Munich, Germany
| | - Matthias Schmidt
- Avail Biomedical Research Institute, 80539 Munich, Germany
- Discovery and Translational Research Center, 80539 Munich, Germany
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21
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Valsecchi C, Croce S, Lenta E, Acquafredda G, Comoli P, Avanzini MA. TITLE: New therapeutic approaches in pediatric diseases: Mesenchymal stromal cell and mesenchymal stromal cell-derived extracellular vesicles as new drugs. Pharmacol Res 2023; 192:106796. [PMID: 37207738 DOI: 10.1016/j.phrs.2023.106796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases.
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Affiliation(s)
- Chiara Valsecchi
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Stefania Croce
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Elisa Lenta
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Gloria Acquafredda
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Patrizia Comoli
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Maria Antonietta Avanzini
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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22
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Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol 2023; 20:613-625. [PMID: 37165014 DOI: 10.1038/s41423-023-01022-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
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Affiliation(s)
- Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sylvie Amu
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ellen Iacobaeus
- Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Erik Boberg
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Cell Therapies and Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
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23
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Jaing TH, Chang TY, Chiu CC. Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease. World J Stem Cells 2023; 15:221-234. [PMID: 37180998 PMCID: PMC10173808 DOI: 10.4252/wjsc.v15.i4.221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency. Despite its increased use, the mortality rate for patients undergoing this procedure remains high, mainly due to the perceived risk of exacerbating graft-versus-host disease (GVHD). However, even with immunosuppressive agents, some patients still develop GVHD. Advanced mesenchymal stem/stromal cell (MSC) strategies have been proposed to achieve better therapeutic outcomes, given their immunosuppressive potential. However, the efficacy and trial designs have varied among the studies, and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs. This review aims to provide real insights into this clinical entity, emphasizing diagnostic, and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues. The indications and timing for the clinical application of MSCs are still subject to debate.
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Affiliation(s)
- Tang-Her Jaing
- Division of Hematology, Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan 333, Taiwan
| | - Tsung-Yen Chang
- Department of Pediatrics, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chia-Chi Chiu
- Department of Nursing, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Yudhawati R, Shimizu K. PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:ijms24087299. [PMID: 37108459 PMCID: PMC10138595 DOI: 10.3390/ijms24087299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation.
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Affiliation(s)
- Resti Yudhawati
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
| | - Kazufumi Shimizu
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Garcia-Rosa M, Abraham A, Bertaina A, Bhoopalan SV, Bonfim C, Cohen S, DeZern A, Louis C, Oved J, Pavel-Dinu M, Purtill D, Ruggeri A, Russell A, Sharma A, Wynn R, Boelens JJ, Prockop S. International society for cell & gene therapy stem cell engineering committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant. Cytotherapy 2023; 25:578-589. [PMID: 36941149 DOI: 10.1016/j.jcyt.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AIMS Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. METHODS We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included. RESULTS Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. CONCLUSIONS There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.
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Affiliation(s)
- Moises Garcia-Rosa
- Pediatric Hematology-Oncology Fellow, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA.
| | - Allistair Abraham
- Center for Cancer and Immunology Research, CETI, Children's National Hospital, Washington, District of Columbia, USA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Senthil Velan Bhoopalan
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Carmem Bonfim
- Pediatric Blood and Marrow Transplantation Division and Pele Pequeno Principe Research Institute, Hospital Pequeno Principe, Curitiba, Brazil
| | - Sandra Cohen
- Universite de Montreal and Maisonneuve Rosemont Hospital, Montreal, Quebec, Canada
| | - Amy DeZern
- Bone Marrow Failure and MDS Program, John Hopkins Medicine Baltimore, Maryland, USA
| | | | - Joseph Oved
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mara Pavel-Dinu
- Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Redwood City, California, USA
| | - Duncan Purtill
- Department of Haematology, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | | | - Athena Russell
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Akshay Sharma
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert Wynn
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Jaap Jan Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Susan Prockop
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts USA
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Strzelec M, Detka J, Mieszczak P, Sobocińska MK, Majka M. Immunomodulation—a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol 2023; 14:1127704. [PMID: 36969193 PMCID: PMC10033545 DOI: 10.3389/fimmu.2023.1127704] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/23/2023] [Indexed: 03/11/2023] Open
Abstract
In recent years, there has been a tremendous development of biotechnological, pharmacological, and medical techniques which can be implemented in the functional modulation of the immune system components. Immunomodulation has attracted much attention because it offers direct applications in both basic research and clinical therapy. Modulation of a non-adequate, amplified immune response enables to attenuate the clinical course of a disease and restore homeostasis. The potential targets to modulate immunity are as multiple as the components of the immune system, thus creating various possibilities for intervention. However, immunomodulation faces new challenges to design safer and more efficacious therapeutic compounds. This review offers a cross-sectional picture of the currently used and newest pharmacological interventions, genomic editing, and tools for regenerative medicine involving immunomodulation. We reviewed currently available experimental and clinical evidence to prove the efficiency, safety, and feasibility of immunomodulation in vitro and in vivo. We also reviewed the advantages and limitations of the described techniques. Despite its limitations, immunomodulation is considered as therapy itself or as an adjunct with promising results and developing potential.
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Validation of an ICH Q2 Compliant Flow Cytometry-Based Assay for the Assessment of the Inhibitory Potential of Mesenchymal Stromal Cells on T Cell Proliferation. Cells 2023; 12:cells12060850. [PMID: 36980191 PMCID: PMC10047294 DOI: 10.3390/cells12060850] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/20/2023] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have the potential to suppress pathological activation of immune cells and have therefore been considered for the treatment of Graft-versus-Host-Disease. The clinical application of MSCs requires a process validation to ensure consistent quality. A flow cytometry-based mixed lymphocyte reaction (MLR) was developed to analyse the inhibitory effect of MSCs on T cell proliferation. Monoclonal antibodies were used to stimulate T cell expansion and determine the effect of MSCs after four days of co-culture based on proliferation tracking with the violet proliferation dye VPD450. Following the guidelines of the International Council for Harmonisation (ICH) Q2 (R1), the performance of n = 30 peripheral blood mononuclear cell (PBMC) donor pairs was assessed. The specific inhibition of T cells by viable MSCs was determined and precision values of <10% variation for repeatability and <15% for intermediate precision were found. Compared to a non-compendial reference method, a linear correlation of r = 0.9021 was shown. Serial dilution experiments demonstrated a linear range for PBMC:MSC ratios from 1:1 to 1:0.01. The assay was unaffected by PBMC inter-donor variability. In conclusion, the presented MLR can be used as part of quality control tests for the validation of MSCs as a clinical product.
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Teryek M, Jadhav P, Bento R, Parekkadan B. 3D Microcapsules for Human Bone Marrow Derived Mesenchymal Stem Cell Biomanufacturing in a Vertical-Wheel Bioreactor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.16.528656. [PMID: 36824906 PMCID: PMC9949076 DOI: 10.1101/2023.02.16.528656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Microencapsulation of human mesenchymal stromal cells (MSCs) via electrospraying has been well documented in tissue engineering and regenerative medicine. Herein, we report the use of microencapsulation, via electrospraying, for MSC expansion using a commercially available hydrogel that is durable, optimized to MSC culture, and enzymatically degradable for cell recovery. Critical parameters of the electrospraying encapsulation process such as seeding density, correlation of microcapsule output with hydrogel volume, and applied voltage were characterized to consistently fabricate cell-laden microcapsules of uniform size. Upon encapsulation, we then verified ~ 10x expansion of encapsulated MSCs within a vertical-wheel bioreactor and the preservation of critical quality attributes such as immunophenotype and multipotency after expansion and cell recovery. Finally, we highlight the genetic manipulation of encapsulated MSCs as an example of incorporating bioactive agents in the capsule material to create new compositions of MSCs with altered phenotypes.
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Affiliation(s)
- Matthew Teryek
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Pankaj Jadhav
- Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Raphaela Bento
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA
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29
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Choi A, Javius-Jones K, Hong S, Park H. Cell-Based Drug Delivery Systems with Innate Homing Capability as a Novel Nanocarrier Platform. Int J Nanomedicine 2023; 18:509-525. [PMID: 36742991 PMCID: PMC9893846 DOI: 10.2147/ijn.s394389] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/12/2023] [Indexed: 01/29/2023] Open
Abstract
Nanoparticle-based drug delivery systems have been designed to treat various diseases. However, many problems remain, such as inadequate tumor targeting and poor therapeutic outcomes. To overcome these obstacles, cell-based drug delivery systems have been developed. Candidates for cell-mediated drug delivery include blood cells, immune cells, and stem cells with innate tumor tropism and low immunogenicity; they act as a disguise to deliver the therapeutic payload. In drug delivery systems, therapeutic agents are encapsulated intracellularly or attached to the surface of the plasma membrane and transported to the desired site. Here, we review the pros and cons of cell-based therapies and discuss their homing mechanisms in the tumor microenvironment. In addition, different strategies to load therapeutic agents inside or on the surface of circulating cells and the current applications for a wide range of disease treatments are summarized.
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Affiliation(s)
- Anseo Choi
- School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Kaila Javius-Jones
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI, USA
| | - Seungpyo Hong
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI, USA
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, Republic of Korea,Correspondence: Hansoo Park; Seungpyo Hong, School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea, Tel +82-2 820 5804, Fax +82-2 813 8159, Email ;
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30
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Torggler R, Margreiter E, Marksteiner R, Thurner M. Potency Assay Development: A Keystone for Clinical Use. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1420:13-28. [PMID: 37258781 DOI: 10.1007/978-3-031-30040-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Potency can be described as the quantitative measure of biological activity, that is, the ability of an Advanced Therapy Medicinal Product (ATMP) to elicit the intended effect necessary for clinical efficacy. Potency testing is part of the quality control strategy necessary for batch release and is required for market approval application of an ATMP. Thus, it is crucial to develop a reliable and accurate potency assay. As a prerequisite for potency assay development, it is essential to define the mode of action of the product and thereby also the relevant biological activity that should be measured. The establishment of a potency assay should be initiated already during early product development followed by its progressive implementation into an ATMP's manufacturing, quality control and release process. Potency testing is indispensable for clinical use with a wide range of applications. A potency assay is a valuable tool to determine the product's stability, detect the impact of changes in the manufacturing process on the product, demonstrate quality and manufacturing consistency from batch to batch, estimate clinical efficacy and define the effective dose. This chapter describes the requirements and challenges to be considered for potency assay development and the importance of a well-established potency assay for clinical use.
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Affiliation(s)
| | | | | | - Marco Thurner
- Innovacell AG, Innsbruck, Austria
- Finnegan, Henderson, Farabow, Garrett & Dunner LLP, Munich, Germany
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31
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Sadeghi B, Ringdén O, Gustafsson B, Castegren M. Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review. Front Immunol 2022; 13:963445. [PMID: 36426365 PMCID: PMC9680556 DOI: 10.3389/fimmu.2022.963445] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening lung disease. It may occur during the pancytopenia phase following allogeneic hematopoietic cell transplantation (HCT). ARDS is rare following HCT. Mesenchymal stromal cells (MSCs) have strong anti-inflammatory effect and first home to the lung following intravenous infusion. MSCs are safe to infuse and have almost no side effects. During the Covid-19 pandemic many patients died from ARDS. Subsequently MSCs were evaluated as a therapy for Covid-19 induced ARDS. We report three patients, who were treated with MSCs for ARDS following HCT. Two were treated with MSCs derived from the bone marrow (BM). The third patient was treated with MSCs obtained from the placenta, so-called decidua stromal cells (DSCs). In the first patient, the pulmonary infiltrates cleared after infusion of BM-MSCs, but he died from multiorgan failure. The second patient treated with BM-MSCs died of aspergillus infection. The patient treated with DSCs had a dramatic response and survived. He is alive after 7 years with a Karnofsky score of 100%. We also reviewed experimental and clinical studies using MSCs or DSCs for ARDS. Several positive reports are using MSCs for sepsis and ARDS in experimental animals. In man, two prospective randomized placebo-controlled studies used adipose and BM-MSCs, respectively. No difference in outcome was seen compared to placebo. Some pilot studies used MSCs for Covid-19 ARDS. Positive results were achieved using umbilical cord and DSCs however, optimal source of MSCs remains to be elucidated using randomized trials.
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Affiliation(s)
- Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Behnam Sadeghi,
| | - Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Markus Castegren
- Center for Clinical Research, Sörmland, Uppsala University, Uppsala, Sweden
- Department of Anesthesiology and Intensive Care, CLINTEC, Karolinska Institutet, Stockholm, Sweden
- Section of Infectious Diseases, Department of Medical Science, Uppsala University, Uppsala, Sweden
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Xue E, Minniti A, Alexander T, Del Papa N, Greco R, on behalf of The Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Cellular-Based Therapies in Systemic Sclerosis: From Hematopoietic Stem Cell Transplant to Innovative Approaches. Cells 2022; 11:3346. [PMID: 36359742 PMCID: PMC9658618 DOI: 10.3390/cells11213346] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 08/28/2023] Open
Abstract
Systemic sclerosis (SSc) is a systemic disease characterized by autoimmune responses, vasculopathy and tissue fibrosis. The pathogenic mechanisms involve a wide range of cells and soluble factors. The complexity of interactions leads to heterogeneous clinical features in terms of the extent, severity, and rate of progression of skin fibrosis and internal organ involvement. Available disease-modifying drugs have only modest effects on halting disease progression and may be associated with significant side effects. Therefore, cellular therapies have been developed aiming at the restoration of immunologic self-tolerance in order to provide durable remissions or to foster tissue regeneration. Currently, SSc is recommended as the 'standard indication' for autologous hematopoietic stem cell transplantation by the European Society for Blood and Marrow Transplantation. This review provides an overview on cellular therapies in SSc, from pre-clinical models to clinical applications, opening towards more advanced cellular therapies, such as mesenchymal stem cells, regulatory T cells and potentially CAR-T-cell therapies.
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Affiliation(s)
- Elisabetta Xue
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
| | - Antonina Minniti
- Department of Rheumatology, ASST G. Pini-CTO, 20122 Milan, Italy
| | - Tobias Alexander
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, 10117 Berlin, Germany
| | | | - Raffaella Greco
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
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Nachmias B, Zimran E, Avni B. Mesenchymal stroma/stem cells: Haematologists' friend or foe? Br J Haematol 2022; 199:175-189. [PMID: 35667616 PMCID: PMC9796884 DOI: 10.1111/bjh.18292] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 01/07/2023]
Abstract
Mesenchymal stromal cells (MSCs) are non-haematopoietic cells found in fetal and adult organs, that play important roles in tissue repair, inflammation and immune modulation. MSCs residing in the bone marrow interact closely with haematopoietic cells and comprise an important component of the microenvironment supporting haematopoiesis, in both health and disease states. Since their identification in 1970, basic scientific and preclinical research efforts have shed light on the role of MSCs in the regulation of haematopoiesis and evoked interest in their clinical application in haematopoietic stem cell transplantation (HSCT) and malignant haematology. Over the last two decades, these research efforts have led to numerous clinical trials, which have established the safety of MSC therapy; however, the optimal mode of administration and the benefit remain inconclusive. In this paper, we will review the clinical experience with use of MSCs in HSCT for enhancement of engraftment, prevention and treatment of graft-versus-host disease and haemorrhagic cystitis. Then, we will discuss the contradictory evidence regarding tumour-promoting versus tumour-suppressing effects of MSCs in haematological malignancies, which may have relevance for future clinical applications.
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Affiliation(s)
- Boaz Nachmias
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Eran Zimran
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Batia Avni
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
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Verbeek AB, Jansen SA, von Asmuth EG, Lankester AC, Bresters D, Bierings M, Mohseny AB, Lindemans CA, Buddingh EP. Clinical Features, Treatment, and Outcome of Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Multicenter Study. Transplant Cell Ther 2022; 28:600.e1-600.e9. [DOI: 10.1016/j.jtct.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/17/2022]
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Shimoyama K, Tsuchiya T, Watanabe H, Ergalad A, Iwatake M, Miyazaki T, Hashimoto Y, Hsu YI, Hatachi G, Matsumoto K, Ishii M, Mizoguchi S, Doi R, Tomoshige K, Yamaoka T, Nagayasu T. Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation. Transplant Proc 2022; 54:1998-2007. [PMID: 36041932 DOI: 10.1016/j.transproceed.2022.05.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/03/2022] [Accepted: 05/22/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.
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Affiliation(s)
- Koichiro Shimoyama
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoshi Tsuchiya
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Division of Nucleic Acid Drug Development, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan.
| | - Hironosuke Watanabe
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Abdelmotagaly Ergalad
- Center for Preclinical Surgical and Interventional Research, Texas Heart Institute, Houston, Texas
| | - Mayumi Iwatake
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takuro Miyazaki
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasumasa Hashimoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yu-I Hsu
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Go Hatachi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Keitaro Matsumoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsutoshi Ishii
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Mizoguchi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryoichiro Doi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Koichi Tomoshige
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tetsuji Yamaoka
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Takeshi Nagayasu
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Nagamura-Inoue T, Kato S, Najima Y, Isobe M, Doki N, Yamamoto H, Uchida N, Takahashi A, Hori A, Nojima M, Ohashi K, Nagamura F, Tojo A. Immunological influence of serum-free manufactured umbilical cord-derived mesenchymal stromal cells for steroid-resistant acute graft-versus-host disease. Int J Hematol 2022; 116:754-769. [PMID: 35908021 DOI: 10.1007/s12185-022-03408-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 06/13/2022] [Indexed: 12/31/2022]
Abstract
This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr ).
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Affiliation(s)
- Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. .,Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. .,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. .,Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Seiko Kato
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | | | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Atsuko Takahashi
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akiko Hori
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masanori Nojima
- Division of Advanced Medicine Promotion, The Advanced Clinical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuteru Ohashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Fumitaka Nagamura
- Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.,Division of Advanced Medicine Promotion, The Advanced Clinical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Institute of Innovation Advancement, Tokyo Medical and Dental University, Tokyo, Japan
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Lederer CW, Koniali L, Buerki-Thurnherr T, Papasavva PL, La Grutta S, Licari A, Staud F, Bonifazi D, Kleanthous M. Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies. Pharmaceutics 2022; 14:pharmaceutics14040793. [PMID: 35456627 PMCID: PMC9031205 DOI: 10.3390/pharmaceutics14040793] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 01/19/2023] Open
Abstract
Advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, cells or tissue engineering. After clear successes in adults, the nascent technology now sees increasing pediatric application. For many still untreatable disorders with pre- or perinatal onset, timely intervention is simply indispensable; thus, prenatal and pediatric applications of ATMPs hold great promise for curative treatments. Moreover, for most inherited disorders, early ATMP application may substantially improve efficiency, economy and accessibility compared with application in adults. Vindicating this notion, initial data for cell-based ATMPs show better cell yields, success rates and corrections of disease parameters for younger patients, in addition to reduced overall cell and vector requirements, illustrating that early application may resolve key obstacles to the widespread application of ATMPs for inherited disorders. Here, we provide a selective review of the latest ATMP developments for prenatal, perinatal and pediatric use, with special emphasis on its comparison with ATMPs for adults. Taken together, we provide a perspective on the enormous potential and key framework parameters of clinical prenatal and pediatric ATMP application.
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Affiliation(s)
- Carsten W. Lederer
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
- Correspondence: ; Tel.: +357-22-392764
| | - Lola Koniali
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Tina Buerki-Thurnherr
- Empa, Swiss Federal Laboratories for Materials Science and Technology, 9014 St. Gallen, Switzerland;
| | - Panayiota L. Papasavva
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Stefania La Grutta
- Institute of Translational Pharmacology, IFT National Research Council, 90146 Palermo, Italy;
| | - Amelia Licari
- Pediatric Clinic, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy;
| | - Frantisek Staud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, 50005 Hradec Králové, Czech Republic;
| | - Donato Bonifazi
- Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF) and European Paediatric Translational Research Infrastructure (EPTRI), 70122 Bari, Italy;
| | - Marina Kleanthous
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
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Mo XD, Hong SD, Zhao YL, Jiang EL, Chen J, Xu Y, Sun ZM, Zhang WJ, Liu QF, Liu DH, Wan DM, Mo WJ, Ren HY, Yang T, Huang H, Zhang X, Wang XN, Song XM, Gao SJ, Wang X, Chen Y, Xu B, Jiang M, Huang XB, Li X, Zhang HY, Wang HT, Wang Z, Niu T, Wang JS, Xia LH, Liu XD, Li F, Zhou F, Lang T, Hu J, Wu SJ, Huang XJ. Basiliximab for steroid-refractory acute graft-versus-host disease: A real-world analysis. Am J Hematol 2022; 97:458-469. [PMID: 35064928 DOI: 10.1002/ajh.26475] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023]
Abstract
Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD.
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Affiliation(s)
- Xiao-Dong Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences (2019RU029), Beijing, China
| | - Shen-Da Hong
- National Institute of Health Data Science at Peking University, Peking University Health Science Center, Beijing, China
| | - Yan-Li Zhao
- Hebei Yanda Lu Daopei Hospital, Beijing Lu Daopei Institute of Hematology, Beijing, China
| | - Er-Lie Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jing Chen
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zi-Min Sun
- Department of Hematology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei-Jie Zhang
- Department of Hematology, Aerospace Center Hospital, Beijing, China
| | - Qi-Fa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dai-Hong Liu
- Department of Hematology, Chinese PLA General Hospital, Beijing, China
| | - Ding-Ming Wan
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wen-Jian Mo
- Department of Hematology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Han-Yun Ren
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Ting Yang
- Fujian Medical University Union Hospital, Fujian Institute of Hematology, Department of Hematology, Fujian Provincial Key Laboratory of Hematology, Fuzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University; State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Xiao-Ning Wang
- Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xian-Min Song
- Department of Hematology, Shanghai general Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Su-Jun Gao
- Department of Hematology, the First Hospital of Jilin University, Changchun, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yi Chen
- Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hematology, Wenzhou, China
| | - Bing Xu
- The First Affiliated Hospital of Xiamen University, Xiamen University Institute of Hematology, Xiamen, China
| | - Ming Jiang
- Hematologic Disease Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Research Institute of Hematology Xinjiang Medical University, Urumqi, China
| | - Xiao-Bing Huang
- Department of Hematology, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xin Li
- Department of Hematology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Yu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Hong-Tao Wang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ting Niu
- Department of Hematology, West China hospital, Sichuan University, Chengdu, China
| | - Ji-Shi Wang
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Department of Hematology, Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ling-Hui Xia
- Division of Bone Marrow Transplantation, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Dan Liu
- Department of Hematology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fei Li
- Department of Hematology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fang Zhou
- Department of Hematology, the 960 Hospital of the PLA Joint Logistics Support Force, Jinan, China
| | - Tao Lang
- Department of Hematology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jiong Hu
- Blood and Marrow Transplantation Center, Department of Hematology, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sui-Jing Wu
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences (2019RU029), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, China
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Tan KX, Chang T, Lin XL. Secretomes as an emerging class of bioactive ingredients for enhanced cosmeceutical applications. Exp Dermatol 2022; 31:674-688. [PMID: 35338666 DOI: 10.1111/exd.14570] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/23/2022] [Accepted: 03/22/2022] [Indexed: 11/30/2022]
Abstract
Skin aging is predominantly caused by either intrinsic or extrinsic factors, leading to undesirable skin features. Advancements in both molecular and cellular fields have created possibilities in developing novel stem cell-derived active ingredients for cosmeceutical applications and the beauty industry. Mesenchymal stromal cell (MSC)-derived secretomes or conditioned media hold great promise for advancing skin repair and regeneration due to the presence of varying cytokines. These cytokines signal our cells and trigger biological mechanisms associated with anti-inflammatory, antioxidant, anti-aging, proliferative, and immunomodulatory effects. In this review, we discuss the potential of MSC secretomes as novel biomaterials for skincare and rejuvenation by illustrating their mechanism of action related to wound healing, anti-aging, and whitening properties. The advantages and disadvantages of secretomes are compared to both plant-based and animal-derived extracts. In addition, this paper reviews the current safety standards, regulations, market products and research work related to the cosmeceutical applications of secretomes along with strategies to maintain and improve the therapeutic efficacy and production of secretomes. The future outlook of beauty industry is also presented. Lastly, we highlight significant challenges to be addressed for the clinical realization of MSC secretomes-based skin therapies as well as providing perspectives for the future direction of secretomes.
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Affiliation(s)
- Kei-Xian Tan
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
| | - Trixie Chang
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
| | - Xiang-Liang Lin
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
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40
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Zhao K, Lin R, Fan Z, Chen X, Wang Y, Huang F, Xu N, Zhang X, Zhang X, Xuan L, Wang S, Lin D, Deng L, Nie D, Weng J, Li Y, Zhang X, Li Y, Xiang AP, Liu Q. Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial. J Hematol Oncol 2022; 15:22. [PMID: 35255929 PMCID: PMC8900437 DOI: 10.1186/s13045-022-01240-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/19/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD. METHODS A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse. RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610). CONCLUSIONS MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .
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Affiliation(s)
- Ke Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhiping Fan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yu Wang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Fen Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Na Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Xin Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shunqing Wang
- Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Dongjun Lin
- Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Lan Deng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Danian Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jianyu Weng
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yonghua Li
- Department of Hematology, General Hospital of Southern Theatre Command, Guangzhou, 440104, China
| | - Xiaohui Zhang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - A P Xiang
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, Wu J. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther 2022; 13:93. [PMID: 35246235 PMCID: PMC8895864 DOI: 10.1186/s13287-022-02751-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. Main body In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. Conclusion In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02751-0.
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Affiliation(s)
- Ying Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,Department of Gastroenterology, The First Hospital, Jilin University, Changchun, 130021, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,International Center of Future Science, Jilin University, Changchun, 130021, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liguang Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China. .,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
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Mukherjee A, Verma A, Bihani S, Burli A, Mantri K, Srivastava S. Proteomics advances towards developing SARS-CoV-2 therapeutics using in silico drug repurposing approaches. DRUG DISCOVERY TODAY. TECHNOLOGIES 2021; 39:1-12. [PMID: 34906319 PMCID: PMC8222565 DOI: 10.1016/j.ddtec.2021.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/21/2021] [Accepted: 06/11/2021] [Indexed: 12/12/2022]
Abstract
Standing amidst the COVID-19 pandemic, we have faced major medical and economic crisis in recent times which remains to be an unresolved issue till date. Although the scientific community has made significant progress towards diagnosis and understanding the disease; however, effective therapeutics are still lacking. Several omics-based studies, especially proteomics and interactomics, have contributed significantly in terms of identifying biomarker panels that can potentially be used for the disease prognosis. This has also paved the way to identify the targets for drug repurposing as a therapeutic alternative. US Food and Drug Administration (FDA) has set in motion more than 500 drug development programs on an emergency basis, most of them are focusing on repurposed drugs. Remdesivir is one such success of a robust and quick drug repurposing approach. The advancements in omics-based technologies has allowed to explore altered host proteins, which were earlier restricted to only SARS-CoV-2 protein signatures. In this article, we have reviewed major contributions of proteomics and interactomics techniques towards identifying therapeutic targets for COVID-19. Furthermore, in-silico molecular docking approaches to streamline potential drug candidates are also discussed.
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Affiliation(s)
- Amrita Mukherjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Ayushi Verma
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Surbhi Bihani
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Ananya Burli
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Krishi Mantri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
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Potential of Bone-Marrow-Derived Mesenchymal Stem Cells for Maxillofacial and Periodontal Regeneration: A Narrative Review. Int J Dent 2021; 2021:4759492. [PMID: 34795761 PMCID: PMC8594991 DOI: 10.1155/2021/4759492] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/19/2021] [Accepted: 10/25/2021] [Indexed: 12/11/2022] Open
Abstract
Bone-marrow-derived mesenchymal stem cells (BM-MSCs) are one of the most widely studied postnatal stem cell populations and are considered to utilize more frequently in cell-based therapy and cancer. These types of stem cells can undergo multilineage differentiation including blood cells, cardiac cells, and osteogenic cells differentiation, thus providing an alternative source of mesenchymal stem cells (MSCs) for tissue engineering and personalized medicine. Despite the ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture which provided a great opportunity and opened the new door for establishing the in vitro disease modeling and generating an unlimited source for cell base therapy, using MSCs for regeneration purposes still have a great chance to cure diseases. In this review, we discuss the important issues in MSCs biology including the origin and functions of MSCs and their application for craniofacial and periodontal tissue regeneration, discuss the potential and clinical applications of this type of stem cells in differentiation to maxillofacial bone and cartilage in vitro, and address important future hopes and challenges in this field.
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Meenakshi Sundaram R, Kadapakkam Nandabalan S, Rupert S, Srinivasan P, Sankar P, Patra B, Verma RS, Vennila R, Sathyanesan J, Rajagopal S. Differential immunomodulation of human Mesenchymal Stromal Cells from various sources in an inflammation mimetic milieu. Cytotherapy 2021; 24:110-123. [PMID: 34740526 DOI: 10.1016/j.jcyt.2021.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 08/21/2021] [Accepted: 09/06/2021] [Indexed: 01/18/2023]
Abstract
Mesenchymal stromal cells (MSCs) are very advantageous in the field of regenerative medicine because of their immunomodulatory properties. However, reports show that these properties vary from source to source. Hence, understanding the source-dependent specificity of MSCs and their immunomodulatory abilities will enable optimal use of MSCs in cell-based therapies. Here, we studied human MSCs from three different sources, adipose tissue (AT), bone marrow (BM) and Wharton's jelly (WJ), with respect to phenotypic responses of human peripheral blood mononuclear immune cells (hPBMCs/MNCs) and the concurrent changes in cytokine expression in MSCs, under mitogen-stimulated co-culture conditions. We used cytometric analysis to study the immunoregulatory properties of MSCs on MNCs and cytokine profiling of MSCs using a customized PCR array and solid-phase sandwich enzyme-linked immunosorbent assay. Our results reveal differential modulation of immune cells as well as MSCs upon activation by the mitogen phytohemagglutinin, independently and in co-culture. Notably, we observed source-specific MSC-cytokine signatures under stimulated conditions. Our results show that AT-MSCs up-regulate VEGF, BM-MSCs up-regulate PTGS-2 and WJ-MSCs increase expression of IDO considerably compared with controls. This remarkable modulation in source-specific cytokine expression was also validated at a functional level by quantitative protein expression studies. In our hands, even though MSCs from AT, BM and WJ sources exhibit characteristic immunomodulatory properties, our results highlight that MSCs sourced from different tissues may exhibit unique cytokine signatures and thus may be suitable for specific regenerative applications.
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Affiliation(s)
| | | | - Secunda Rupert
- Stem Cell Research Centre, Government Stanley Hospital, Chennai, India
| | | | - Pavithra Sankar
- Stem Cell Research Centre, Government Stanley Hospital, Chennai, India
| | - Bamadeb Patra
- Stem Cell and Molecular Biology Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
| | - Rama Shankar Verma
- Stem Cell and Molecular Biology Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
| | - Rosy Vennila
- Government Medical College Hospital, Karur, India
| | | | - Surendran Rajagopal
- Hepato-Pancreato Biliary Centre for Surgery and Transplantation, MIOT International Hospital, Chennai, India.
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45
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Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy 2021; 23:961-973. [PMID: 34376336 PMCID: PMC8569889 DOI: 10.1016/j.jcyt.2021.06.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
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Affiliation(s)
- Julia Riedl
- Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Courtney Popp
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cindy Eide
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christen Ebens
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
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Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell 2021; 28:1708-1725. [PMID: 34624232 DOI: 10.1016/j.stem.2021.09.006] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
An exceptional safety profile has been shown in a large number of cell therapy clinical trials that use mesenchymal stromal cells (MSCs). However, reliable potency assays are still lacking to predict MSC immunosuppressive efficacy in the clinical setting. Nevertheless, MSCs are approved in Japan and Europe for the treatment of graft-versus-host and Crohn's fistular diseases, but not in the United States for any clinical indication. We discuss potential mechanisms of action for the therapeutic effects of MSC transplantation, experimental models that dissect tissue modulating function of MSCs, and approaches for identifying MSC effects in vivo by integrating biomarkers of disease and MSC activity.
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Affiliation(s)
- Mauro Krampera
- Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy.
| | - Katarina Le Blanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Allogeneic Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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Chuang HM, Ho LI, Harn HJ, Liu CA. Recent Findings on Cell-Based Therapies for COVID19-Related Pulmonary Fibrosis. Cell Transplant 2021; 30:963689721996217. [PMID: 33845643 PMCID: PMC8047934 DOI: 10.1177/0963689721996217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
COVID-19 has spread worldwide, including the United States, United Kingdom, and Italy, along with its site of origin in China, since 2020. The virus was first found in the Wuhan seafood market at the end of 2019, with a controversial source. The clinical symptoms of COVID-19 include fever, cough, and respiratory tract inflammation, with some severe patients developing an acute and chronic lung injury, such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). It has already claimed approximately 300 thousand human lives and the number is still on the rise; the only way to prevent the infection is to be safe till vaccines and reliable treatments develop. In previous studies, the use of mesenchymal stem cells (MSCs) in clinical trials had been proven to be effective in immune modulation and tissue repair promotion; however, their efficacy in treating COVID-19 remains underestimated. Here, we report the findings from past experiences of SARS and MSCs, and how SARS could also induce PF. Such studies may help to understand the rationale for the recent cell-based therapies for COVID-19.
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Affiliation(s)
- Hong-Meng Chuang
- Laboratory of Translational Medicine Office, Development Center for Biotechnology, Taipei
| | - Li-Ing Ho
- Division of Respiratory Therapy, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei
| | - Horng-Jyh Harn
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien.,Department of Pathology, Hualien Tzu Chi Hospital & Tzu Chi University, Hualien
| | - Ching-Ann Liu
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien.,Department of Medical Research, Hualien Tzu Chi Hospital, Hualien.,Department of Neuroscience Center, Hualien Tzu Chi Hospital, Hualien
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48
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Corbett JM, Hawthorne I, Dunbar H, Coulter I, Chonghaile MN, Flynn CM, English K. Cyclosporine A and IFNγ licencing enhances human mesenchymal stromal cell potency in a humanised mouse model of acute graft versus host disease. Stem Cell Res Ther 2021; 12:238. [PMID: 33853687 PMCID: PMC8048195 DOI: 10.1186/s13287-021-02309-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo.
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Affiliation(s)
- Jennifer M Corbett
- Cellular Immunology Laboratory, Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Ian Hawthorne
- Cellular Immunology Laboratory, Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Hazel Dunbar
- Cellular Immunology Laboratory, Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Ivan Coulter
- Sigmoid Pharma Ltd., Eden BioPharma Limited, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin 4, Ireland
| | | | | | - Karen English
- Cellular Immunology Laboratory, Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland.
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49
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Astarita C, Arora CL, Trovato L. Tissue regeneration: an overview from stem cells to micrografts. J Int Med Res 2021; 48:300060520914794. [PMID: 32536230 PMCID: PMC7297485 DOI: 10.1177/0300060520914794] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Regenerative medicine represents a major challenge for the scientific community. The choice of the biological sources used, such as stem cells and grafts, is crucial. Stem cell therapy is mainly related to the use of mesenchymal stem cells; however, clinical trials are still needed to investigate their safety. The micrografting technique was conceived by Cicero Parker Meek in 1958. It is based on the principle that by increasing the superficial area of skin grafts and reducing the size of its particles, it is possible to cover an area larger than the original donor site. Stem cells are pluripotent cells that have the capacity to differentiate into all cell types and are self-renewing, whereas micrografts derive from a small fragment of an autologous tissue and exhibit limited differentiative potential compared with stem cells. Therefore, stem cells and micrografts cannot be considered equivalent, although in some cases they exhibit similar regenerative potential, which is the focus of this review. Last, stem cell therapies remain limited because of complex and costly processes, making them not very feasible in clinical practice, whereas obtaining micrografts is generally a one-step procedure that does not require any advanced tissue manipulation.
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Affiliation(s)
- Carlo Astarita
- Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA.,Human Brain Wave, corso Galileo Ferraris 63, 10128 Turin, Italy
| | - Camilla L Arora
- Human Brain Wave, corso Galileo Ferraris 63, 10128 Turin, Italy
| | - Letizia Trovato
- Human Brain Wave, corso Galileo Ferraris 63, 10128 Turin, Italy
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50
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Gruhn B, Brodt G, Ernst J. Extended Treatment With Mesenchymal Stromal Cells-Frankfurt am Main in a Pediatric Patient With Steroid-refractory Acute Gastrointestinal Graft-Versus-Host Disease: Case Report and Review of the Literature. J Pediatr Hematol Oncol 2021; 43:e419-e425. [PMID: 32118816 DOI: 10.1097/mph.0000000000001758] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/30/2020] [Indexed: 12/14/2022]
Abstract
In acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation, there are various options available after the failure of initial steroid therapy. Since the publication of the first study in 2008, mesenchymal stromal cells (MSCs) have also been used with increasing frequency, including in pediatric patients with steroid-refractory aGVHD, and the manufacturing process has undergone further development. MSC-Frankfurt am Main (MSC-FFM, Obnitix), which is manufactured from pooled mononuclear bone marrow cells from 8 donors using a standardized process, resulted in a response rate of 84% in children with steroid-refractory aGVHD. We report on a 13-year-old female patient with acute myeloid leukemia who received Obnitix as a third-line treatment for gastrointestinal (GI) aGVHD in a life-threatening situation. The patient was initially given a total of 4 Obnitix infusions as per the regulatory approval, with her symptoms improving from day 9 after the first infusion. The second cycle of 4 Obnitix infusions followed due to persistent severe protein-losing enteropathy and resulted in complete remission. A systematic review of the literature on MSC in pediatric patients with steroid-refractory aGVHD confirms that MSC treatment beyond 4 weeks is employed in accordance with treatment protocols or on a case-by-case basis. To summarize, aGVHD activity can be checked endoscopically in patients with persistent GI symptoms and a second Obnitix cycle can then be administered if appropriate, with the goal of achieving complete remission. Future studies should also investigate the potential influence of tissue repair properties as an element in MSCs' efficacy in GI aGVHD.
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Affiliation(s)
- Bernd Gruhn
- Department of Pediatrics, Jena University Hospital, Jena, Germany
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