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Lu W, Allickson J. Mesenchymal stromal cell therapy: Progress to date and future outlook. Mol Ther 2025; 33:2679-2688. [PMID: 39916329 DOI: 10.1016/j.ymthe.2025.02.003] [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: 11/07/2024] [Revised: 01/16/2025] [Accepted: 02/03/2025] [Indexed: 02/28/2025] Open
Abstract
In clinical trials, mesenchymal stromal/stem cells (MSCs) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably, there has been a recent approval of an MSC therapy for pediatric graft-vs.-host disease in the United States, marking the first MSC therapy approved by the U.S. Food and Drug Administration. This review provides a background of the history and potential therapeutic value of MSCs, an overview of MSC products with regulatory approval, and a summary of registered MSC trials. It concludes with a discussion on current and ongoing challenges and questions surrounding MSC therapy that remains to be resolved before becoming available for routine clinical use outside of clinical trials.
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Affiliation(s)
- Wen Lu
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA.
| | - Julie Allickson
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA
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2
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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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Wada K, Takeuchi A, Katayama Y, Ohkawa N, Kantake M, Fujioka K, Nishikubo T, Yamamoto Y, Yamada Y, Yoshimoto S, Sumi K, Ioroi T, Mure T, Wada N, Nakano Y, Takasao N, Tada K, Yamamoto T, Hirai H, Sato Y, Ide H, Kusuda S. Combined treatment with mesenchymal stem cells and therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy: a phase 1/2 randomized trial. Sci Rep 2025; 15:16302. [PMID: 40348804 PMCID: PMC12065831 DOI: 10.1038/s41598-025-98504-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Neonatal hypoxic ischemic encephalopathy (nHIE) is a serious disease that causes severe and chronic neurological damage. Hypothermia therapy improves patients' outcomes albeit with some limitations, but combining it with treatment with cord blood cells (analogous to mesenchymal stem cells [MSCs]) reportedly improves its effectiveness. TEMCELL HS Inj. (Temcell), a human bone marrow-derived MSC product used for acute graft-versus-host disease, seems an appropriate candidate for this combination therapy. Therefore, we performed a randomized, parallel-group study to compare combined treatment with Temcell and hypothermia versus hypothermia therapy-alone to evaluate the safety and efficacy of Temcell in nHIE patients. The primary endpoint was treatment response defined as an overall developmental quotient of ≥ 85 at 18 months of age. Fourteen patients were enrolled and randomized, with 7 assigned to each group. Both groups had similar demographic characteristics and nHIE severity. Treatment response was observed in 4 of the 6 (66.7%) patients in the Temcell combination group, and in 4 of the 7 patients (57.1%) in the hypothermia therapy-alone group. No marked differences in safety profile were observed between the groups. These results indicate that the efficacy of Temcell combined with hypothermia is comparable to therapeutic hypothermia for patients with nHIE.Clinical Trial Registration: jRCT1080224818.
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Affiliation(s)
- Kazuko Wada
- Department of Neonatal Medicine, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka, 594-1101, Japan.
| | - Akihito Takeuchi
- Division of Neonatology, NHO Okayama Medical Center, Okayama, Japan
| | | | - Natsuki Ohkawa
- Department of Neonatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Masato Kantake
- Division of Neonatology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Toshiya Nishikubo
- Division of Neonatal Intensive Care, Fetal and Neonatal Medical Center, Nara Medical University Hospital, MaternalNara, Japan
| | - Yutaka Yamamoto
- Department of Neonatology, Gifu Prefectural General Medical Center, Gifu, Japan
| | - Yasumasa Yamada
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, Aichi, Japan
| | - Seiji Yoshimoto
- Department of Neonatology, Hyogo Prefectural Kobe Children's Hospital, Hyogo, Japan
| | - Kiyoaki Sumi
- Department of Pediatrics, Aizenbashi Hospital, Osaka, Japan
| | - Tomoaki Ioroi
- Department of Pediatrics, Perinatal Medical Center, Himeji Red Cross Hospital, Hyogo, Japan
| | - Takeo Mure
- Department of Pediatrics, Chibune General Hospital, Osaka, Japan
| | - Norihisa Wada
- Kindai University Hospital Perinatal Medical Center, Osaka, Japan
| | | | - Naoko Takasao
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan
| | - Kenji Tada
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan
| | - Tatsuyoshi Yamamoto
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan
| | - Hideaki Hirai
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan
| | - Yuji Sato
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan
| | - Hideyuki Ide
- Development Division, JCR Pharmaceuticals, 3-19 Kasuga-cho, Ashiya, Hyogo, 659-0021, Japan.
| | - Satoshi Kusuda
- Neonatal Research Network of Japan, Shinjuku Park Tower N30, 3-7-1, Nishishinjuku, Shinjuku, Tokyo, 163-1030, Japan.
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Blanc KL, Dazzi F, English K, Farge D, Galipeau J, Horwitz EM, Kadri N, Krampera M, Lalu MM, Nolta J, Patel NM, Shi Y, Weiss DJ, Viswanathan S. ISCT MSC committee statement on the US FDA approval of allogenic bone-marrow mesenchymal stromal cells. Cytotherapy 2025; 27:413-416. [PMID: 39864015 DOI: 10.1016/j.jcyt.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2025]
Abstract
The December 2024 US Food and Drug Administration (FDA) approval of Mesoblast's Ryoncil (remestemcel-L-rknd)-allogeneic bone marrow mesenchymal stromal cell (MSC(M)) therapy-in pediatric acute steroid-refractory graft-versus-host-disease finally ended a long-lasting drought on approved MSC clinical products in the United States. While other jurisdictions-including Europe, Japan, India, and South Korea-have marketed autologous or allogeneic MSC products, the United States has lagged in its approval. The sponsor's significant efforts and investments, working closely with the FDA addressing concerns regarding clinical efficacy and consistent MSC potency through an iterative process that spanned several years, was rewarded with this landmark approval. This approval will revive investment and enthusiasm in MSC products, further approvals in major markets, and will continue to foreshadow the long-predicted success of MSCs as a pharmaceutical.
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Affiliation(s)
- 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
| | - Francesco Dazzi
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, United Kingdom; AstraZeneca Biopharma R&D, Cambridge, United Kingdom
| | - Karen English
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland; Department of Biology, Maynooth University, Maynooth, Ireland
| | - Dominique Farge
- Internal Medicine Unit (UF 04) CRMR MATHEC, Autoimmune Diseases and Cell Therapy, Reference Center for Rare Systemic Autoimmune Diseases of Ile-de-France MATHEC, AP-HP, St-Louis Hospital, Paris, France; Université Paris Cité, IRSL, Clinical Research in Hematology, Immunology and Transplantation, Paris, France; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Jacques Galipeau
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Edwin M Horwitz
- Marcus Center for Advanced Cellular Therapy, Children's Healthcare of Atlanta, Atlanta, Georgia, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA; Graduate Division of Biology and Biomedical Sciences, Emory University Laney Graduate School, Atlanta, Georgia, USA
| | - Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mauro Krampera
- Hematology and Bone Marrow Transplant Unit, Section of Biomedicine of Innovation, Department of Engineering for Innovative Medicine (DIMI), University of Verona, Verona, Italy
| | - Manoj Mathew Lalu
- Acute Care Research Program, Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jan Nolta
- Department of Internal Medicine, Stem Cell Program and Institute for Regenerative Cures, University of California Davis, Sacramento, California, USA
| | - Nikita M Patel
- INmune Bio International, Royal Free Hospital, London, UK
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University Institutes for Translational Medicine, and Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China; Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Daniel J Weiss
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Sowmya Viswanathan
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada; Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Division of Hematology, University of Toronto, Toronto, Ontario, Canada.
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Yan W, Zhang H, Zhang J, Zhao Y, Wu Y, Ma X, Luan X. Human placental mesenchymal stem cells regulate the antioxidant capacity of CD8 +PD-1 + T cells through the CD73/ADO/Nrf2 pathway to protect against liver damage in mice with acute graft-versus-host disease. Mol Immunol 2025; 179:71-83. [PMID: 39923662 DOI: 10.1016/j.molimm.2025.01.016] [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: 12/01/2024] [Revised: 01/17/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025]
Abstract
Graft-versus-host disease (GVHD) constitutes a severe complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT), significantly reducing the survival rate of patients. Mesenchymal stem cells (MSCs) are capable of ameliorating the tissue damage caused by GVHD through exerting immunosuppressive effects; however, the relevant mechanisms require further investigation. This study used a GVHD mouse model to explore the therapeutic effects and mechanisms of human placental mesenchymal stem cells (hPMSCs) in mitigating GVHD-induced liver injury. The findings indicated that hPMSCs reduced the proportion of CD8+PD-1+ T cells in both the liver and spleen of GVHD mice, decreased reactive oxygen species (ROS) levels, and upregulated glutathione S transferase (GST) and glutathione (GSH) levels. Consistently, this led to a decrease in the expression of liver fibrosis markers, including alpha-smooth muscle actin (α-SMA) and fibronectin (FN). Moreover, CD8+PD-1+ T cells and ROS were positively correlated with α-SMA and FN, respectively, whereas GST and GSH were negatively correlated with them. hPMSCs with low expression in CD73 attenuated this effect. In vitro studies demonstrated that hPMSCs upregulated the expression of nuclear factor-E2-related factor 2 (Nrf2) via the CD73/adenosine (ADO) pathway, regulated oxidative metabolism, and reduced the number of CD8+PD-1+ T cells. The results suggested that hPMSCs contributed to the regulation of redox homeostasis and reduced the proportion of CD8+PD-1+ T cells through the CD73/ADO/Nrf2 signaling pathway, thereby alleviating liver injury associated with GVHD.
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Affiliation(s)
- Wei Yan
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China; Department of Reproductive Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province 264000, China
| | - Hengchao Zhang
- Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Jiashen Zhang
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Yaxuan Zhao
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Yunhua Wu
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China
| | - Xiaolin Ma
- Hematology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province 266000, China.
| | - Xiying Luan
- Department of Immunology, Binzhou Medical University, Yantai, Shandong Province 264000, China.
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Sawada R, Kusakawa S, Kusuhara M, Tanaka K, Miura T, Yasuda S, Sato Y. Increasing robustness of in vitro assay for immnosuppressive effect of mesenchymal stromal/stem cells: The role of inflammatory cytokine production by peripheral blood mononuclear cells. Regen Ther 2025; 28:321-332. [PMID: 39877252 PMCID: PMC11773150 DOI: 10.1016/j.reth.2024.12.016] [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: 11/26/2024] [Revised: 12/22/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Introduction The Quality by Design (QbD) approach for developing cell therapy products using mesenchymal stromal/stem cells (MSCs) is a promising method for designing manufacturing processes to improve the quality of MSC products. It is crucial to ensure the reproducibility and robustness of the test system for evaluating critical quality attributes (CQAs) in the QbD approach for manufacturing of pharmaceutical products. In this study, we explored the key factors involved in establishing a robust evaluation system for the immunosuppressive effect of MSCs, which can be an example of a CQA in developing and manufacturing therapeutic MSCs for treating graft-versus-host disease, etc, and we have identified method attributes to increase the robustness of a simple in vitro assay to assess the immunosuppressive effects of MSCs. Methods We evaluated the performance of an assay system to examine the proliferation of peripheral blood mononuclear cells (PBMCs) activated with the mitogen phytohemagglutinin (PHA) when co-cultured with MSCs, the so-called one-way mixed lymphocyte reaction (MLR) assay. The MLR assay was performed on the same MSCs using 10 PBMC lots from different donors. In addition, 13 cytokine production levels in PHA-stimulated PBMCs were assessed. Results The PHA-stimulated proliferation response of PBMCs, the action of MSCs in the MLR test, and the cytokine release of the respective PBMCs significantly differed among the PBMC lots (p < 0.05). A correlation analysis between the amounts of cytokines released by PBMCs and the immunosuppressive potency of MSCs showed that IFNγ, TNFα, CXCL10, PD-L1, HGF, and CCL5 production in PBMCs was significantly correlated with the MSC-mediated inhibition of PBMC proliferation (p < 0.05). Therefore, we selected two PBMC lots with high PBMC proliferation and PHA-stimulated cytokine (such as IFNγ and TNFα) release for the subsequent one-way MLR assay. The robustness of the established test system was confirmed by repeating the assay several times on different days for the same MSCs (coefficient of variation <0.2). Conclusions To make robust the MSC immunosuppressive potency assay system, controlling the quality of PBMCs used for the assay is essential. Evaluating the inflammatory cytokine production capacity of PBMCs is effective in assessing the quality of the MLR assay system.
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Affiliation(s)
- Rumi Sawada
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Shinji Kusakawa
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Mika Kusuhara
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Kazusa Tanaka
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Takumi Miura
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Satoshi Yasuda
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Yoji Sato
- Division of Drugs, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
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Fath MK, Zadian SS, Torbati SMB, Saqagandomabadi V, Afshar OY, Khalilzad M, Abedi S, Moliani A, Barati G. Roles of Mesenchymal Stem Cells in Breast Cancer Therapy: Engineered Stem Cells and Exosomal Cell-Free Based Therapy. Curr Mol Med 2025; 25:431-444. [PMID: 38275063 DOI: 10.2174/0115665240274818231207054037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 01/27/2024]
Abstract
Breast cancer has a high prevalence among women, with a high mortality rate. The number of people who suffer from breast cancer disease is increasing, whereas metastatic cancers are mostly incurable, and existing therapies have unfavorable side effects. For an extended duration, scientists have dedicated their efforts to exploring the potential of mesenchymal stem cells (MSCs) for the treatment of metastatic cancers, including breast cancer. MSCs could be genetically engineered to boost their anticancer potency. Furthermore, MSCs can transport oncolytic viruses, suicide genes, and anticancer medicines to tumors. Extracellular vesicles (EVs) are MSC products that have attracted scientist's attention as a cell-free treatment. This study narratively reviews the current state of knowledge on engineered MSCs and their EVs as promising treatments for breast cancer.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Seyed Sajjad Zadian
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Vahid Saqagandomabadi
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | | | - Mohammad Khalilzad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Abedi
- Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Afshin Moliani
- Isfahan Medical Students Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Miura Y, Fujii S, Ichinohe T. Cell-based and extracellular vesicle-based MSC therapies for acute radiation syndrome affecting organ systems. JOURNAL OF RADIATION RESEARCH 2024; 65:i80-i87. [PMID: 39679884 DOI: 10.1093/jrr/rrae009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/28/2024] [Indexed: 12/17/2024]
Abstract
Exposure to ionizing radiation can induce harmful biological effects on the human body, particularly in cases of high-dose γ-irradiation affecting the gastrointestinal tract, bone marrow, skin and lung. Such exposures lead to lethal outcomes as individuals experience a breakdown in their immune system's ability to defend against pathogens, predisposing them to sepsis-induced multiple organ failures. Mesenchymal stromal/stem cells (MSCs) possess diverse biological characteristics, including immunomodulation, anti-inflammation and tissue regeneration. Off-the-shelf culture-expanded human bone marrow- or adipose tissue-derived MSCs are clinically available to treat graft-versus-host disease following hematopoietic cell transplantation and perianal fistulas in Crohn's disease in Japan. While preclinical studies showcase encouraging outcomes in radiation-induced injuries, the effectiveness of MSC transplantation in addressing acute radiation syndrome affecting organs in irradiated individuals is limited. Recent studies have highlighted MSC-releasing extracellular vesicles as nanoparticle substances responsible for outlining the mechanism of action and have identified various components, including proteins and microRNA, that serve as functional molecules. MSC-releasing extracellular vesicle-based therapy emerges as a promising avenue, offering a potential solution to the challenges posed by radiation-induced injuries. However, further investigation is required, especially regarding whether MSC-releasing extracellular vesicles have regenerative effects on tissue-resident stem cells. These unresolved issues represent key aspects that need to be addressed to optimize the therapeutic potential of cell-based and extracellular vesicle-based MSC therapies for interventions in the context of radiation-induced injuries.
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Affiliation(s)
- Yasuo Miura
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, 1-93 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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Sher EK, Kalić A, Džidić-Krivić A, Zećo MB, Pinjić E, Sher F. Cellular therapeutic potential of genetically engineered stem cells in cancer treatment. Biotechnol Genet Eng Rev 2024; 40:4062-4097. [PMID: 37132363 DOI: 10.1080/02648725.2023.2204720] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/13/2023] [Indexed: 05/04/2023]
Abstract
Traditional therapeutic approaches in the treatment of cancer have many side effects and are often ineffective and non-specific, leading to the development of therapy-resistant tumour cells. Recently, numerous discoveries about stem cells have given a new outlook on their application in oncology. Stem cells are unique because of their biological attributes, including self-renewal, differentiation in different types of specialized cells and synthesis of molecules that interplay with tumour niche. They are already used as an effective therapeutic option for haematological malignancies, such as multiple myeloma and leukaemia. The main goal of this study is to investigate the possible applications of different types of stem cells in cancer treatment and to summarize novel advances, as well as the limitations of their application in cancer treatment. Research and clinical trials that are underway revealed and confirmed the enormous potential of regenerative medicine in the treatment of cancer, especially when combined with different nanomaterials. Nanoengineering of stem cells has been the focus of novel studies in the area of regenerative medicine, such as the production of nanoshells and nanocarriers that enhance the transport and uptake of stem cells in their targeted tumour niche and enable the effective monitoring of stem cell effects on tumour cells. Although nanotechnology has a lot of limitations, it provides new opportunities for the development of effective and innovative stem cell therapies.
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Affiliation(s)
- Emina Karahmet Sher
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Azra Kalić
- Faculty of pharmacy, University of modern sciences - CKM, Mostar, Bosnia and Herzegovina
| | - Amina Džidić-Krivić
- International Society of Engineering Science and Technology, Nottingham, UK
- Department of Neurology, Cantonal Hospital Zenica, Zenica, Bosnia and Herzegovina
| | - Merima Beća- Zećo
- Faculty of pharmacy, University of modern sciences - CKM, Mostar, Bosnia and Herzegovina
- International Society of Engineering Science and Technology, Nottingham, UK
| | - Emma Pinjić
- Department of Radiology, Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, USA
| | - Farooq Sher
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK
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Soder RP, Dudley NR, Dawn B. Microcarrier-based clinical-grade manufacturing of therapeutic Wharton's jelly mesenchymal stromal cells. Cytotherapy 2024; 26:1556-1565. [PMID: 39093227 DOI: 10.1016/j.jcyt.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 08/04/2024]
Abstract
Due to their immunomodulatory and anti-inflammatory properties, tissue repair capabilities and regenerative potential, Wharton's jelly mesenchymal stem/stromal cells (WJMSCs) have been widely investigated as potential treatment for diverse clinical indications. WJMSCs have been found to be well-tolerated and safe, positioning them as a promising candidate for cellular therapy. To address the commercial need for manufacturing WJMSCs for clinical applications, the production scale should be capable of generating large quantities of cells that retain their expected identity, purity and potency. This study aimed to establish a current Good Manufacturing Practice (cGMP) compliant robust and scalable expansion process representing a critical step towards a cGMP-compliant large-scale production platform for WJMSC-based clinical applications. Using our in-house cGMP-manufactured WJMSCs, which are currently being tested in a Phase Ib clinical trial (NCT03158896) using two-dimensional (2D) planar systems, we optimized various culture parameters including type of microcarrier, seeding density, agitation and culture feed regime in a 3D microcarrier-based culture system in spinner flasks. The results showed that cell adhesion was potentiated under intermittent stirring (3 min of agitation at 25 rpm followed by a period of non-agitation for 30 min), with reduced supplementation (0.05%) during the initial 8 h of cultivation with an initial cell concentration of 0.45 × 105 cells/mL. Microcarrier-based WJMSC expansion in spinner flasks achieved greater cell densities of 1.67 × 106 cells/mL with a maximum of 37-fold expansion, yielding ∼84 × 106 cells after 6 days of culture with a 95% harvest efficiency. Additionally, post 3D expansion, WJMSCs maintained their phenotypic characteristics, differentiation potential, normal karyotype, functional properties and sterility in the culture systems evaluated. This cGMP-compliant expansion process described herein demonstrates a successful transition of an established 2D planar culture process of clinical grade WJMSCs to 3D microcarrier-based suspension process generating higher cell yields, is cost-effective and represents an important step toward fulfilling the commercial demand of clinical grade mesenchymal stromal cells.
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Affiliation(s)
- Rupal P Soder
- Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
| | - Nathaniel R Dudley
- Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Buddhadeb Dawn
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Nevada, USA
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11
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Alsultan A, Farge D, Kili S, Forte M, Weiss DJ, Grignon F, Boelens JJ. International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges. Cytotherapy 2024; 26:1132-1140. [PMID: 38804990 PMCID: PMC12046531 DOI: 10.1016/j.jcyt.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.
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Affiliation(s)
- Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dominique Farge
- Internal Medicine Unit (UF 04): CRMR MATHEC, Autoimmune diseases and Cellular Therapy, St-Louis Hospital, Center of reference for rare systemic autoimmune diseases of Ile-de-France (FAI2R), AP-HP, Hôpital St-Louis, Paris University, IRSL, Paris, France; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sven Kili
- Sven Kili Consulting Ltd., Shrewsbury, UK; Saisei Ventures, Boston, Massachusetts, USA; CCRM, Toronto, Canada
| | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Felix Grignon
- International Society for Cell & Gene Therapy, Vancouver, Canada
| | - Jaap Jan Boelens
- Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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12
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Akabane M, Imaoka Y, Kawashima J, Endo Y, Schenk A, Sasaki K, Pawlik TM. Innovative Strategies for Liver Transplantation: The Role of Mesenchymal Stem Cells and Their Cell-Free Derivatives. Cells 2024; 13:1604. [PMID: 39404368 PMCID: PMC11475694 DOI: 10.3390/cells13191604] [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: 08/20/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia-reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yutaka Endo
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Austin Schenk
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
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Takakura Y, Hanayama R, Akiyoshi K, Futaki S, Hida K, Ichiki T, Ishii-Watabe A, Kuroda M, Maki K, Miura Y, Okada Y, Seo N, Takeuchi T, Yamaguchi T, Yoshioka Y. Quality and Safety Considerations for Therapeutic Products Based on Extracellular Vesicles. Pharm Res 2024; 41:1573-1594. [PMID: 39112776 PMCID: PMC11362369 DOI: 10.1007/s11095-024-03757-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/28/2024] [Indexed: 08/30/2024]
Abstract
Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.
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Affiliation(s)
- Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
| | - Rikinari Hanayama
- WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kanazawa, Japan.
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Shiroh Futaki
- Institute for Chemical Research, Kyoto University, Kyoto, Japan
| | - Kyoko Hida
- Vascular Biology and Molecular Biology, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Takanori Ichiki
- Department of Materials Engineering, School of Engineering, The University of Tokyo, Bunkyō, Japan
| | - Akiko Ishii-Watabe
- Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Kawasaki, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Shinjuku, Japan
| | - Kazushige Maki
- Pharmaceuticals and Medical Devices Agency, Chiyoda-ku, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine and Cell Therapy, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Yoshiaki Okada
- Department of Transfusion Medicine and Cell Transplantation, Saitama Medical University Hospital, Kawagoe, Japan
| | - Naohiro Seo
- Department of Bioengineering, School of Engineering, The University of Tokyo, Bunkyō, Japan
| | - Toshihide Takeuchi
- Life Science Research Institute, Kindai University, Higashi-osaka, Japan
| | | | - Yusuke Yoshioka
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Shinjuku, Japan
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14
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Strecanska M, Sekelova T, Csobonyeiova M, Danisovic L, Cehakova M. Therapeutic applications of mesenchymal/medicinal stem/signaling cells preconditioned with external factors: Are there more efficient approaches to utilize their regenerative potential? Life Sci 2024; 346:122647. [PMID: 38614298 DOI: 10.1016/j.lfs.2024.122647] [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: 02/21/2024] [Revised: 03/25/2024] [Accepted: 04/10/2024] [Indexed: 04/15/2024]
Abstract
Mesenchymal/medicinal stem/signaling cells (MSCs) have emerged as a promising treatment option for various disorders. However, the donor's age, advanced stage of disease, and prolonged in vitro expansion often diminish the innate regenerative potential of MSCs. Besides that, the absence of MSCs' comprehensive "pre-admission testing" can result in the injection of cells with reduced viability and function, which may negatively affect the overall outcome of MSC-based therapies. It is, therefore, essential to develop effective strategies to improve the impaired biological performance of MSCs. This review focuses on the comprehensive characterization of various methods of external MSCs stimulation (hypoxia, heat shock, caloric restriction, acidosis, 3D culture, and application of extracellular matrix) that augment their medicinal potential. To emphasize the significance of MSCs priming, we summarize the effects of individual and combined preconditioning approaches, highlighting their impact on MSCs' response to either physiological or pathological conditions. We further investigate the synergic action of exogenous factors to maximize MSCs' therapeutic potential. Not to omit the field of tissue engineering, the application of pretreated MSCs seeded on scaffolds is discussed as well.
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Affiliation(s)
- Magdalena Strecanska
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
| | - Tatiana Sekelova
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
| | - Maria Csobonyeiova
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
| | - Lubos Danisovic
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
| | - Michaela Cehakova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
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15
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Abstract
Regenerative medicine is a highly anticipated field with hopes to provide cures for previously uncurable diseases such as spinal cord injuries and retinal blindness. Most regenerative medical products use either autologous or allogeneic stem cells, which may or may not be genetically modified. The introduction of induced-pluripotent stem cells (iPSCs) has fueled research in the field, and several iPSC-derived cells/tissues are currently undergoing clinical trials. The cornea is one of the pioneering areas of regenerative medicine, and already four cell therapy products are approved for clinical use in Japan. There is one other government-approved cell therapy product approved in Europe, but none are approved in the USA at present. The cornea is transparent and avascular, making it unique as a target for stem cell therapy. This review discusses the unique properties of the cornea and ongoing research in the field.
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Affiliation(s)
- Shigeto Shimmura
- Department of Clinical Regenerative Medicine, Fujita Medical Innovation Center, Tokyo, Japan
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Emi Inagaki
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Masatoshi Hirayama
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Shin Hatou
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
- Cellusion Inc., Tokyo, Japan
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16
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Fu H, Sun X, Lin R, Wang Y, Xuan L, Yao H, Zhang Y, Mo X, Lv M, Zheng F, Kong J, Wang F, Yan C, Han T, Chen H, Chen Y, Tang F, Sun Y, Chen Y, Xu L, Liu K, Zhang X, Liu Q, Huang X, Zhang X. Mesenchymal stromal cells plus basiliximab improve the response of steroid-refractory acute graft-versus-host disease as a second-line therapy: a multicentre, randomized, controlled trial. BMC Med 2024; 22:85. [PMID: 38413930 PMCID: PMC10900595 DOI: 10.1186/s12916-024-03275-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 01/25/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT). METHODS The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981). RESULTS Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031). CONCLUSIONS For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.
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Affiliation(s)
- Haixia Fu
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Xueyan Sun
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Ren Lin
- Medical Center of Haematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Li Xuan
- Medical Center of Haematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Han Yao
- Department of Haematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yuanyuan Zhang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Xiaodong Mo
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Meng Lv
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Fengmei Zheng
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Jun Kong
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Fengrong Wang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Chenhua Yan
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Tingting Han
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Huan Chen
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Yao Chen
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Feifei Tang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Yuqian Sun
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Yuhong Chen
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Lanping Xu
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Kaiyan Liu
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China
- National Clinical Research Center for Haematologic Disease, Beijing, China
| | - Xi Zhang
- Medical Center of Haematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - Qifa Liu
- Department of Haematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Xiaojun Huang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China.
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China.
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China.
- National Clinical Research Center for Haematologic Disease, Beijing, China.
| | - Xiaohui Zhang
- Peking University People's Hospital, Peking University Institute of Haematology, No. 11 Xizhimen South Street, Beijing, 100044, China.
- Collaborative Innovation Center of Haematology, Peking University, Beijing, China.
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Beijing, China.
- National Clinical Research Center for Haematologic Disease, Beijing, China.
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Hong J, Fraebel J, Yang Y, Tkacyk E, Kitko C, Kim TK. Understanding and treatment of cutaneous graft-versus-host-disease. Bone Marrow Transplant 2023; 58:1298-1313. [PMID: 37730800 PMCID: PMC11759061 DOI: 10.1038/s41409-023-02109-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/28/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023]
Abstract
The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients' quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.
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Affiliation(s)
- Junshik Hong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Johnathan Fraebel
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yenny Yang
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric Tkacyk
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carrie Kitko
- Monroe Carell Jr Children's Hospital, Vanderbilt Division of Pediatric Hematology-Oncology, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Tae Kon Kim
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
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18
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Zeiser R, Ringden O, Sadeghi B, Gonen-Yaacovi G, Segurado OG. Novel therapies for graft versus host disease with a focus on cell therapies. Front Immunol 2023; 14:1241068. [PMID: 37868964 PMCID: PMC10585098 DOI: 10.3389/fimmu.2023.1241068] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/11/2023] [Indexed: 10/24/2023] Open
Abstract
Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.
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Affiliation(s)
- Robert Zeiser
- Department of Medicine at the University of Freiburg, Freiburg, Germany
| | - Olle Ringden
- Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
| | - Behnam Sadeghi
- Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
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19
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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20
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Jakl V, Popp T, Haupt J, Port M, Roesler R, Wiese S, Friemert B, Rojewski MT, Schrezenmeier H. Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells. Cells 2023; 12:2105. [PMID: 37626914 PMCID: PMC10453497 DOI: 10.3390/cells12162105] [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: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
| | - Tanja Popp
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Julian Haupt
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Matthias Port
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Reinhild Roesler
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Sebastian Wiese
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Markus T. Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
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21
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Lin T, Yang Y, Chen X. A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation. Eur J Med Res 2023; 28:268. [PMID: 37550742 PMCID: PMC10405442 DOI: 10.1186/s40001-023-01244-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.
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Affiliation(s)
- Ting Lin
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunfan Yang
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xinchuan Chen
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
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22
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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23
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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: 48] [Impact Index Per Article: 24.0] [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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24
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Jaing TH, Chang TY, Chiu CC. Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease. World J Stem Cells 2023; 15:221-234. [PMID: 37180998 PMCID: PMC10173808 DOI: 10.4252/wjsc.v15.i4.221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency. Despite its increased use, the mortality rate for patients undergoing this procedure remains high, mainly due to the perceived risk of exacerbating graft-versus-host disease (GVHD). However, even with immunosuppressive agents, some patients still develop GVHD. Advanced mesenchymal stem/stromal cell (MSC) strategies have been proposed to achieve better therapeutic outcomes, given their immunosuppressive potential. However, the efficacy and trial designs have varied among the studies, and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs. This review aims to provide real insights into this clinical entity, emphasizing diagnostic, and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues. The indications and timing for the clinical application of MSCs are still subject to debate.
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Affiliation(s)
- Tang-Her Jaing
- Division of Hematology, Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan 333, Taiwan
| | - Tsung-Yen Chang
- Department of Pediatrics, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chia-Chi Chiu
- Department of Nursing, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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25
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Garcia-Rosa M, Abraham A, Bertaina A, Bhoopalan SV, Bonfim C, Cohen S, DeZern A, Louis C, Oved J, Pavel-Dinu M, Purtill D, Ruggeri A, Russell A, Sharma A, Wynn R, Boelens JJ, Prockop S. International society for cell & gene therapy stem cell engineering committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant. Cytotherapy 2023; 25:578-589. [PMID: 36941149 DOI: 10.1016/j.jcyt.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AIMS Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. METHODS We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included. RESULTS Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. CONCLUSIONS There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.
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Affiliation(s)
- Moises Garcia-Rosa
- Pediatric Hematology-Oncology Fellow, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA.
| | - Allistair Abraham
- Center for Cancer and Immunology Research, CETI, Children's National Hospital, Washington, District of Columbia, USA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Senthil Velan Bhoopalan
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Carmem Bonfim
- Pediatric Blood and Marrow Transplantation Division and Pele Pequeno Principe Research Institute, Hospital Pequeno Principe, Curitiba, Brazil
| | - Sandra Cohen
- Universite de Montreal and Maisonneuve Rosemont Hospital, Montreal, Quebec, Canada
| | - Amy DeZern
- Bone Marrow Failure and MDS Program, John Hopkins Medicine Baltimore, Maryland, USA
| | | | - Joseph Oved
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mara Pavel-Dinu
- Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Redwood City, California, USA
| | - Duncan Purtill
- Department of Haematology, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | | | - Athena Russell
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Akshay Sharma
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert Wynn
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Jaap Jan Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Susan Prockop
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts USA
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26
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Itonaga H, Miyazaki Y, Aoki K, Shingai N, Ozawa Y, Fukuda T, Kataoka K, Kawakita T, Ueda Y, Ara T, Tanaka M, Katayama Y, Sawa M, Eto T, Kanda J, Atsuta Y, Ishiyama K. Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database. Ann Hematol 2023; 102:1215-1227. [PMID: 36918415 DOI: 10.1007/s00277-023-05167-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/06/2023] [Indexed: 03/15/2023]
Abstract
Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P = .129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00-1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13-1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation.
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Affiliation(s)
- Hidehiro Itonaga
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.
| | - Yasushi Miyazaki
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.,Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Kazunari Aoki
- Laboratory of Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Naoki Shingai
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yukiyasu Ozawa
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.,Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Toshiro Kawakita
- Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
| | - Yasunori Ueda
- Department of Hematology/Oncology and Transfusion and Hemapheresis Center, Kurashiki Central Hospital, Okayama, Japan
| | - Takahide Ara
- Department of Hematology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Aichi, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Junya Kanda
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan.,Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Aichi, Japan
| | - Ken Ishiyama
- Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan
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27
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Takeuchi Y, Miyao K, Negishi S, Ohara F, Motegi K, Wakabayashi H, Yokota H, Kuwano S, Sawa H, Inagaki Y, Sawa M. Clinical Benefit of Low-Dose Antithymocyte Globulin-Thymoglobulin as Graft-versus-Host Disease Prophylaxis in Patients Receiving Allogeneic Peripheral Blood Stem Cell Transplantation from HLA-Identical Donors. Transplant Cell Ther 2023; 29:325.e1-325.e10. [PMID: 36736783 DOI: 10.1016/j.jtct.2023.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 01/05/2023] [Accepted: 01/23/2023] [Indexed: 02/05/2023]
Abstract
Graft-versus-host disease (GVHD) is a major complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Previous randomized studies have already shown that the use of several types of antihuman T lymphocyte immune globulin (ATG) as GVHD prophylaxis can reduce the incidence of acute GVHD and chronic GVHD. However, the efficacy and safety of PBSCT from HLA-identical donors with low-dose ATG remain unclear. This study aimed to clarify the efficacy and safety of PBSCT from HLA-identical donors with low-dose ATG compared with PBSCT from HLA-identical donors without ATG. To do so, we retrospectively analyzed the outcomes of patients who underwent allogeneic PBSCT from HLA-identical donors with low-dose ATG-thymoglobulin (ATG-T; 2.5 mg/kg) versus those who did not receive ATG-T. Patient data were collected retrospectively from the medical records of Anjo Kosei Hospital. This study was conducted from 2009 to the final follow-up in October 2022. Forty-seven of 91 patients received ATG-T between January 2009 and March 2020. ATG-T reduced the incidence rates of moderate-to-severe chronic GVHD (hazard ratio [HR], .15; 95% confidence interval [CI], .057 to .41; P < .0010) and nonrelapse mortality (HR, .21; 95% CI, .0058 to.75, P = .016) without increasing the risk of relapse. Overall survival did not differ significantly between the 2 groups; however, the low-dose ATG-T group had better moderate-to-severe chronic GVHD-free, relapse-free survival rates (HR, .47; 95% CI, .27 to .80, P = .0054) than the non-ATG-T group. In addition, multistate analysis revealed that the low-dose ATG-T group had better current GVHD-free, relapse-free survival at 24 months after transplantation (45% [95% CI, 29% to 63%)] versus 21% [95% CI, 9.1% to 34%]; P = .015). Low-dose ATG-T was not associated with increased incidence of infections or adverse events. Our findings suggest that low-dose ATG-T can be beneficial for patients receiving PBSCT from HLA-identical donors. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Affiliation(s)
- Yuki Takeuchi
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan.
| | - Kotaro Miyao
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Shuto Negishi
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Fumiya Ohara
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kenta Motegi
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | | | - Hirofumi Yokota
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Shihomi Kuwano
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Hitomi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Yuichiro Inagaki
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
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28
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Liu YJ, Miao HB, Lin S, Chen Z. Current Progress in Treating Systemic Lupus Erythematosus Using Exosomes/MicroRNAs. Cell Transplant 2023; 32:9636897221148775. [PMID: 36661068 PMCID: PMC9903023 DOI: 10.1177/09636897221148775] [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] [Indexed: 01/21/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease associated with impaired organ functions that can seriously affect the daily life of patients. Recent SLE therapies frequently elicit adverse reactions and side effects in patients, and clinical heterogeneity is considerable. Mesenchymal stromal cells (MSCs) have anti-inflammatory, tissue repair, and immunomodulatory properties. Their ability to treat autoimmune diseases largely depends on secreted extracellular vesicles, especially exosomes. The effects of exosomes and microRNAs (miRNAs) on SLE have recently attracted interest. This review summarizes the applications of MSCs derived from bone marrow, adipocyte tissue, umbilical cord, synovial membrane, and gingival tissue, as well as exosomes to treating SLE and the key roles of miRNAs. The efficacy of MSCs infusion in SLE patients with impaired autologous MSCs are reviewed, and the potential of exosomes and their contents as drug delivery vectors for treating SLE and other autoimmune diseases in the future are briefly described.
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Affiliation(s)
- Yi-jing Liu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Hai-bing Miao
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Zhen Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,Zhen Chen, Department of Rheumatology and Immunology, The Second Affiliated Hospital of Fujian Medical University, 34 Zhongshan Road, Quanzhou 362000, Fujian, P.R. China.
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29
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Hervás-Salcedo R, Fernández-García M, Hernando-Rodríguez M, Suárez-Cabrera C, Bueren JA, Yáñez RM. Improved efficacy of mesenchymal stromal cells stably expressing CXCR4 and IL-10 in a xenogeneic graft versus host disease mouse model. Front Immunol 2023; 14:1062086. [PMID: 36817457 PMCID: PMC9929539 DOI: 10.3389/fimmu.2023.1062086] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/04/2023] [Indexed: 02/04/2023] Open
Abstract
Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. In vitro experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF-1α and also improved their immunomodulatory properties compared to unmodified Ad-MSCs (WT-MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3+-IL10+ cells), and increased the number of regulatory T and B cells. Our in vitro and in vivo studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.
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Affiliation(s)
- Rosario Hervás-Salcedo
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Madrid, Spain
| | - María Fernández-García
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Madrid, Spain
| | - Miriam Hernando-Rodríguez
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Madrid, Spain
| | - Cristian Suárez-Cabrera
- Translational Oncology Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de 8 Cancer (CIBERONC), Madrid, Spain.,Biomedical Research Institute I + 12, Hospital 12 de Octubre, Madrid, Spain
| | - Juan A Bueren
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Madrid, Spain
| | - Rosa M Yáñez
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Advanced Therapies Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Madrid, Spain
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30
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Yuan P, Qin HY, Wei JY, Chen G, Li X. Proteomics reveals the potential mechanism of Tanshinone IIA in promoting the Ex Vivo expansion of human bone marrow mesenchymal stem cells. Regen Ther 2022; 21:560-573. [DOI: 10.1016/j.reth.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/25/2022] Open
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31
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Optimal Intravenous Administration Procedure for Efficient Delivery of Canine Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2022; 23:ijms232314681. [PMID: 36499004 PMCID: PMC9740176 DOI: 10.3390/ijms232314681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
Mesenchymal stem cells (MSC) are currently being investigated for their therapeutic applications in a wide range of diseases. Although many studies examined peripheral venous administration of MSC, few have investigated the detailed intravenous administration procedures of MSC from their preparation until they enter the body. The current study therefore aimed to explore the most efficient infusion procedure for MSC delivery by preparing and infusing them under various conditions. Canine adipose-derived mesenchymal stem cells (cADSC) were infused using different infusion apparatuses, suspension solutions, allogenic serum supplementation, infusion time and rates, and cell densities, respectively. Live and dead cell counts were then assessed by manual measurements and flow cytometry. Efficiency of live- and dead-cell infusion and cell viability were calculated from the measured cell counts and compared under each condition. Efficiency of live-cell infusion differed significantly according to the infusion apparatus, infusion rate, and combination of cell density and serum supplementation. Cell viability after infusion differed significantly between the infusion apparatuses. The optimal infusion procedure resulting in the highest cell delivery and viability involved suspending cADSC in normal saline supplemented with 5% allogenic serum at a density of 5 × 105 cells/mL, and infusing them using an automatic infusion device for 15 min. This procedure is therefore recommended as the standard procedure for the intravenous administration of ADSC in terms of cell-delivery efficiency.
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32
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Liu Z, Zeng Q, Chen X, He C, Wang F, Liu T. Donor peritoneal-derived cells can attenuate graft-versus-host disease after MHC-incompatible bone marrow transplantation in mice. Int Immunopharmacol 2022; 112:109296. [DOI: 10.1016/j.intimp.2022.109296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/05/2022]
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33
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Novel and Promising Strategies for Therapy of Post-Transplant Chronic GVHD. Pharmaceuticals (Basel) 2022; 15:ph15091100. [PMID: 36145321 PMCID: PMC9503665 DOI: 10.3390/ph15091100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/22/2022] [Accepted: 08/31/2022] [Indexed: 11/17/2022] Open
Abstract
Despite the achievements that have increased viability after the transplantation of allogeneic hematopoietic stem cells (aHSCT), chronic graft-versus-host disease (cGVHD) remains the main cause of late complications and post-transplant deaths. At the moment, therapy alternatives demonstrate limited effectiveness in steroid-refractory illness; in addition, we have no reliable data on the mechanism of this condition. The lack of drugs of choice for the treatment of GVHD underscores the significance of the design of new therapies. Improved understanding of the mechanism of chronic GVHD has secured new therapy goals, and organized diagnostic recommendations and the development of medical tests have ensured a general language and routes for studies in this field. These factors, combined with the rapid development of pharmacology, have helped speed up the search of medicines and medical studies regarding chronic GVHD. At present, we can hope for success in curing this formidable complication. This review summarizes the latest clinical developments in new treatments for chronic GVHD.
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34
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Huang Y, Wu Q, Tam PKH. Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci 2022; 23:ijms231710023. [PMID: 36077421 PMCID: PMC9456387 DOI: 10.3390/ijms231710023] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/19/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn’s disease, graft-versus-host disease, and COVID-19.
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Affiliation(s)
- Yutong Huang
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qiang Wu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Correspondence: (Q.W.); (P.K.H.T.)
| | - Paul Kwong Hang Tam
- Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China
- Correspondence: (Q.W.); (P.K.H.T.)
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35
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Insights into mechanisms of graft-versus-host disease through humanised mouse models. Biosci Rep 2022; 42:231673. [PMID: 35993192 PMCID: PMC9446388 DOI: 10.1042/bsr20211986] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection. Therefore, further insights into the disease mechanisms and development of predictive and prognostic biomarkers are key to improving outcomes and reducing GVHD development following allogeneic HSCT. An important preclinical tool to examine the pathophysiology of GVHD and to understand the key mechanisms that lead to GVHD development are preclinical humanised mouse models. Such models of GVHD are now well-established and can provide valuable insights into disease development. This review will focus on models where human peripheral blood mononuclear cells are injected into immune-deficient non-obese diabetic (NOD)-scid-interleukin-2(IL-2)Rγ mutant (NOD-scid-IL2Rγnull) mice. Humanised mouse models of GVHD can mimic the clinical setting for GVHD development, with disease progression and tissues impacted like that observed in humans. This review will highlight key findings from preclinical humanised mouse models regarding the role of donor human immune cells, the function of cytokines and cell signalling molecules and their impact on specific target tissues and GVHD development. Further, specific therapeutic strategies tested in these preclinical models reveal key molecular pathways important in reducing the burden of GVHD following allogeneic HSCT.
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36
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Nagamura-Inoue T, Kato S, Najima Y, Isobe M, Doki N, Yamamoto H, Uchida N, Takahashi A, Hori A, Nojima M, Ohashi K, Nagamura F, Tojo A. Immunological influence of serum-free manufactured umbilical cord-derived mesenchymal stromal cells for steroid-resistant acute graft-versus-host disease. Int J Hematol 2022; 116:754-769. [PMID: 35908021 DOI: 10.1007/s12185-022-03408-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 06/13/2022] [Indexed: 12/31/2022]
Abstract
This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr ).
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Affiliation(s)
- Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. .,Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. .,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. .,Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Seiko Kato
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | | | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Atsuko Takahashi
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akiko Hori
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,IMSUT CORD, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masanori Nojima
- Division of Advanced Medicine Promotion, The Advanced Clinical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuteru Ohashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Fumitaka Nagamura
- Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.,Division of Advanced Medicine Promotion, The Advanced Clinical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology and Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Institute of Innovation Advancement, Tokyo Medical and Dental University, Tokyo, Japan
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37
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Vo P, Gooley TA, Carpenter PA, Sorror ML, MacMillan ML, DeFor TE, Martin PJ. Prediction of outcomes after second-line treatment for acute graft-versus-host disease. Blood Adv 2022; 6:3220-3229. [PMID: 35235948 PMCID: PMC9198915 DOI: 10.1182/bloodadvances.2021006220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 02/22/2022] [Indexed: 11/20/2022] Open
Abstract
Acute graft-versus-host disease (GVHD) requiring second-line treatment represents a highly morbid complication of allogenic hematopoietic cell transplantation (HCT). Recent studies have defined short-term outcomes after second-line treatment for acute GVHD, but longer-term outcomes have not been well defined. We examined overall survival (OS) and failure-free-survival (FFS) of 216 patient who had HCT who received second-line treatment for acute GVHD. Failure time for FFS was defined as the earliest of death, relapse, or implementation of third-line treatment. Multivariable Cox regression was used to identify risk factors for mortality and failure, and predictive models were derived for 6- and 12-month mortality. Point estimates of OS at 6 and 12 months were 59% (95% confidence interval [CI], 52-65) and 52% (95% CI, 45-68), respectively. Point estimates of FFS at 6 and 12 months were 42% (95% CI, 35-48) and 37% (95% CI, 31-43), respectively. Predictive models for both end points included serum albumin and total bilirubin concentrations at the onset of second-line treatment, patient age at onset of second-line therapy, and a combination of abdominal pain/stage 4 gut involvement. Optimism-corrected areas under the receiver-operator characteristic curve and Brier scores were 77.4 and 0.169 for 6-month mortality, respectively, and 80.0 and 0.169 for 12-month mortality. We identify risk factors associated with mortality and failure after second-line treatment of acute GVHD, provide historical benchmarks for assessment of FFS and OS in other studies, and propose predictive models for 6- and 12-month mortality that could be used to generate population-specific benchmarks.
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Affiliation(s)
- Phuong Vo
- Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, WA
- Department of Medicine, and
| | - Ted A. Gooley
- Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, WA
| | - Paul A. Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, WA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA
| | - Mohamed L. Sorror
- Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, WA
- Department of Medicine, and
| | - Margaret L. MacMillan
- Blood and Marrow Transplantation & Cellular Therapy Program
- Department of Pediatrics, Masonic Cancer Center, and
| | - Todd E. DeFor
- Blood and Marrow Transplantation & Cellular Therapy Program
- Biostatistics and Informatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Paul J. Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center; Seattle, WA
- Department of Medicine, and
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38
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Cabanillas Stanchi KM, Böhringer J, Strölin M, Groeschel S, Lenglinger K, Treuner C, Kehrer C, Laugwitz L, Bevot A, Kaiser N, Schumm M, Lang P, Handgretinger R, Krägeloh-Mann I, Müller I, Döring M. Hematopoietic stem cell transplantation with mesenchymal stromal cells in children with metachromatic leukodystrophy. Stem Cells Dev 2022; 31:163-175. [PMID: 35323019 DOI: 10.1089/scd.2021.0352] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients (MSCG) underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 x 106 MSCs/kg bodyweight at day +30 and +60 after HSCT between 2007 and 2018. MSC safety, occurrence of graft-versus-host disease (GvHD), blood ARSA levels, chimerism, cell regeneration and engraftment, MRI changes, and the gross motor function were assessed within the first year of HSCT. The long-term data included clinical outcomes and safety aspects of MSCs. Data were compared to a control cohort of seven pediatric MLD patients (CG) who underwent HSCT only. The application of MSC in pediatric MLD patients after allogeneic HSCT was safe and well tolerated and long-term potentially MSC-related adverse effects up to 13.5 years after HSCT were not observed. Patients achieved significantly higher ARSA levels (CG: median 1.03 nmol∙10-6, range 0.41-1.73 | MSCG: median 1.58 nmol∙10-6, range 0.44-2.6; p<0.05), as well as significantly higher leukocyte (p<0.05) and thrombocyte (p<0.001) levels within 365 days of MSC application compared to CG patients. Statistically significant effects on acute GvHD, regeneration of immune cells, engraftment, MRI changes, gross motor function, and clinical outcomes were not detected. In conclusion, the application of MSCs in pediatric MLD patients after allogeneic HSCT was safe and well tolerated. The two applications of 2 x 106/kg allogeneic MSCs were followed by improved engraftment and hematopoiesis within the first year after HSCT. Larger, prospective trials are necessary to evaluate the impact of MSC application on engraftment and hematopoietic recovery.
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Affiliation(s)
| | - Judith Böhringer
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Manuel Strölin
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Samuel Groeschel
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Katrin Lenglinger
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Claudia Treuner
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Christiane Kehrer
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Lucia Laugwitz
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Andrea Bevot
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Nadja Kaiser
- University Children's Hospital Tübingen, Dpt. III - Neuropediatrics, Germany;
| | - Michael Schumm
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Peter Lang
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
| | - Rupert Handgretinger
- Children's University Hospital, Hematology/Oncology, Hoppe-Seyler-Str. 1, Tuebingen, Germany, 72076;
| | | | - Ingo Müller
- University Medical Center Hamburg-Eppendorf, 37734, Department of Pediatric Hematology and Oncology, Hamburg, Hamburg, Germany;
| | - Michaela Döring
- University Children's Hospital Tübingen, Dpt. I - General Pediatrics, Hematology and Oncology, Germany;
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Nito C, Suda S, Nitahara-Kasahara Y, Okada T, Kimura K. Dental-Pulp Stem Cells as a Therapeutic Strategy for Ischemic Stroke. Biomedicines 2022; 10:biomedicines10040737. [PMID: 35453487 PMCID: PMC9032844 DOI: 10.3390/biomedicines10040737] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/03/2022] [Accepted: 03/16/2022] [Indexed: 02/01/2023] Open
Abstract
Regenerative medicine aims to restore human functions by regenerating organs and tissues using stem cells or living tissues for the treatment of organ and tissue defects or dysfunction. Clinical trials investigating the treatment of cerebral infarction using mesenchymal stem cells, a type of somatic stem cell therapy, are underway. The development and production of regenerative medicines using somatic stem cells is expected to contribute to the treatment of cerebral infarction, a central nervous system disease for which there is no effective treatment. Numerous experimental studies have shown that cellular therapy, including the use of human dental pulp stem cells, is an attractive strategy for patients with ischemic brain injury. This review describes the basic research, therapeutic mechanism, clinical trials, and future prospects for dental pulp stem cell therapy, which is being investigated in Japan in first-in-human clinical trials for the treatment of patients with acute cerebral ischemia.
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Affiliation(s)
- Chikako Nito
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (S.S.); (K.K.)
- Collaborative Research Center, Laboratory for Clinical Research, Nippon Medical School, Tokyo 113-8603, Japan
- Correspondence: ; Tel.: +81-3-3822-2131; Fax: +81-3-5814-6176
| | - Satoshi Suda
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (S.S.); (K.K.)
| | - Yuko Nitahara-Kasahara
- Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (Y.N.-K.); (T.O.)
| | - Takashi Okada
- Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (Y.N.-K.); (T.O.)
| | - Kazumi Kimura
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (S.S.); (K.K.)
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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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Cellular therapies for the treatment and prevention of SARS-CoV-2 infection. Blood 2022; 140:208-221. [PMID: 35240679 PMCID: PMC8896869 DOI: 10.1182/blood.2021012249] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/01/2022] [Indexed: 12/15/2022] Open
Abstract
Patients with blood disorders who are immune suppressed are at increased risk for infection with severe acute respiratory syndrome coronavirus 2. Sequelae of infection can include severe respiratory disease and/or prolonged duration of viral shedding. Cellular therapies may protect these vulnerable patients by providing antiviral cellular immunity and/or immune modulation. In this recent review of the field, phase 1/2 trials evaluating adoptive cellular therapies with virus-specific T cells or natural killer cells are described along with trials evaluating the safety, feasibility, and preliminary efficacy of immune modulating cellular therapies including regulatory T cells and mesenchymal stromal cells. In addition, the immunologic basis for these therapies is discussed.
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Shen MZ, Liu XX, Qiu ZY, Xu LP, Zhang XH, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu SN, Liu KY, Huang XJ, Mo XD. Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft- versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation. Ther Adv Hematol 2022; 13:20406207211072838. [PMID: 35096361 PMCID: PMC8796067 DOI: 10.1177/20406207211072838] [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] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/17/2021] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT. METHODS MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0-2.0) × 106/kg once a week. RESULTS A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8-1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1-7) and 3 (range, 2-12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16-118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22-84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1). CONCLUSION MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.
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Affiliation(s)
- Meng-Zhu Shen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xin-Xin Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Department of Hematology, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Zhi-Yuan Qiu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Department of Hematology, Weifang People’s Hospital, Weifang, China
| | - Lan-Ping Xu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiao-Hui Zhang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Yu Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Chen-Hua Yan
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Huan Chen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Yu-Hong Chen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Wei Han
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Feng-Rong Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Jing-Zhi Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Si-Ning Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Kai-Yan Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiao-Jun Huang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Dong Mo
- Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing 2019RU029, China
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Kelly K, Rasko JEJ. Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease. Front Immunol 2021; 12:761616. [PMID: 34764962 PMCID: PMC8577186 DOI: 10.3389/fimmu.2021.761616] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 12/28/2022] Open
Abstract
Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment via multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.
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Affiliation(s)
- Kilian Kelly
- Cynata Therapeutics Limited, Cremorne, VIC, Australia
| | - John E J Rasko
- Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Gene and Stem Cell Therapy Program Centenary Institute, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia
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Kouchakian MR, Baghban N, Moniri SF, Baghban M, Bakhshalizadeh S, Najafzadeh V, Safaei Z, Izanlou S, Khoradmehr A, Nabipour I, Shirazi R, Tamadon A. The Clinical Trials of Mesenchymal Stromal Cells Therapy. Stem Cells Int 2021; 2021:1634782. [PMID: 34745268 PMCID: PMC8566082 DOI: 10.1155/2021/1634782] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/22/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a heterogeneous population of adult stem cells, which are multipotent and possess the ability to differentiate/transdifferentiate into mesodermal and nonmesodermal cell lineages. MSCs display broad immunomodulatory properties since they are capable of secreting growth factors and chemotactic cytokines. Safety, accessibility, and isolation from patients without ethical concern make MSCs valuable sources for cell therapy approaches in autoimmune, inflammatory, and degenerative diseases. Many studies have been conducted on the application of MSCs as a new therapy, but it seems that a low percentage of them is related to clinical trials, especially completed clinical trials. Considering the importance of clinical trials to develop this type of therapy as a new treatment, the current paper is aimed at describing characteristics of MSCs and reviewing relevant clinical studies registered on the NIH database during 2016-2020 to discuss recent advances on MSC-based therapeutic approaches being used in different diseases.
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Affiliation(s)
- Mohammad Reza Kouchakian
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Neda Baghban
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Seyedeh Farzaneh Moniri
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mandana Baghban
- Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shabnam Bakhshalizadeh
- Reproductive Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Vahid Najafzadeh
- Department of Veterinary and Animal Sciences, Anatomy & Biochemistry Section, University of Copenhagen, Copenhagen, Denmark
| | - Zahra Safaei
- Department of Obstetrics and Gynecology, School of Medicine, Amir Al Mo'menin Hospital, Amir Al Mo'menin IVF Center, Arak University of Medical Sciences, Arak, Iran
| | - Safoura Izanlou
- Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Reza Shirazi
- Department of Anatomy, School of Medical Sciences, Medicine & Health, UNSW Sydney, Sydney, Australia
| | - Amin Tamadon
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
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Murata M, Terakura S, Wake A, Miyao K, Ikegame K, Uchida N, Kataoka K, Miyamoto T, Onizuka M, Eto T, Doki N, Ota S, Sato M, Hashii Y, Ichinohe T, Fukuda T, Atsuta Y, Okamoto S, Teshima T. Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence. Bone Marrow Transplant 2021; 56:2355-2366. [PMID: 33976381 DOI: 10.1038/s41409-021-01304-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/29/2021] [Accepted: 04/09/2021] [Indexed: 11/08/2022]
Abstract
Temcell is a cryopreserved, human bone marrow-derived mesenchymal stem cell (MSC) product approved for the treatment of patients of all ages with acute graft-versus-host disease (GVHD). Initial experience with Temcell in a real-world setting from a cellular therapy registry in Japan is presented. A total of 381 consecutive patients were enrolled since its approval in 2016. The median cell number infused was 2.00 × 106/kg. The most common number of infusions was 8 in 100 patients. Of the 306 evaluable patients, the overall response rate (ORR) on day 28 after the start of MSC therapy was 56%. Of the 151 evaluable patients who received it as second-line therapy following first-line steroid therapy for classic acute GVHD, the ORR was 61%. Liver involvement of GVHD and ≥14 days from first-line steroid therapy to second-line MSC therapy was associated with a lower ORR. Day 28 ORR, patient age, GVHD grade, GVHD organ involvement, and a number of GVHD therapies before MSC therapy were associated with nonrelapse mortality. Overall survival at 6 months in 381 patients was 40%. This study suggests that Temcell is one of the treatment options for steroid-refractory acute GVHD until a new treatment with survival benefit is developed.
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Affiliation(s)
- Makoto Murata
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Wake
- Department of Hematology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Kotaro Miyao
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kazuhiro Ikegame
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshihiro Miyamoto
- Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Maho Sato
- Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan
| | - Yoshiko Hashii
- Department of Cancer Immunotherapy/Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takahiro Fukuda
- Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Graduate School of Medical Science, Sapporo, Japan
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Shimazawa Y, Kusamori K, Tsujimura M, Shimomura A, Takasaki R, Takayama Y, Shimizu K, Konishi S, Nishikawa M. Intravenous injection of mesenchymal stem cell spheroids improves the pulmonary delivery and prolongs in vivo survival. Biotechnol J 2021; 17:e2100137. [PMID: 34581003 DOI: 10.1002/biot.202100137] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 01/16/2023]
Abstract
BACKGROUND Because of the excellent therapeutic potential, mesenchymal stem cells (MSCs) have been used as cell therapeutics for various diseases. However, the survival rate and duration of MSCs after transplantation are extremely low and short, respectively. To solve these problems, in this study, we prepared multicellular spheroids of MSCs and investigated their survival and function after intravenous injection in mice. METHODS AND RESULTS The murine adipose-derived MSC line m17.ASC was cultured in agarose-based microwell plates to obtain size-controlled m17.ASC spheroids of an average diameter and cell number of approximately 170 μm and 1100 cells/spheroid, respectively. The intravenously injected m17.ASC spheroids mainly accumulated in the lung and showed a higher survival rate than suspended m17.ASC cells during the experimental period of 7 days. m17.ASC spheroids efficiently reduced the lipopolysaccharide-induced increase in plasma concentrations of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS These results indicate that spheroid formation improved the pulmonary delivery and survival of MSCs, as well as their therapeutic potential against inflammatory pulmonary diseases.
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Affiliation(s)
- Yoshihiko Shimazawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Kosuke Kusamori
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Mari Tsujimura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Asuka Shimomura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Ryo Takasaki
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Yukiya Takayama
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Kazunori Shimizu
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Aichi, Japan
| | - Satoshi Konishi
- Department of Mechanical Engineering, Graduate School of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
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Takao S, Nakashima T, Masuda T, Namba M, Sakamoto S, Yamaguchi K, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takahashi S, Nakashima A, Hattori N. Human bone marrow-derived mesenchymal stromal cells cultured in serum-free media demonstrate enhanced antifibrotic abilities via prolonged survival and robust regulatory T cell induction in murine bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther 2021; 12:506. [PMID: 34530920 PMCID: PMC8444523 DOI: 10.1186/s13287-021-02574-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/27/2021] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) are a potential therapeutic tool for pulmonary fibrosis. However, ex vivo MSC expansion using serum poses risks of harmful immune responses or unknown pathogen infections in the recipients. Therefore, MSCs cultured in serum-free media (SF-MSCs) are ideal for clinical settings; however, their efficacy in pulmonary fibrosis is unknown. Here, we investigated the effects of SF-MSCs on bleomycin-induced pulmonary inflammation and fibrosis compared to those of MSCs cultured in serum-containing media (S-MSCs). Methods SF-MSCs and S-MSCs were characterized in vitro using RNA sequence analysis. The in vivo kinetics and efficacy of SF-MSC therapy were investigated using a murine model of bleomycin-induced pulmonary fibrosis. For normally distributed data, Student’s t test and one-way repeated measures analysis of variance followed by post hoc Tukey’s test were used for comparison between two groups and multiple groups, respectively. For non-normally distributed data, Kruskal–Wallis and Mann–Whitney U tests were used for comparison between groups, using e Bonferroni’s correction for multiple comparisons. All tests were two-sided, and P < 0.05 was considered statistically significant. Results Serum-free media promoted human bone marrow-derived MSC expansion and improved lung engraftment of intravenously administered MSCs in recipient mice. SF-MSCs inhibited the reduction in serum transforming growth factor-β1 and the increase of interleukin-6 in both the serum and the bronchoalveolar lavage fluid during bleomycin-induced pulmonary fibrosis. SF-MSC administration increased the numbers of regulatory T cells (Tregs) in the blood and lungs more strongly than in S-MSC administration. Furthermore, SF-MSCs demonstrated enhanced antifibrotic effects on bleomycin-induced pulmonary fibrosis, which were diminished by antibody-mediated Treg depletion. Conclusions SF-MSCs significantly suppressed BLM-induced pulmonary inflammation and fibrosis through enhanced induction of Tregs into the lungs and corrected the dysregulated cytokine balance. Therefore, SF-MSCs could be a useful tool for preventing pulmonary fibrosis progression without the demerits of serum use. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02574-5.
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Affiliation(s)
- Shun Takao
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masashi Namba
- Department of Clinical Oncology, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinya Takahashi
- Department of Cardiovascular Surgery, Graduate School of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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Murata M, Teshima T. Treatment of Steroid-Refractory Acute Graft- Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products. Front Immunol 2021; 12:724380. [PMID: 34489977 PMCID: PMC8417106 DOI: 10.3389/fimmu.2021.724380] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 07/29/2021] [Indexed: 01/09/2023] Open
Abstract
Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.
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Affiliation(s)
- Makoto Murata
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
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Infusion of Mesenchymal Stem Cells to Treat Graft Versus Host Disease: the Role of HLA-G and the Impact of its Polymorphisms. Stem Cell Rev Rep 2021; 16:459-471. [PMID: 32088839 DOI: 10.1007/s12015-020-09960-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem-cell transplantation is widely performed for the treatment of hematologic diseases and is increasingly being used for the experimental treatment of various autoimmune diseases. Despite the rapid evolution of this therapy, the mortality rate of patients undergoing this procedure is still high, mainly due to the development of graft versus host disease (GvHD). Even with the administration of immunosuppressive therapy, some patients manifest the chronic form of the disease. For these cases, infusion of mesenchymal stem cells (MSCs) was proposed as a therapeutic strategy, considering the immunosuppressive potential of these cells. This review describes the main results obtained in cell therapy with MSCs for the treatment of GvHD. Despite the encouraging results found, some points differed among the studies. Although the factors that influence the different results are uncertain, some investigators have suggested that variations in immunosuppressive molecules are responsible for these divergences. We highlight the key role of the HLA-G gene in modulating the immune response, and the importance of the polymorphisms and alleles of this gene associated with the outcome of the transplants. We suggest that the HLA-G gene and its polymorphisms be analyzed as a factor in selecting the MSCs to be used in treating GvHD, given its strong immunosuppressive role.
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Ciccocioppo R, Gibellini D, Astori G, Bernardi M, Bozza A, Chieregato K, Elice F, Ugel S, Caligola S, De Sanctis F, Canè S, Fiore A, Trovato R, Vella A, Petrova V, Amodeo G, Santimaria M, Mazzariol A, Frulloni L, Ruggeri M, Polati E, Bronte V. The immune modulatory effects of umbilical cord-derived mesenchymal stromal cells in severe COVID-19 pneumonia. Stem Cell Res Ther 2021; 12:316. [PMID: 34078447 PMCID: PMC8170427 DOI: 10.1186/s13287-021-02376-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/09/2021] [Indexed: 12/11/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.
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Affiliation(s)
- Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
| | - Davide Gibellini
- Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Giuseppe Astori
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Martina Bernardi
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Angela Bozza
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Katia Chieregato
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Francesca Elice
- Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Stefano Ugel
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Simone Caligola
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Francesco De Sanctis
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Stefania Canè
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Alessandra Fiore
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Rosalinda Trovato
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Antonio Vella
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Varvara Petrova
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Giuseppe Amodeo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Monica Santimaria
- Nuclear Medicine Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Annarita Mazzariol
- Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Luca Frulloni
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Marco Ruggeri
- Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Enrico Polati
- Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, A.O.U.I. Ospedale Maggiore & University of Verona, Verona, Italy
| | - Vincenzo Bronte
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
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