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Peltier D, Anh Do-Thi V, Devos T, Blazar BR, Toubai T. Cellular therapies for the prevention and treatment of acute graft-versus-host disease. Stem Cells 2025; 43:sxaf009. [PMID: 40117296 PMCID: PMC12111709 DOI: 10.1093/stmcls/sxaf009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/14/2024] [Indexed: 03/23/2025]
Abstract
Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) that is caused by donor immune cells attacking and damaging host tissues. Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, naïve T-cells) without loss of T-cells with beneficial functions and retaining and/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.
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Affiliation(s)
- Daniel Peltier
- Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Van Anh Do-Thi
- Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Timothy Devos
- Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven 3000, Belgium
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, United States
| | - Tomomi Toubai
- Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
- Clinical Research and Trial Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo City, Tokyo 113-8677, Japan
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Huang R, Zhang X. Exploration and practice: New integration of cellular therapy and hematopoietic stem cell transplantation. Chin Med J (Engl) 2025:00029330-990000000-01554. [PMID: 40387529 DOI: 10.1097/cm9.0000000000003558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Indexed: 05/20/2025] Open
Affiliation(s)
- Ruihao Huang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Xi Zhang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China
- Jinfeng Laboratory, Chongqing 401329, China
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Bukauskas A, Jucaitienė R, Stoškus M, Valčeckienė V, Bušmaitė G, Slobinas A, Davainis L, Šlepikienė I, Trociukas I, Pečeliūnas V, Griškevičius L, Žučenka A. Mesenchymal stromal cells for steroid-refractory biopsy-proven grade III-IV acute Graft-versus-Host Disease with predominant gastrointestinal involvement. Front Immunol 2025; 16:1600019. [PMID: 40433379 PMCID: PMC12106019 DOI: 10.3389/fimmu.2025.1600019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction Steroid-refractory acute Graft-versus-Host Disease (SR-aGVHD) is a potentially fatal complication occurring in approximately 60-70% of severe grade III-IV GVHD cases, with a higher incidence in patients with gastrointestinal (GI) involvement. GI aGVHD is associated with poor prognosis, with a 2-year overall survival (OS) rate of only 25% in patients with stage 3-4 GI involvement. Mesenchymal stromal cells (MSC) have emerged as a promising therapeutic option due to their favorable efficacy and safety profile. However, data on bone marrow (BM)-derived MSC use in biopsy-proven grade III-IV SR-aGVHD with GI involvement, particularly in stage 3-4 cases, remain limited. Methods This prospective, observational, single-arm, single-center study assessed the efficacy and safety of BM-derived MSC for treating adult patients with biopsy-proven grade III-IV SR-aGVHD with predominant GI involvement. Early (1st-2nd) passage BM-derived MSC were administered weekly at a target dose of 1x106 MSC/kg in two regimens: up to three (MSC3) and six doses (MSC6). Results Fifty-seven adult patients with biopsy-proven III-IV grade SR-aGVHD (93% with GI involvement) received MSC treatment. The overall response rate (ORR) was 39% and 42% on Days 14 and 28, respectively, with no significant differences between the two MSC groups (Day 28 ORR 38% for MSC3 and 44% for MSC6). In patients with stage 3-4 GI involvement, the ORR was 26% and 36% at the corresponding time points with comparable efficacy between the two MSC groups (Day 28 ORR 31% for MSC3 and 38% for MSC6). Day 14 and Day 28 responders had significantly higher OS compared to non-responders (52% vs. 7%, p=0.000; 54% vs. 5%, p=0.000), with a comparable OS benefit observed in patients with stage 3-4 GI involvement (45% vs. 8%, p=0.005; 42% vs. 6%, p=0.005), respectively. MSC treatment had a favorable safety profile. The one, 5 and 10-year OS rates were 27%, 24%, and 24%, respectively. Conclusions The grade III-IV SR-aGVHD patients, including cases with biopsy-proven severe GI involvement, had significantly better clinical outcomes if responses to MSC treatment were observed on Days 14 and 28. Intensified MSC administration schedule has failed to improve the clinical outcomes. MSC studies focusing on aGVHD prevention and (or) first-line treatment in combination with other agents should be considered.
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Affiliation(s)
- Adomas Bukauskas
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Renata Jucaitienė
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Mindaugas Stoškus
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Vilma Valčeckienė
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Greta Bušmaitė
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Artūras Slobinas
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Linas Davainis
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Inga Šlepikienė
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Igoris Trociukas
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
| | - Valdas Pečeliūnas
- Department of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Laimonas Griškevičius
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Andrius Žučenka
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
- Department of Hematology and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Elliott J, Koldej R, Khot A, Ritchie D. Graft-Versus-Host Disease Mouse Models: A Clinical-Translational Perspective. Methods Mol Biol 2025; 2907:1-56. [PMID: 40100591 DOI: 10.1007/978-1-0716-4430-0_1] [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] [Indexed: 03/20/2025]
Abstract
A variety of graft-versus-host disease (GVHD) models have been developed in mice for the purpose of allowing laboratory investigation of the pathobiology, prevention, and treatment of GVHD in humans. While such models are crucial in advancing our knowledge in this field, there are some key limitations that need to be considered when translating laboratory discoveries into the clinical context. This chapter will discuss current clinical practices in transplantation and GVHD and the relative strengths and weaknesses of mouse models that attempt to replicate these states.
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Affiliation(s)
- Jessica Elliott
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
| | - Rachel Koldej
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Amit Khot
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - David Ritchie
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
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Bao Y, Liu J, Li Z, Sun Y, Chen J, Ma Y, Li G, Wang T, Liu H, Zhang X, Yan R, Yao Z, Guo X, Fang R, Feng J, Xia W, Xiang AP, Chen X. Ex vivo-generated human CD1c + regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. Mol Ther 2024; 32:4372-4382. [PMID: 39489917 PMCID: PMC11638867 DOI: 10.1016/j.ymthe.2024.10.026] [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: 06/18/2024] [Revised: 10/06/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024] Open
Abstract
IL-10+ regulatory B cells (Bregs) show great promise in treating graft-versus-host disease (GVHD), a life-threatening complication of post-hematopoietic stem cell transplantation. However, obtaining high-quality human IL-10+ Bregs in vitro remains a challenge due to the lack of unique specific markers and the triggering of pro-inflammatory cytokine expression. Here, by uncovering the critical signaling pathways in Breg induction by mesenchymal stromal cells (MSCs), we first established an efficient Breg induction system based on MSCs and GSK-3β blockage (CHIR-99021), which had a robust capacity to induce IL-10+ Bregs while suppressing tumor necrosis factor α (TNF-α) expression. Furthermore, these Breg populations could be identified and enriched by CD1c+. Mechanistically, MSCs induced the expansion of Bregs through the PKA-mediated phosphorylation of cAMP response element-binding protein (CREB). Thus, we developed a chemically defined inducing protocol by PKA-CREB agonist, instead of MSCs, which can also effectively induce CD1c+ Bregs with lower TNF-α expression. Importantly, induced CD1c+ Bregs suppressed the proliferation of peripheral blood mononuclear cells and the inflammatory cytokine secretion of T cells. When adoptively transferred into a humanized mouse model of GVHD, induced CD1c+ Bregs effectively alleviated GVHD. Overall, we established an efficient ex vivo induction system for human Bregs, which has implications for developing novel Bregs-based therapies for GVHD.
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Affiliation(s)
- Yingying Bao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China; Institute of Gene and Cell Therapy, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jialing Liu
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Zhishan Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Yueming Sun
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Junhua Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Yuanchen Ma
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Tao Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Huanyi Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Rong Yan
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Zhenxia Yao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Xiaolu Guo
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Rui Fang
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Jianqi Feng
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Wenjie Xia
- Institute of Blood Transfusion, Guangzhou Blood Centre, Guangzhou 510095, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China.
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China.
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Lombardo G, Lechanteur C, Briquet A, Seidel L, Willems E, Servais S, Baudoux E, Kerre T, Zachee P, Herman J, Janssen A, Muller J, Baron F, Beguin Y. Co-infusion of mesenchymal stromal cells to prevent GVHD after allogeneic hematopoietic cell transplantation from HLA-mismatched unrelated donors after reduced-intensity conditioning: a double-blind randomized study and literature review. Stem Cell Res Ther 2024; 15:461. [PMID: 39627816 PMCID: PMC11613890 DOI: 10.1186/s13287-024-04064-w] [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: 09/17/2024] [Accepted: 11/14/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have immunomodulatory and hematopoiesis-supporting properties that could potentially benefit hematopoietic stem cell (HSC) engraftment and decrease the incidence and/or severity of graft-versus-host disease (GVHD). METHODS Based on our previous pilot study, we established a multicenter, prospective, randomized, double-blind trial evaluating the efficacy of co-infusing third-party MSC (1.5-3 × 106/kg) versus placebo on the day of HSC transplantation (HCT) to prevent GVHD in recipients of HLA-mismatched unrelated donors after reduced-intensity conditioning. RESULTS The study planned to include 120 patients to improve 1-year overall survival (OS) from 55 to 77% but was stopped after 9 years for low recruitment (n = 38). One-year OS was 74% in the MSC group and 80% in the placebo group. In multivariate analysis, the incidence of grade II-IV acute GVHD was significantly lower in patients receiving MSC (HR 0.332, 95% CI 0.124-0.890, p = 0.0284). No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival at 1 year or long-term, or hematopoietic and immune reconstitution. CONCLUSIONS Despite premature study closure, the suggested beneficial effect of MSC co-transplantation for the prevention of acute GVHD in HLA-mismatched HCT warrants further investigation.
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Affiliation(s)
- Gérôme Lombardo
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Laurence Seidel
- Center for Biostatistics and Research Methods, CHU and University of Liège, Liège, Belgium
| | - Evelyne Willems
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Sophie Servais
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Etienne Baudoux
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Tessa Kerre
- Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium
| | - Pierre Zachee
- Department of Clinical Hematology, ZNA Stuivenberg, Antwerp, Belgium
| | - Julie Herman
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Audrey Janssen
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Joséphine Muller
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Frédéric Baron
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Yves Beguin
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium.
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium.
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Zhu P, Tan H, Gao H, Wang J, Liu Y, Yang D, Wu T. Potential Mechanism and Perspectives of Mesenchymal Stem Cell Therapy for Ischemic Stroke: A Review. Glob Med Genet 2024; 11:278-284. [PMID: 39224463 PMCID: PMC11368559 DOI: 10.1055/s-0044-1790231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
Mesenchymal stem cells (MSCs), as a stem cell type with multiple differentiation potentials and immune regulatory abilities, have shown broad prospects in the treatment of ischemic stroke in recent years. The main characteristics of MSCs include their self-renewal ability, differentiation potential for different types of cells, and the ability to secrete various bioactive factors such as cytokines, chemokines, and growth factors, which play a key role in tissue repair and regeneration. In the treatment of ischemic stroke, MSCs exert therapeutic effects through various mechanisms, including promoting vascular regeneration of damaged brain tissue, reducing inflammatory responses, and protecting neurons from damage caused by apoptosis. Research have shown that MSCs can promote the repair of ischemic areas by releasing neurotrophic factors and angiogenic factors, while inhibiting immune responses triggered by ischemia, thereby improving neurological function. With the in-depth study of its biological mechanism, MSCs have gradually shown good safety and effectiveness in clinical applications. Therefore, fully exploring and utilizing the potential of MSCs in the treatment of ischemic stroke may provide new ideas and solutions for future neural repair and regenerative medicine.
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Affiliation(s)
- Pengcheng Zhu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Hongtu Tan
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Haobo Gao
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Jiabin Wang
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Yangyang Liu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Dongyi Yang
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Tao Wu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
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Labusca L, Zugun-Eloae F. Understanding host-graft crosstalk for predicting the outcome of stem cell transplantation. World J Stem Cells 2024; 16:232-236. [PMID: 38577233 PMCID: PMC10989282 DOI: 10.4252/wjsc.v16.i3.232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/14/2024] [Accepted: 02/18/2024] [Indexed: 03/25/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) hold great promise for tissue regeneration in debilitating disorders. Despite reported improvements, the short-term outcomes of MSC transplantation, which is possibly linked to poor cell survival, demand extensive investigation. Disease-associated stress microenvironments further complicate outcomes. This debate underscores the need for a deeper understanding of the phenotypes of transplanted MSCs and their environment-induced fluctuations. Additionally, questions arise about how to predict, track, and comprehend cell fate post-transplantation. In vivo cellular imaging has emerged as a critical requirement for both short- and long-term safety and efficacy studies. However, translating preclinical imaging methods to clinical settings remains challenging. The fate and function of transplanted cells within the host environment present intricate challenges, including MSC engraftment, variability, and inconsistencies between preclinical and clinical data. The study explored the impact of high glucose concentrations on MSC survival in diabetic environments, emphasizing mitochondrial factors. Preserving these factors may enhance MSC survival, suggesting potential strategies involving genetic modification, biomaterials, and nanoparticles. Understanding stressors in diabetic patients is crucial for predicting the effects of MSC-based therapies. These multifaceted challenges call for a holistic approach involving the incorporation of large-scale data, computational disease modeling, and possibly artificial intelligence to enable deterministic insights.
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Affiliation(s)
- Luminita Labusca
- Magnetic Materials and Sensors, National Institute of Research and Development for Technical Physics, Iasi 700050, Romania
- Orthopedics and Trauma, Emergency County Hospital Saint Spiridon, Iasi 700000, Romania.
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Zhang X, Huang RH. [Exploration and practice of novel models of cellular therapy and hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:105-108. [PMID: 38604784 PMCID: PMC11078672 DOI: 10.3760/cma.j.cn121090-20230928-00150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Indexed: 04/13/2024]
Abstract
Hematopoietic stem cell transplantation provides an effective cure for various hematological diseases, especially malignant hematological diseases, its treatment system has been continuously optimized, the source of donors has been expanding, the indications have been expanding, and the therapeutic effect has also made breakthroughs to a certain extent. At present, the status of hematopoietic stem cell transplantation technology in most hematological diseases is still unshakable, but the recurrence of the primary disease and complications related to hematopoietic stem cell transplantation are still two major clinical challenges that affect the long-term survival and quality of life of patients. Cell therapy represented by chimeric antigen receptor T (CAR-T) has made breakthrough progress in the treatment of refractory/recurrent B-cell malignancies. Compared with traditional drugs, cell therapy has unique in vivo metabolic characteristics, relying on immune specific recognition and the repair ability of stem cells. It is currently emerging in the treatment of blood tumors and the management of transplant complications. Multiple clinical studies have preliminarily demonstrated a new diagnostic and therapeutic model combining cell therapy with hematopoietic stem cell transplantation.
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Affiliation(s)
- X Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China Jinfeng Laboratory, Chongqing 400037, China
| | - R H Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China
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Jiang Y, Zhao J, Wang M, Huang F, Li J, Liu R, Wan J, Hao S. Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models. Front Immunol 2023; 14:1284936. [PMID: 38124750 PMCID: PMC10731297 DOI: 10.3389/fimmu.2023.1284936] [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: 08/29/2023] [Accepted: 11/23/2023] [Indexed: 12/23/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) can alleviate graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). MSCs-derived exosomes (MEXs) can mirror the biological function of their parent cells. Whether MEXs can alleviate GVHD like their parent cells or not is unclear. In this study, we investigate the effects of MEXs on GVHD and graft-versus-leukemia (GVL) effect in vitro and in HSCT animal models. Method MSCs were produced using bone marrow mononuclear cells (MNCs), and MEXs were separated from the supernatants of MSCs. Electron microscopy, western blot, and nanoparticle tracking analysis (NTA) were used to determine the characteristics of MEXs. The immunomodulatory function of MEXs and their effects on GVHD and GVL were examined in vitro and in vivo. Result Like other cell-type derived exosomes, our data revealed that MEXs were also disc-shaped vesicles with a diameter of 100-200 nm under electron microscopy and were positive for the exosomal hallmark proteins. MEXs can notably inhibit the expression of costimulatory molecules and functional cytokine secretion of dendritic cells (DCs). Meanwhile, MEXs can exert suppressive effects on T lymphocyte proliferation and activation. Moreover, MEXs can also encourage the polarization of macrophages toward the M2 type. In animal HSCT models, MEXs can promote the differentiation of Treg cells in spleens, decrease the GVHD score, increase the survival rate of mice, and preserve the cytotoxic antileukemia effects of CD8+ T lymphocytes from recipient mice. Conclusion These findings showed that MEXs exert their effects by inhibiting the immunomodulatory function of DCs, macrophages, and T lymphocytes. In the animal model, MEXs ameliorate the clinical symptoms of GVHD, while maintaining the antitumor effects of CD8+ T lymphocytes. Therefore, it can be inferred that MEXs can separate GVHD from GVL in HSCT. Our study suggests that MEXs have broad clinical application potential in the prevention and treatment of GVHD in HSCT in the near future.
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Affiliation(s)
| | | | | | | | | | | | - Jiangbo Wan
- Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siguo Hao
- *Correspondence: Siguo Hao, ; Jiangbo Wan,
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Luo C, Huang X, Wei L, Wu G, Huang Y, Ding Y, Huang Z, Chen J, Li X, Zou Y, Xu S. Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials. Front Immunol 2023; 14:1211171. [PMID: 37409129 PMCID: PMC10318925 DOI: 10.3389/fimmu.2023.1211171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/08/2023] [Indexed: 07/07/2023] Open
Abstract
Objective Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Methods Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Results Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Conclusions Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.
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Affiliation(s)
- Chengxin Luo
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Xiangtao Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Ling Wei
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Guixian Wu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Yarui Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Yaqun Ding
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Zhen Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Jieping Chen
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Xi Li
- Department of Hematology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yunding Zou
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
| | - Shuangnian Xu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Tumor Immunotherapy, Chongqing Science & Technology Commission, Chongqing, China
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12
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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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Ilan U, Brivio E, Algeri M, Balduzzi A, Gonzalez-Vincent M, Locatelli F, Zwaan CM, Baruchel A, Lindemans C, Bautista F. The Development of New Agents for Post-Hematopoietic Stem Cell Transplantation Non-Infectious Complications in Children. J Clin Med 2023; 12:2149. [PMID: 36983151 PMCID: PMC10054172 DOI: 10.3390/jcm12062149] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/12/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment option for patients suffering from various types of malignant diseases and some non-cancerous conditions. Nevertheless, it is associated with a high risk of complications leading to transplant-related mortality and long-term morbidity. An increasing number of therapeutic and prevention strategies have been developed over the last few years to tackle the complications arising in patients receiving an HSCT. These strategies have been mainly carried out in adults and some are now being translated into children. In this manuscript, we review the recent advancements in the development and implementation of treatment options for post-HSCT non-infectious complications in pediatric patients with leukemia and other non-malignant conditions, with a special attention on the new agents available within clinical trials. We focused on the following conditions: graft failure, prevention of relapse and early interventions after detection of minimal residual disease positivity following HSCT in acute lymphoblastic and myeloid leukemia, chronic graft versus host disease, non-infectious pulmonary complications, and complications of endothelial origin.
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Affiliation(s)
- Uri Ilan
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Erica Brivio
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Mattia Algeri
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, 00165 Rome, Italy
| | - Adriana Balduzzi
- Clinica Pediatrica Università degli Studi di Milano Bicocca, 20900 Monza, Italy
| | - Marta Gonzalez-Vincent
- Department of Stem Cell Transplantation, Hospital Infantil Universitario Nino Jesus, 28009 Madrid, Spain
| | - Franco Locatelli
- Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, 00165 Rome, Italy
| | | | - Andre Baruchel
- Department of Pediatric Hematology, AP-HP, Robert Debré Hospital, 75019 Paris, France
| | - Caroline Lindemans
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Division of Pediatrics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Stem Cell Transplantation, Regenerative Medicine Center, University Medical Center, 3584 CX Utrecht, The Netherlands
| | - Francisco Bautista
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
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Doglio M, Crossland RE, Alho AC, Penack O, Dickinson AM, Stary G, Lacerda JF, Eissner G, Inngjerdingen M. Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease. Front Immunol 2022; 13:1045168. [PMID: 36466922 PMCID: PMC9714556 DOI: 10.3389/fimmu.2022.1045168] [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: 09/15/2022] [Accepted: 10/31/2022] [Indexed: 08/31/2023] Open
Abstract
Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.
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Affiliation(s)
- Matteo Doglio
- Experimental Haematology Unit, Division of Immunology Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy
| | - Rachel E. Crossland
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ana C. Alho
- JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
| | - Olaf Penack
- Department of Hematology, Oncology, and Cancer Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anne M. Dickinson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- Alcyomics Ltd, Newcastle upon Tyne, United Kingdom
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - João F. Lacerda
- JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
| | - Günther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Marit Inngjerdingen
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
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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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Garrigós MM, de Oliveira FA, Nucci MP, Nucci LP, Alves ADH, Dias OFM, Gamarra LF. How mesenchymal stem cell cotransplantation with hematopoietic stem cells can improve engraftment in animal models. World J Stem Cells 2022; 14:658-679. [PMID: 36157912 PMCID: PMC9453272 DOI: 10.4252/wjsc.v14.i8.658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/27/2022] [Accepted: 07/26/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Bone marrow transplantation (BMT) can be applied to both hematopoietic and nonhematopoietic diseases; nonetheless, it still comes with a number of challenges and limitations that contribute to treatment failure. Bearing this in mind, a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.
AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.
METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment. We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English. In PubMed, we initially identified 555 articles and after selection, only 12 were chosen. In Scopus, 2010 were identified, and six were left after the screening and eligibility process.
RESULTS Of the 2565 articles found in the databases, only 18 original studies met the eligibility criteria. HSC distribution by source showed similar ratios, with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1 × 107 cells by intravenous or intrabone routes. However, MSCs had a high prevalence of human donors with a variety of sources (umbilical cord blood, bone marrow, tonsil, adipose tissue or fetal lung), using a lower dose, mainly 106 cells and ranging 104 to 1.5 × 107 cells, utilizing the same routes. MSCs were characterized prior to administration in almost every experiment. The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy. The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism, followed by hematopoietic reconstitution and survival analysis. Besides the engraftment, homing and cellularity were also evaluated in some studies.
CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models, in the absence of toxicity.
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Affiliation(s)
- Murilo Montenegro Garrigós
- Hospital Israelita Albert Einstein, São Paulo 05652-900, São Paulo, Brazil
- Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, São Paulo, Brazil
| | | | - Mariana Penteado Nucci
- Hospital Israelita Albert Einstein, São Paulo 05652-900, São Paulo, Brazil
- LIM44-Hospital das Clínicas, Faculdade Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil
| | - Leopoldo Penteado Nucci
- Centro Universitário do Planalto Central, Área Especial para Industria nº 02 Setor Leste - Gama-DF, Brasília 72445-020, Distrito Federal, Brazil
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Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice. Int J Mol Sci 2022; 23:ijms23126433. [PMID: 35742877 PMCID: PMC9224120 DOI: 10.3390/ijms23126433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells.
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A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2124627. [PMID: 35571252 PMCID: PMC9098338 DOI: 10.1155/2022/2124627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.
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Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol 2022; 13:839844. [PMID: 35371003 PMCID: PMC8973075 DOI: 10.3389/fimmu.2022.839844] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, All Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
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20
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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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21
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Treatment with Mesenchymal Stromal Cells Overexpressing Fas-Ligand Ameliorates Acute Graft-versus-Host Disease in Mice. Int J Mol Sci 2022; 23:ijms23010534. [PMID: 35008964 PMCID: PMC8745472 DOI: 10.3390/ijms23010534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/22/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) has the potential to cure malignant and non-malignant hematological disorders, but because of the serious side effects of this intervention its applications are limited to a restricted number of diseases. Graft-versus-host disease (GvHD) is the most frequent complication and the leading cause of mortality and morbidity following allo-HCT. It results from the attack of the transplanted T cells from the graft against the cells of the recipient. There is no clear treatment for this severe complication. Due to their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed to treat GvHD, but the results did not meet expectations. We have previously showed that the immunomodulatory effect of the MSC was significantly enhanced through adenoviral-mediated overexpression of FasL. In this study, we have tested the properties of FasL-overexpressing MSC in vivo, in a mouse model for acute GvHD. We found that treatment with FasL-overexpressing MSC delayed the onset of the disease and increased survival of the mice.
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22
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Human mesenchymal stromal cells maintain their stem cell traits after high-LET particle irradiation - Potential implications for particle radiotherapy and manned space missions. Cancer Lett 2022; 524:172-181. [PMID: 34688844 DOI: 10.1016/j.canlet.2021.10.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/19/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022]
Abstract
The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using γH2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0-1.1 for 1H, 1.7-2.3 for 4He, 2.9-3.4 for 12C and 2.6-3.3 for 16O. Particle radiation did not alter the MSCs' characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as γH2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.
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23
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Sobkowiak-Sobierajska A, Lindemans C, Sykora T, Wachowiak J, Dalle JH, Bonig H, Gennery A, Lawitschka A. Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan. Front Pediatr 2022; 10:808103. [PMID: 35252060 PMCID: PMC8894895 DOI: 10.3389/fped.2022.808103] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/24/2022] [Indexed: 12/18/2022] Open
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
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Affiliation(s)
| | - Caroline Lindemans
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Pediatric Blood and Bone Marrow Transplantation, Princess Máxima Center, Utrecht, Netherlands
| | - Tomas Sykora
- Department of Pediatric Hematology and Oncology - Haematopoietic Stem Cell Transplantation Unit, National Institute of Children's Diseases and Medical Faculty, Comenius University, Bratislava, Slovakia
| | - Jacek Wachowiak
- Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jean-Hugues Dalle
- Hematology and Immunology Department, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris and University of Paris, Paris, France
| | - Halvard Bonig
- Goethe University Medical Center, Institute of Transfusion Medicine and Immunohematology, and German Red Cross Blood Center Frankfurt, Frankfurt, Germany
| | - Andrew Gennery
- Medical School, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Anita Lawitschka
- Stem Cell Transplantation Unit, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria.,St. Anna Children's Cancer Research Institute, Vienna, Austria
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24
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Macías-Sánchez MDM, Morata-Tarifa C, Cuende N, Cardesa-Gil A, Cuesta-Casas MÁ, Pascual-Cascon MJ, Pascual A, Martín-Calvo C, Jurado M, Perez-Simón JA, Espigado I, Garzón López S, Carmona Sánchez G, Mata-Alcázar-Caballero R, Sánchez-Pernaute R. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:343-355. [PMID: 35348788 PMCID: PMC9052408 DOI: 10.1093/stcltm/szac003] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 12/12/2021] [Indexed: 11/30/2022] Open
Abstract
Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7–66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years’ survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.
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Affiliation(s)
- María del Mar Macías-Sánchez
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
- Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Cynthia Morata-Tarifa
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | - Natividad Cuende
- Coordinación Autonómica de Trasplantes de Andalucía. Servicio Andaluz de Salud, Sevilla, Spain
| | - Ana Cardesa-Gil
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | | | | | - Antonia Pascual
- Departamento de Hematología y Hemoterapia, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Carmen Martín-Calvo
- Departamento de Hematología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Manuel Jurado
- Departamento de Hematología, Hospital Virgen de las Nieves, Granada, Spain
| | - José Antonio Perez-Simón
- Departamento de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
- Instituto de Investigación Biomédica de Sevilla (IBIS)/CSIC, Sevilla, Spain
| | - Ildefonso Espigado
- Departamento de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
- Instituto de Investigación Biomédica de Sevilla (IBIS)/CSIC, Sevilla, Spain
- Universidad de Sevilla, Sevilla, Spain
- Hospital Universitario Virgen Macarena, Sevilla, Spain
| | | | - Gloria Carmona Sánchez
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | - Rosario Mata-Alcázar-Caballero
- Corresponding author: Rosario Mata Alcázar-Caballero, c/ Américo Vespucio 15 Edif. S2, 41092 Seville, Spain. Tel: +34 955 89 01 24; Fax: +34 955 267 002;
| | - Rosario Sánchez-Pernaute
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
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25
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Inamoto Y, Zeiser R, Chan GCF. Novel Treatment for Graft-versus-Host Disease. BLOOD CELL THERAPY 2021; 4:101-109. [PMID: 36714067 PMCID: PMC9847314 DOI: 10.31547/bct-2021-022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 10/16/2021] [Indexed: 02/01/2023]
Abstract
Allogeneic hematopoietic cell transplantation is a curative therapy for a variety of hematological diseases, but its success is hampered by acute and chronic graft-versus-host disease (GvHD). In the last five years, multiple novel therapeutic approaches for GvHD have entered the arena. The National Institutes of Health consensus criteria for chronic GvHD have set standards for designing and reporting clinical trials, and preclinical experiments of chronic GvHD have revealed the central roles of regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These scientific efforts and the resulting clinical studies led to the approval of ibrutinib, belumosudil and ruxolitinib for the treatment of refractory chronic GvHD. Recently, large randomized phase III trials showed that ruxolitinib was superior to the best available therapy for glucocorticoid-refractory acute GvHD (REACH2 trial) and glucocorticoid-refractory chronic GvHD (REACH3 trial). Furthermore, novel regenerative approaches, including IL-22, R-spondin, and glucogon-like peptide-2, and cellular therapies, such as the transfer of mesenchymal stem cells and regulatory T cells, are under intensive investigation. GvHD prevention using abatacept, dipeptidyl peptidase 4 inhibition, and post-transplant cyclophosphamide are also promising strategies that require further evaluation. In this article, we summarize the emerging knowledge of acute GvHD, chronic GvHD, and preclinical and clinical data of mesenchymal stem cells as GvHD therapy. In the next five years, basic and clinical studies will further advance the field, and dramatic changes in GvHD management will be encountered.
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Affiliation(s)
- Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Godfrey Chi-Fung Chan
- Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong,Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital,Department of Paediatrics and Adolescent Medicine, HKU-Shenzhen Hospital
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26
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Chen XY, Chen YY, Lin W, Chen CH, Wen YC, Hsiao TC, Chou HC, Chung KF, Chuang HC. Therapeutic Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Recovering From Murine Pulmonary Emphysema Under Cigarette Smoke Exposure. Front Med (Lausanne) 2021; 8:713824. [PMID: 34646841 PMCID: PMC8502916 DOI: 10.3389/fmed.2021.713824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/31/2021] [Indexed: 01/08/2023] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 106 (low dose), 1 × 107 (medium dose), and 3 × 107 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.
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Affiliation(s)
- Xiao-Yue Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Ying Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Willie Lin
- Meridigen Biotech Co., Ltd., Taipei, Taiwan
| | | | | | - Ta-Chih Hsiao
- Graduate Institute of Environmental Engineering, National Taiwan University, Taipei, Taiwan
| | - Hsiu-Chu Chou
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kian Fan Chung
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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27
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Oncolytic virotherapy in hematopoietic stem cell transplantation. Hum Immunol 2021; 82:640-648. [PMID: 34119352 DOI: 10.1016/j.humimm.2021.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/29/2021] [Accepted: 05/29/2021] [Indexed: 12/28/2022]
Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative option for various hematologic malignancies. However, fatal complications, such as relapse and graft-versus-host disease (GVHD) hampered favorable HSCT outcomes. Cancer cells remained in the body following the conditioning regimen, or those contaminating the autologous graft can cause relapse. Although the relapse is much lesser in allogeneic HSCT, GVHD is still a life-threatening complication in this type of HSCT. Researchers are seeking various strategies to reduce relapse and GVHD in HSCT with minimum effects on the engraftment and immune-reconstitution. Oncolytic viruses (OVs) are emerging anti-cancer agents with promising results in battling solid tumors. OVs can selectively replicate in the malignant cells in which the antiviral immune responses have defected. Hence, they could be used as a purging agent to eradicate the tumoral contamination of autologous grafts with no damages to hematopoietic stem cells. Moreover, they have been shown to alleviate GVHD complications through modulating alloreactive T cell responses. Primary results promise using OVs as a strategy to reduce both relapse and GVHD in the HSCT without affecting hematologic and immunologic engraftment. Herein, we provide the latest findings in the field of OV therapy in HSCT and discuss their pros and cons.
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28
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Mendt M, Daher M, Basar R, Shanley M, Kumar B, Wei Inng FL, Acharya S, Shaim H, Fowlkes N, Tran JP, Gokdemir E, Uprety N, Nunez-Cortes AK, Ensley E, Mai T, Kerbauy LN, Melo-Garcia L, Lin P, Shen Y, Mohanty V, Lu J, Li S, Nandivada V, Wang J, Banerjee P, Reyes-Silva F, Liu E, Ang S, Gilbert A, Li Y, Wan X, Gu J, Zhao M, Baran N, Muniz-Feliciano L, Wilson J, Kaur I, Gagea M, Konopleva M, Marin D, Tang G, Chen K, Champlin R, Rezvani K, Shpall EJ. Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD. Front Immunol 2021; 12:631353. [PMID: 34017325 PMCID: PMC8130860 DOI: 10.3389/fimmu.2021.631353] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/24/2021] [Indexed: 12/26/2022] Open
Abstract
Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.
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Affiliation(s)
- Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Bijender Kumar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Francesca Lim Wei Inng
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hila Shaim
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalie Fowlkes
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jamie P Tran
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elif Gokdemir
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ana K Nunez-Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily Ensley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Thao Mai
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Lucila N Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, São Paulo, Brazil.,Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo, São Paulo, Brazil
| | - Luciana Melo-Garcia
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yifei Shen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - JunJun Lu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sufang Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vandana Nandivada
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Pinaki Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Francia Reyes-Silva
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sonny Ang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - April Gilbert
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Xinhai Wan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jun Gu
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ming Zhao
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jeffrey Wilson
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Indreshpal Kaur
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mihai Gagea
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - David Marin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Guilin Tang
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Richard Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Rühle A, Grosu AL, Nicolay NH. The Particle Radiobiology of Multipotent Mesenchymal Stromal Cells: A Key to Mitigating Radiation-Induced Tissue Toxicities in Cancer Treatment and Beyond? Front Oncol 2021; 11:616831. [PMID: 33912447 PMCID: PMC8071947 DOI: 10.3389/fonc.2021.616831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent stromal cells that have gained attention for the treatment of irradiation-induced normal tissue toxicities due to their regenerative abilities. As the vast majority of studies focused on the effects of MSCs for photon irradiation-induced toxicities, little is known about the regenerative abilities of MSCs for particle irradiation-induced tissue damage or the effects of particle irradiation on the stem cell characteristics of MSCs themselves. MSC-based therapies may help treat particle irradiation-related tissue lesions in the context of cancer radiotherapy. As the number of clinical proton therapy centers is increasing, there is a need to decidedly investigate MSC-based treatments for particle irradiation-induced sequelae. Furthermore, therapies with MSCs or MSC-derived exosomes may also become a useful tool for manned space exploration or after radiation accidents and nuclear terrorism. However, such treatments require an in-depth knowledge about the effects of particle radiation on MSCs and the effects of MSCs on particle radiation-injured tissues. Here, the existing body of evidence regarding the particle radiobiology of MSCs as well as regarding MSC-based treatments for some typical particle irradiation-induced toxicities is presented and critically discussed.
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Affiliation(s)
- Alexander Rühle
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany.,Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany
| | - Nils H Nicolay
- Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany.,Department of Molecular Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany
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Potential Use of Mesenchymal Multipotent Cells for Hemopoietic Stem Cell Transplantation: Pro and Contra. J Pediatr Hematol Oncol 2021; 43:90-94. [PMID: 33560076 DOI: 10.1097/mph.0000000000002065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/06/2020] [Indexed: 12/25/2022]
Abstract
The potential of mesenchymal multipotent (stem) cells (MSC) to modify immune reactions and mediate hematopoiesis boosted great interest for their use in allogeneic hemopoietic stem cell transplantation. Because of MSC production of a wide range of cytokines and growth factors, these cells are included in the therapy of graft-versus-host disease (GVHD). A number of clinical studies have demonstrated safety and efficacy of MSC-based therapy in acute GVHD. Japan and some other countries approved biomedical cell products on the base of allogeneic bone marrow (BM) MSCs as medical agents for acute GVHD treatment. Besides, MSCs may form BM stroma and improve hematopoiesis. Simultaneous transplantation of hematopoietic stem cells and MSCs effectively improved engraftment and prevented GVHD in transplantation of umbilical cord blood and human leukocyte antigens-incompatible BM stem cells. The review presents the analysis of clinical studies of MSCs in allogeneic hematopoietic stem cell transplantation and discusses different approaches for improvement of MSC-based GVHD treatment and prophylaxis.
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Johnstone BH, Messner F, Brandacher G, Woods EJ. A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance. Front Immunol 2021; 12:622604. [PMID: 33732244 PMCID: PMC7959805 DOI: 10.3389/fimmu.2021.622604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed "hematopoietic progenitor cell (HPC), Marrow," recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to "delayed tolerance." Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.
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Affiliation(s)
- Brian H. Johnstone
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
| | - Franka Messner
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Erik J. Woods
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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Li R, Tu J, Zhao J, Pan H, Fang L, Shi J. Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:106. [PMID: 33541414 PMCID: PMC7860635 DOI: 10.1186/s13287-021-02170-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. METHODS Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n = 1456) were included, in which eight (n = 241) studies combined with MSCs and eleven (n = 1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. RESULTS Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p = 0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p = 0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p = 0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p = 1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p = 0.018). CONCLUSIONS Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.
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Affiliation(s)
- Ruonan Li
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Jingke Tu
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Jingyu Zhao
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Hong Pan
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Liwei Fang
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China
| | - Jun Shi
- Regenerative Medicine Clinic, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 288 Nanjing Road, Heping District, Tianjin, 300020, China.
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Tani S, Okada H, Chung UI, Ohba S, Hojo H. The Progress of Stem Cell Technology for Skeletal Regeneration. Int J Mol Sci 2021; 22:1404. [PMID: 33573345 PMCID: PMC7866793 DOI: 10.3390/ijms22031404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/22/2021] [Accepted: 01/28/2021] [Indexed: 01/05/2023] Open
Abstract
Skeletal disorders, such as osteoarthritis and bone fractures, are among the major conditions that can compromise the quality of daily life of elderly individuals. To treat them, regenerative therapies using skeletal cells have been an attractive choice for patients with unmet clinical needs. Currently, there are two major strategies to prepare the cell sources. The first is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which can recapitulate the skeletal developmental process and differentiate into various skeletal cells. Skeletal tissues are derived from three distinct origins: the neural crest, paraxial mesoderm, and lateral plate mesoderm. Thus, various protocols have been proposed to recapitulate the sequential process of skeletal development. The second strategy is to extract stem cells from skeletal tissues. In addition to mesenchymal stem/stromal cells (MSCs), multiple cell types have been identified as alternative cell sources. These cells have distinct multipotent properties allowing them to differentiate into skeletal cells and various potential applications for skeletal regeneration. In this review, we summarize state-of-the-art research in stem cell differentiation based on the understanding of embryogenic skeletal development and stem cells existing in skeletal tissues. We then discuss the potential applications of these cell types for regenerative medicine.
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Affiliation(s)
- Shoichiro Tani
- Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (S.T.); (H.O.)
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
| | - Hiroyuki Okada
- Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (S.T.); (H.O.)
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
| | - Ung-il Chung
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Shinsuke Ohba
- Department of Cell Biology, Institute of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan;
| | - Hironori Hojo
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
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Wölfl M, Qayed M, Benitez Carabante MI, Sykora T, Bonig H, Lawitschka A, Diaz-de-Heredia C. Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia. Front Pediatr 2021; 9:784377. [PMID: 35071133 PMCID: PMC8771910 DOI: 10.3389/fped.2021.784377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality-which is predominantly caused by severe GvHD-is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.
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Affiliation(s)
- Matthias Wölfl
- Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Würzburg University Hospital, Würzburg, Germany
| | - Muna Qayed
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, United States
| | - Maria Isabel Benitez Carabante
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Tomas Sykora
- Haematopoietic Stem Cell Transplantation Unit, Department of Pediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Frankfurt, Germany.,German Red Cross Blood Service BaWüHe, Frankfurt, Germany
| | - Anita Lawitschka
- Department of Pediatrics, St. Anna Kinderspital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria
| | - Cristina Diaz-de-Heredia
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
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Introna M, Golay J. Tolerance to Bone Marrow Transplantation: Do Mesenchymal Stromal Cells Still Have a Future for Acute or Chronic GvHD? Front Immunol 2020; 11:609063. [PMID: 33362797 PMCID: PMC7759493 DOI: 10.3389/fimmu.2020.609063] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/12/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are fibroblast-like cells of mesodermal origin present in many tissues and which have the potential to differentiate to osteoblasts, adipocytes and chondroblasts. They also have a clear immunosuppressive and tissue regeneration potential. Indeed, the initial classification of MSCs as pluripotent stem cells, has turned into their identification as stromal progenitors. Due to the relatively simple procedures available to expand in vitro large numbers of GMP grade MSCs from a variety of different tissues, many clinical trials have tested their therapeutic potential in vivo. One pathological condition where MSCs have been quite extensively tested is steroid resistant (SR) graft versus host disease (GvHD), a devastating condition that may occur in acute or chronic form following allogeneic hematopoietic stem cell transplantation. The clinical and experimental results obtained have outlined a possible efficacy of MSCs, but unfortunately statistical significance in clinical studies has only rarely been reached and effects have been relatively limited in most cases. Nonetheless, the extremely complex pathogenetic mechanisms at the basis of GvHD, the fact that studies have been conducted often in patients who had been previously treated with multiple lines of therapy, the variable MSC doses and schedules administered in different trials, the lack of validated potency assays and clear biomarkers, the difference in MSC sources and production methods may have been major factors for this lack of clear efficacy in vivo. The heterogeneity of MSCs and their different stromal differentiation potential and biological activity may be better understood through more refined single cell sequencing and proteomic studies, where either an “anti-inflammatory” or a more “immunosuppressive” profile can be identified. We summarize the pathogenic mechanisms of acute and chronic GvHD and the role for MSCs. We suggest that systematic controlled clinical trials still need to be conducted in the most promising clinical settings, using better characterized cells and measuring efficacy with specific biomarkers, before strong conclusions can be drawn about the therapeutic potential of these cells in this context. The same analysis should be applied to other inflammatory, immune or degenerative diseases where MSCs may have a therapeutic potential.
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Affiliation(s)
- Martino Introna
- Center of Cellular Therapy "G. Lanzani", Division of Haematology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Josée Golay
- Center of Cellular Therapy "G. Lanzani", Division of Haematology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.,Fondazione per la Ricerca Ospedale Maggiore, Bergamo, Italy
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Trujillo-Rodríguez M, Viciana P, Rivas-Jeremías I, Álvarez-Ríos AI, Ruiz-García A, Espinosa-Ibáñez O, Arias-Santiago S, Martínez-Atienza J, Mata R, Fernández-López O, Ruiz-Mateos E, Gutiérrez-Valencia A, López-Cortés LF. Mesenchymal stromal cells in human immunodeficiency virus-infected patients with discordant immune response: Early results of a phase I/II clinical trial. Stem Cells Transl Med 2020; 10:534-541. [PMID: 33264515 PMCID: PMC7980217 DOI: 10.1002/sctm.20-0213] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/16/2020] [Accepted: 10/10/2020] [Indexed: 01/09/2023] Open
Abstract
Between 15% and 30% of HIV‐infected subjects fail to increase their CD4+ T‐cell counts despite continuous viral suppression (immunological nonresponders [INRs]). These subjects have a higher morbidity and mortality rate, but there are no effective treatments to reverse this situation so far. This study used data from an interrupted phase I/II clinical trial to evaluate safety and immune recovery after INRs were given four infusions, at baseline and at weeks 4, 8, and 20, with human allogeneic mesenchymal stromal cells from adipose tissue (Ad‐MSCs). Based on the study design, the first 5 out of 15 INRs recruited received unblinded Ad‐MSC infusions. They had a median CD4+ nadir count of 16/μL (range, 2‐180) and CD4+ count of 253 cells per microliter (171‐412) at baseline after 109 (54‐237) months on antiretroviral treatment and 69 (52‐91) months of continuous undetectable plasma HIV‐RNA. After a year of follow‐up, an independent committee recommended the suspension of the study because no increase of CD4+ T‐cell counts or CD4+/CD8+ ratios was observed. There were also no significant changes in the phenotype of different immunological lymphocyte subsets, percentages of natural killer cells, regulatory T cells, and dendritic cells, the inflammatory parameters analyzed, and cellular associated HIV‐DNA in peripheral blood mononuclear cells. Furthermore, three subjects suffered venous thrombosis events directly related to the Ad‐MSC infusions in the arms where the infusions were performed. Although the current study is based on a small sample of participants, the findings suggest that allogeneic Ad‐MSC infusions are not effective to improve immune recovery in INR patients or to reduce immune activation or inflammation. ClinicalTrials.gov identifier: NCT0229004. EudraCT number: 2014‐000307‐26.
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Affiliation(s)
- María Trujillo-Rodríguez
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
| | - Pompeyo Viciana
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
| | - Inmaculada Rivas-Jeremías
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
| | - Ana I Álvarez-Ríos
- Departamento de Bioquímica Clínica, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Servicio Andaluz de Salud (SAS)/Universidad de Sevilla, Seville, Spain
| | - Antonio Ruiz-García
- Unidad de Producción Celular e Ingeniería Tisular, Complejo Hospitalario Universitario de Granada, Granada, Spain
| | - Olga Espinosa-Ibáñez
- Unidad de Producción Celular e Ingeniería Tisular, Complejo Hospitalario Universitario de Granada, Granada, Spain
| | - Salvador Arias-Santiago
- Unidad de Producción Celular e Ingeniería Tisular, Complejo Hospitalario Universitario de Granada, Granada, Spain
| | - Juliana Martínez-Atienza
- Red Andaluza en Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Seville, Spain
| | - Rosario Mata
- Red Andaluza en Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Seville, Spain
| | - Olga Fernández-López
- Red Andaluza en Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Seville, Spain
| | - Ezequiel Ruiz-Mateos
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
| | - Alicia Gutiérrez-Valencia
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
| | - Luis F López-Cortés
- Unidad Clínica Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Avd. Manuel Siurto s/n, SEVILLA, España, Spain
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Petinati N, Kapranov N, Davydova Y, Bigildeev A, Pshenichnikova O, Karpenko D, Drize N, Kuzmina L, Parovichnikova E, Savchenko V. Immunophenotypic characteristics of multipotent mesenchymal stromal cells that affect the efficacy of their use in the prevention of acute graft vs host disease. World J Stem Cells 2020; 12:1377-1395. [PMID: 33312405 PMCID: PMC7705461 DOI: 10.4252/wjsc.v12.i11.1377] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/31/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are widely used in the clinic due to their unique properties, namely, their ability to differentiate in all mesenchymal directions and their immunomodulatory activity. Healthy donor MSCs were used to prevent the development of acute graft vs host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). The administration of MSCs to patients was not always effective. The MSCs obtained from different donors have individual characteristics. The differences between MSC samples may affect their clinical efficacy.
AIM To study the differences between effective and ineffective MSCs.
METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution. Aliquots of 52 MSC samples that were administered to patients were examined, and the same cells were cultured in the presence of peripheral blood mononuclear cells (PBMCs) from a third-party donor or treated with the pro-inflammatory cytokines IL-1β, IFN and TNF. Flow cytometry revealed the immunophenotype of the nontreated MSCs, the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines. The proportions of CD25-, CD146-, CD69-, HLA-DR- and PD-1-positive CD4+ and CD8+ cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined.
RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed. In the effective samples, the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD105, and CD146 was significantly higher. After MSCs were treated with IFN or cocultured with PBMCs, the HLA-ABC, HLA-DR, CD90 and CD54 MFI showed a stronger increase in the effective MSCs, which indicated an increase in the immunomodulatory activity of these cells. When PBMCs were cocultured with effective MSCs, the proportions of CD4+ and CD8+central memory cells significantly decreased, and the proportion of CD8+CD146+ lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD; in addition, the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples. The proportion of CD4+CD146+ lymphocytes increased only when cocultured with the inefficient samples.
CONCLUSION For the first time, differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective. Thus, it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.
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Affiliation(s)
- Nataliya Petinati
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Nikolay Kapranov
- Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, National Research Center for Hematology, Moscow 125167, Russia
| | - Yulia Davydova
- Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, National Research Center for Hematology, Moscow 125167, Russia
| | - Alexey Bigildeev
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Olesya Pshenichnikova
- Laboratory for Genetic Engineering, National Research Center for Hematology, Moscow 125167, Russia
| | - Dmitriy Karpenko
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Nina Drize
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Larisa Kuzmina
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
| | - Elena Parovichnikova
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
| | - Valeriy Savchenko
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
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Surgical Treatment of Severe Bowel Obstruction as a Rare Complication Following Allogenic Hematopoietic Stem Cell Transplantation. TRANSPLANTOLOGY 2020. [DOI: 10.3390/transplantology1020010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Gastrointestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) disease are common complications occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and contribute to a high degree of morbidity and mortality associated with allo-HSCT. Herein, we present a patient with severe intestinal GVHD complicated by recurring CMV enteritis, which overall resulted in severe terminal ileum stenosis. The patient underwent laparoscopic ileocecal resection that significantly reduced symptoms and possibly prevented the development of fulminant ileus. Surgical treatment is rarely used in the treatment of gastrointestinal GVHD; however, the current patient history illustrates that patients with inadequate symptom control and severe inflammatory bowel stenosis can be successfully managed with surgery. We also review published case reports on surgical treatment for severe gastrointestinal GVHD.
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Choudhery MS, Harris DT. Stem cell therapy for COVID-19: Possibilities and challenges. Cell Biol Int 2020; 44:2182-2191. [PMID: 32767687 PMCID: PMC7436138 DOI: 10.1002/cbin.11440] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023]
Abstract
Since its eruption in China, novel coronavirus disease (COVID-19) has been reported in most of the countries and territories (>200) of the world with ∼18 million confirmed cases (as of August 3, 2020). In most of the countries, COVID-19 upsurge is uncontrolled with a significant mortality rate. Currently, no treatment effective for COVID-19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although the majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against the COVID-19 pandemic, novel alternative therapies may reduce the mortality rate. Recent use of stem cells for critically ill COVID-19 patients in a small group of patients in China and subsequent Emergency Use Authorization of stem cells by Food and Drug Administration to Global Institute of Stem Cell Therapy and Research and Athersys has created excitement among the medical community. As a result, several clinical trials have been registered using stem cells for COVID-19 treatment that aim to use different cell sources, dosage, and importantly diverse targeted patient groups. In this brief review, the possibilities of stem cell use in COVID-19 patients and relevant challenges in their use have been discussed.
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Affiliation(s)
- Mahmood S. Choudhery
- Tissue Engineering and Regenerative Medicine Laboratory, Department of Biomedical SciencesKing Edward Medical UniversityLahorePakistan
| | - David T. Harris
- Department of ImmunobiologyThe University of ArizonaTucsonArizona
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40
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Ringdén O, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease. Front Immunol 2020; 11:567210. [PMID: 33193339 PMCID: PMC7604265 DOI: 10.3389/fimmu.2020.567210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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41
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Ding L, Han DM, Zheng XL, Yan HM, Xue M, Liu J, Zhu L, Li S, Mao N, Guo ZK, Ning HM, Wang HX, Zhu H. A study of human leukocyte antigen-haploidentical hematopoietic stem cells transplantation combined with allogenic mesenchymal stem cell infusion for treatment of severe aplastic anemia in pediatric and adolescent patients. Stem Cells Transl Med 2020; 10:291-302. [PMID: 32978903 PMCID: PMC7848315 DOI: 10.1002/sctm.20-0345] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/27/2020] [Accepted: 09/12/2020] [Indexed: 01/03/2023] Open
Abstract
The clinical applications of human leukocyte antigen (HLA) haploidentical hematopoietic stem cells transplantation (haplo‐HSCT) have offered most of the young severe aplastic anemia (SAA) patients an opportunity to accept curative therapy at the early stage of bone marrow lesions. However, the outcome of juvenile SAA patients received haplo‐HSCT remain to be improved due to high incidence of graft failure and graft vs host disease (GVHD). Mesenchymal stem cells (MSCs) have been characterized by their hematopoiesis‐supporting and immunomodulatory properties. In the current study, we designed a combination of haplo‐HSCT with allogenic MSC for treatment of SAA in pediatric and adolescent patients and evaluated its effects. Juvenile patients (<18 years) with SAA (n = 103) were given HLA‐haploidentical HSC combined with allogenic MSC after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin and an intensive GVHD prophylaxis, including cyclosporine, short‐term methotrexate, mycophenolate mofetil, and basiliximab. Neutrophil engraftment was achieved in 102 of 103 patients in a median time of 14.3 days (range 9‐25 days). The median time of platelet engraftment was 25.42 days (range 8‐93 days). The cumulative incidence of II‐IV acute GVHD at day +100 was 26.32% ± 0.19% and III‐IV acute GVHD was 6.79% ± 0.06% at day +100, respectively. The cumulative incidence of chronic GVHD was 25.56% ± 0.26%. The overall survival was 87.15% ± 3.3% at a median follow‐up of 40 (1.3‐98) months. Our data suggest that cotransplantation of HLA‐haploidentical HSC and allogenic mesenchymal stem cell may provide an effective and safe treatment for children and adolescents with SAA who lack matched donors.
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Affiliation(s)
- Li Ding
- Air Force Medical Center, PLA, Beijing, People's Republic of China.,Department of Experimental Hematology & Biochemistry, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Dong-Mei Han
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Xiao-Li Zheng
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Hong-Min Yan
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Mei Xue
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Jing Liu
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Ling Zhu
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Sheng Li
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Ning Mao
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Zi-Kuan Guo
- Department of Experimental Hematology & Biochemistry, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.,Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Hong-Mei Ning
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China.,The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Heng-Xiang Wang
- Air Force Medical Center, PLA, Beijing, People's Republic of China
| | - Heng Zhu
- Department of Experimental Hematology & Biochemistry, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.,Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China.,Graduate School of Anhui Medical University, Hefei, Anhui, People's Republic of China
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42
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Liu J, Liu Q, Chen X. The Immunomodulatory Effects of Mesenchymal Stem Cells on Regulatory B Cells. Front Immunol 2020; 11:1843. [PMID: 32922398 PMCID: PMC7456948 DOI: 10.3389/fimmu.2020.01843] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/09/2020] [Indexed: 12/16/2022] Open
Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) has been investigated in many preclinical and clinical studies. This potential is dominantly based on the immunosuppressive properties of MSCs. Although the therapeutic profiles of MSC transplantation are still not fully characterized, accumulating evidence has revealed that B cells change after MSC infusion, in particular inducing regulatory B cells (Bregs). The immunosuppressive effects of Bregs have been demonstrated, and these cells are being evaluated as new targets for the treatment of inflammatory diseases. MSCs are capable of educating B cells and inducing regulatory B cell production via cell-to-cell contact, soluble factors, and extracellular vesicles (EVs). These cells thus have the potential to complement each other's immunomodulatory functions, and a combined approach may enable synergistic effects for the treatment of immunological diseases. However, compared with investigations regarding other immune cells, investigations into how MSCs specifically regulate Bregs have been superficial and insufficient. In this review, we discuss the current findings related to the immunomodulatory effects of MSCs on regulatory B cells and provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Jialing Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyong Chen
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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43
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Campos L, Rezende SB, Simões A, Palma LF, Tateno RY, da Silva RL, Macedo MC. Photobiomodulation and photodynamic therapy for the management of oral graft-versus-host disease: A case report. Photodiagnosis Photodyn Ther 2020; 30:101776. [DOI: 10.1016/j.pdpdt.2020.101776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/28/2020] [Accepted: 04/10/2020] [Indexed: 11/25/2022]
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44
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Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Res Ther 2020; 11:169. [PMID: 32366290 PMCID: PMC7197031 DOI: 10.1186/s13287-020-01678-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 12/21/2022] Open
Abstract
The outbreak of 2019 novel coronavirus disease (COVID-19) worldwide is becoming rapidly a major concern. The number of severe cases has increased dramatically worldwide, while specific treatment options are scarce. The main pathologic features of severe or critical COVID-19 were consistent with acute lung injure (ALI)/acute respiratory distress syndrome (ARDS), characterized by cellular fibromyxoid exudates, extensive pulmonary inflammation, pulmonary edema, and hyaline membrane formation. Mesenchymal stem cells (MSCs) can balance the inflammatory response and has been mentioned to be effective on ALI/ARDS from both infectious and noninfectious causes previously, presenting an important opportunity to be applied to COVID-19. In this commentary, we summarize the clinical trials of MSCs treatments on ALI/ARDS and raise MSCs as a hopefully alternative therapy for severe or critical COVID-19.
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45
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Liu S, Peng D, Qiu H, Yang K, Fu Z, Zou L. Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Res Ther 2020. [PMID: 32366290 DOI: 10.1186/s13287-020-01678-8.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The outbreak of 2019 novel coronavirus disease (COVID-19) worldwide is becoming rapidly a major concern. The number of severe cases has increased dramatically worldwide, while specific treatment options are scarce. The main pathologic features of severe or critical COVID-19 were consistent with acute lung injure (ALI)/acute respiratory distress syndrome (ARDS), characterized by cellular fibromyxoid exudates, extensive pulmonary inflammation, pulmonary edema, and hyaline membrane formation. Mesenchymal stem cells (MSCs) can balance the inflammatory response and has been mentioned to be effective on ALI/ARDS from both infectious and noninfectious causes previously, presenting an important opportunity to be applied to COVID-19. In this commentary, we summarize the clinical trials of MSCs treatments on ALI/ARDS and raise MSCs as a hopefully alternative therapy for severe or critical COVID-19.
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Affiliation(s)
- Shan Liu
- Center for Clinical Molecular Laboratory Medicine/Newborn Screening Center National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Danyi Peng
- Department of Respiratory Medicine; Ministry of Education Key Laboratory of Child Development and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Huijun Qiu
- Department of Respiratory Medicine; Ministry of Education Key Laboratory of Child Development and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Yang
- Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, China
| | - Zhou Fu
- Department of Respiratory Medicine; Ministry of Education Key Laboratory of Child Development and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. .,Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, China.
| | - Lin Zou
- Center for Clinical Molecular Laboratory Medicine/Newborn Screening Center National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. .,Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, China.
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