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Sato S, Teramura Y, Ogawa Y, Shimizu E, Otake M, Hori K, Kamata T, Shu Y, Seta Y, Kuramochi A, Asai K, Shimizu S, Negishi K, Hirayama M. Conditioned media of stem cells from human exfoliated deciduous teeth contain factors related to extracellular matrix organization and promotes corneal epithelial wound healing. Regen Ther 2025; 29:148-161. [PMID: 40170802 PMCID: PMC11960544 DOI: 10.1016/j.reth.2025.03.002] [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: 12/27/2024] [Revised: 02/27/2025] [Accepted: 03/09/2025] [Indexed: 04/03/2025] Open
Abstract
This study aimed to investigate the therapeutic potential of cell-free conditioned media (CM) from human mesenchymal stem cells (hMSCs), specifically stem cells from human exfoliated deciduous teeth (SHED), for treating ocular surface diseases. The proteomes of various hMSC-CMs were compared using cytokine array and liquid chromatography-mass spectrometry (LC-MS). Bioinformatic analysis identified key biological pathways associated with SHED-CM, immortalized SHED-CM (IM-SHED-CM), and a fractionated component of IM-SHED-CM in which low weight molecules (less than 3.5kD) were depleted. Corneal epithelial wound healing models were constructed by epithelial scraping and treated with eye drops derived from SHED-CM. For the migration assay, the human corneal epithelial cells were wounded and then incubated with SHED-CM. SHED-CM, IM-SHED-CM, and >3.5 kD fractionated component eyedrops were administered to a chronic graft-versus-host disease (cGVHD) mouse model with sever corneal epithelial damages. SHED-CM, IM-SHED-CM, and >3.5 kD fractionated component of IM-SHED-CM were enriched in factors involved in epithelial wound healing, particularly extracellular matrix (ECM) organization. Both in vitro and in vivo assays demonstrated that SHED-CM significantly enhanced corneal epithelial wound healing. Furthermore, SHED-CM-derived eye drops reduced corneal epithelial damage, inflammatory cell infiltration, and oxidative stress in the corneal epithelium and maintained the expression of limbal stem cell markers in the cGVHD mouse model. These findings suggest that SHED-CM eye drops could be a novel treatment for corneal epithelial damage, highlighting the role of bioactive factors in promoting wound healing and offering an alternative to cell-based MSC therapies for corneal wound healing.
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Affiliation(s)
- Shinri Sato
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuji Teramura
- Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
- Department of Immunology, Genetics and Pathology (IGP), Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden
- Master's/Doctoral Program in Life Science Innovation (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Eisuke Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masato Otake
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Keigo Hori
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Takamitsu Kamata
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Yujing Shu
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Yasuhiro Seta
- Hitonowa Medical, K. PLAZA 2F, 1-7 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Akiko Kuramochi
- Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Kazuki Asai
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Shota Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masatoshi Hirayama
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Huang R, Zhang X. Exploration and practice: New integration of cellular therapy and hematopoietic stem cell transplantation. Chin Med J (Engl) 2025:00029330-990000000-01554. [PMID: 40387529 DOI: 10.1097/cm9.0000000000003558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Indexed: 05/20/2025] Open
Affiliation(s)
- Ruihao Huang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Xi Zhang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing 400037, China
- Jinfeng Laboratory, Chongqing 401329, China
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Xu Q, Wang R, Sui K, Xu Y, Zhou Y, He Y, Hu Z, Wang Q, Xie X, Wang X, Yang S, Zeng L, Zhong JF, Wang Z, Song Q, Zhang X. Enhance the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells in prevention of acute graft-versus-host disease through CRISPLD2 modulation. Stem Cell Res Ther 2025; 16:222. [PMID: 40312744 PMCID: PMC12044869 DOI: 10.1186/s13287-025-04321-6] [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: 01/26/2025] [Accepted: 04/07/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) remains a major life-threatening complication of allogeneic haematopoietic cell transplantation (allo-HSCT), often limiting the therapeutic efficacy of allo-HSCT. Recent studies have suggested that mesenchymal stem cells (MSCs) may be beneficial for the treatment of aGVHD. However, the therapeutic potential of MSCs is often negatively impacted by their heterogeneity. METHODS To investigate MSCs heterogeneity, we conducted single-cell transcriptomic analysis of human umbilical cord-derived MSCs (HUC-MSCs) and identified key feature genes that distinguish MSCs subpopulations. The function of the newly discovered biomarker CRISPLD2 was also explored. We engineered human umbilical cord-derived MSCs (HUC-MSCs) to overexpress the CRISPLD2 gene using lentiviral vectors. The downstream regulatory effects of CRISPLD2 overexpression were assessed through bulk RNA sequencing. Additionally, we evaluated its impact on cellular senescence using Western blotting and β-galactosidase (SA-β-gal) staining. The immunoregulatory capability of HUC-MSCs was tested through coculture experiments with T cells and liver organoids in vitro. Mitochondrial function was analysed via flow cytometry and electron microscopy. The in vivo therapeutic effects of HUC-MSCs on aGVHD were evaluated using an aGVHD murine model. The graft-versus-leukaemia (GVL) effect was measured via the inoculation of luciferase-positive A20 cells, and tumour growth was monitored via bioluminescence imaging. RESULTS Our findings indicated that the CRISPLD2 gene is heterogeneously expressed in HUC-MSCs subsets characterized by stemness and immunosuppressive properties. Transcriptomic analysis revealed that CRISPLD2 overexpression suppressed calcium ion binding and G protein-coupled receptor signalling. In vitro studies demonstrated a marked increase in IL-10 secretion, which enhanced T-cell suppression in CRISPLD2-modified HUC-MSCs. The in vivo results demonstrated that transfusion of CRISPLD2-overexpressing HUC-MSCs ameliorated aGVHD while maintaining GVL activity. Mechanistically, CRISPLD2 overexpression overcomes the mitochondrial damage mediated by extracellular ATP and LPS in HUC-MSCs by inhibiting P2Y11 receptor signalling, thereby preserving their stemness and IL-10-mediated immunosuppressive functions. CONCLUSIONS Our study revealed that CRISPLD2 is a novel marker for identifying HUC-MSCs subpopulation with enhanced immunosuppressive functions. CRISPLD2 overexpression enhances the immunosuppressive function of HUC-MSCs by inhibiting P2Y11 receptor signalling. Targeting CRISPLD2 is a promising strategy to improve the therapeutic efficacy of HUC-MSCs in aGVHD while maintaining GVL activity.
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Affiliation(s)
- Qing Xu
- School of Life Sciences, Chongqing University, Chongqing, 405200, China
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Ke Sui
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Yuxi Xu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Ya Zhou
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Yuxuan He
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Ziyi Hu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Qi Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Xiaodong Xie
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
| | - Jiang F Zhong
- Department of Basic Sciences, Loma Linda University, Loma Linda, CA, 92354, USA
| | - Zheng Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China.
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China.
| | - Qingxiao Song
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China.
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China.
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China.
- Institute of Science Innovation for Blood Ecology and Intelligent Cells, Medical Center of Hematology, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400037, China.
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Liu S, Wan X, Gou Y, Yang W, Xu W, Du Y, Peng X, Wang X, Zhang X. The emerging functions and clinical implications of circRNAs in acute myeloid leukaemia. Cancer Cell Int 2025; 25:167. [PMID: 40296024 PMCID: PMC12038945 DOI: 10.1186/s12935-025-03772-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Acute myeloid leukaemia (AML) is a prevalent haematologic malignancy characterized by significant heterogeneity. Despite the application of aggressive therapeutic approaches, AML remains associated with poor prognosis. Circular RNAs (circRNAs) constitute a unique class of single-stranded RNAs featuring covalently closed loop structures that are ubiquitous across species. These molecules perform crucial regulatory functions in the pathogenesis of various diseases through diverse mechanisms, including acting as miRNA sponges, interacting with DNA or proteins, and encoding functional proteins/polypeptides. Recently, numerous circRNAs have been confirmed to have aberrant expression patterns in AML patients. In particular, certain circRNAs are closely associated with specific clinicopathological characteristics and thus have great potential as diagnostic/prognostic biomarkers and therapeutic targets in AML. Herein, we systematically summarize the biogenesis, degradation, and functional mechanisms of circRNAs while highlighting their clinical relevance. We also outline a series of online databases and analytical tools available to facilitate circRNA research. Finally, we discuss the current challenges and future research priorities in this evolving field.
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Affiliation(s)
- Shuiqing Liu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Xingyu Wan
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Yang Gou
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Wuchen Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Wei Xu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Yuxuan Du
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Xiangui Peng
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China.
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, 400037, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
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Yao H, Huang R, Fu H, Lin R, Zhang Y, Feng Y, Wang Y, Chen T, Wang X, Zhu L, Liu J, Liu Y, Zhao L, Wang L, Kong P, Wen Q, Zhang C, Gao L, Gao L, Liu Q, Zhang X, Huang X, Zhang X. Sequential Infusion of Mesenchymal Stem Cell for Graft-Versus-Host Disease Prevention in Haploidentical Hematopoietic Stem Cell Transplantation: An Open-Label, Multicenter, Randomized Controlled Clinical Trial. J Clin Oncol 2025:JCO2402119. [PMID: 40233291 DOI: 10.1200/jco-24-02119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 02/14/2025] [Accepted: 02/28/2025] [Indexed: 04/17/2025] Open
Abstract
PURPOSE The aim of this open-label, multicenter, randomized controlled trial was to determine the efficacy and safety of sequential umbilical cord-derived mesenchymal stem cell (UC-MSC) infusion for graft-versus-host disease (GVHD) prevention within 3 months of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). METHODS This open-label study evaluated UC-MSC infusion (administer 1 × 106/kg 4 hours before the commencement of day 0, once weekly for the first month after transplantation, once every 2 weeks for the second month, and once during the third month, totaling eight doses). The primary end point was the 2-year cumulative incidence of severe chronic GVHD (cGVHD). RESULTS In the primary analysis, 192 qualified participants between age 18 and 60 years with haplo-HSCT in three transplant centers in China were enrolled and randomly assigned to the MSC and control groups. In the primary analysis, the estimated 2-year cumulative incidence of severe cGVHD and all grades of cGVHD was lower in the MSC group than in the control group (P = .033 and P = .022). The cumulative incidence of grade 1 to 4, 2 to 4, and 3 to 4 acute GVHD (aGVHD) in patients in the MSC group significantly decreased (all P < .001). The 3-year GVHD-free and relapse-free survival (GRFS) rate in the MSC group was 62.4%, which was significantly higher than that in the control group (32.0%, hazard ratio [HR], 0.34, P < .001). MSC infusion did not influence the cumulative incidence of relapse (P = .34) and nonrelapse mortality (P = .45). CONCLUSION Our findings suggest that sequential infusion of MSCs within 3 months after haplo-HSCT significantly reduced both the incidence and severity of cGVHD and aGVHD, manifesting as a better GRFS rate for patients.
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Affiliation(s)
- Han Yao
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Ruihao Huang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Haixia Fu
- National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanqi Zhang
- Department of Health Statistics, College of Military Preventive Medicine, Army Medical University, Chongqing, China
| | - Yimei Feng
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Yu Wang
- National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Ting Chen
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lidan Zhu
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jia Liu
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Yuqing Liu
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lu Zhao
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lu Wang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Peiyan Kong
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Qin Wen
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Cheng Zhang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Li Gao
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaohui Zhang
- National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiaojun Huang
- National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xi Zhang
- Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
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6
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Fernández-Pérez AG, Herrera-González A, López-Naranjo EJ, Martínez-Álvarez IA, Uribe-Rodríguez D, Ramírez-Arreola DE, Sánchez-Peña MJ, Navarro-Partida J. Extracellular Vesicles from Different Mesenchymal Stem Cell Types Exhibit Distinctive Surface Protein Profiling and Molecular Characteristics: A Comparative Analysis. Int J Mol Sci 2025; 26:3393. [PMID: 40244251 PMCID: PMC11989379 DOI: 10.3390/ijms26073393] [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: 02/19/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025] Open
Abstract
The current medical need to respond to different diseases has sparked great interest in extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) due to their great regenerative potential and as drug carriers by playing a critical role in cell-cell communication. However, due to their heterogeneity, there is no standardized universal method for their identification and characterization, which limits their clinical application. This study, following the recommendations and methodologies proposed by MISEV2023 for the characterization of EVs, shows for the first time a detailed morphological, protein, and biochemical comparison between EVs derived from three different MSCs sources (placenta, endometrium, and dental pulp). The information obtained from the different applied assays suggests that there are substantial differences between one EVs source and another. It also offers valuable insights that provide the guidelines to ease their profiling and therefore improve their selection, in order to speed up their use and clinical application; additionally, the knowledge obtained from each characterization test could facilitate new researchers in the field to choose a specific cell source to obtain EVs and select the appropriate methods that provide the necessary information according to their requirements.
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Affiliation(s)
- Atziri G. Fernández-Pérez
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Azucena Herrera-González
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Edgar J. López-Naranjo
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | | | - David Uribe-Rodríguez
- Centro de Biotecnología Santer S.C., Guadalajara 45040, Jalisco, Mexico; (I.A.M.-Á.); (D.U.-R.)
| | - Daniel E. Ramírez-Arreola
- Centro Universitario de la Costa Sur (CUCSUR), University of Guadalajara, Autlan 48900, Jalisco, Mexico;
| | - María Judith Sánchez-Peña
- Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), University of Guadalajara, Guadalajara 44430, Jalisco, Mexico; (A.G.F.-P.); (A.H.-G.); (E.J.L.-N.); (M.J.S.-P.)
| | - Jose Navarro-Partida
- School of Medicine and Health Sciences, Monterrey Institute of Technology, Zapopan 45201, Jalisco, Mexico
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7
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Smallbone P, Kebriaei P, Mendt M, Shpall EJ, Olson AL, Fingrut WB. Mesenchymal stem cells in hematology: Therapeutic initiatives and future directions. Best Pract Res Clin Haematol 2025; 38:101613. [PMID: 40274341 DOI: 10.1016/j.beha.2025.101613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 03/13/2025] [Accepted: 03/18/2025] [Indexed: 04/26/2025]
Abstract
In recent years, the landscape of hematology has undergone rapid transformation, driven by innovative therapeutic strategies harnessing the properties of novel cellular therapies. Mesenchymal stem cells (MSCs) represent one of these promising therapies, with potential applications across a range of hematologic conditions. These cells are notable for their immunomodulatory properties, key role in supporting the hematopoietic micro-environment and capacity for multi-directional differentiation. This review will focus on the biologic mechanisms underlying MSC therapeutic use, current avenues of clinical investigation, and potential challenges and future directions for MSC derived therapies.
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Affiliation(s)
- Portia Smallbone
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amanda L Olson
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Warren B Fingrut
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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8
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Chen B, Chen Z, He M, Zhang L, Yang L, Wei L. Recent advances in the role of mesenchymal stem cells as modulators in autoinflammatory diseases. Front Immunol 2024; 15:1525380. [PMID: 39759531 PMCID: PMC11695405 DOI: 10.3389/fimmu.2024.1525380] [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: 11/09/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Mesenchymal stem cells (MSCs), recognized for their self-renewal and multi-lineage differentiation capabilities, have garnered considerable wide attention since their discovery in bone marrow. Recent studies have underscored the potential of MSCs in immune regulation, particularly in the context of autoimmune diseases, which arise from immune system imbalances and necessitate long-term treatment. Traditional immunosuppressive drugs, while effective, can lead to drug tolerance and adverse effects, including a heightened risk of infections and malignancies. Consequently, adjuvant therapy incorporating MSCs has emerged as a promising new treatment strategy, leveraging their immunomodulatory properties. This paper reviews the immunomodulatory mechanisms of MSCs and their application in autoimmune diseases, highlighting their potential to regulate immune responses and reduce inflammation. The immunomodulatory mechanisms of MSCs are primarily mediated through direct cell contact and paracrine activity with immune cells. This review lays the groundwork for the broader clinical application of MSCs in the future and underscores their significant scientific value and application prospects. Further research is expected to enhance the efficacy and safety of MSCs-based treatments for autoimmune diseases.
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Affiliation(s)
- Baiyu Chen
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Zhilei Chen
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Mengfei He
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Lijie Zhang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Lingling Wei
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
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9
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AlOraibi S, Taurin S, Alshammary S. Advancements in Umbilical Cord Biobanking: A Comprehensive Review of Current Trends and Future Prospects. Stem Cells Cloning 2024; 17:41-58. [PMID: 39655226 PMCID: PMC11626973 DOI: 10.2147/sccaa.s481072] [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: 06/02/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
Biobanking has emerged as a transformative concept in advancing the medical field, particularly with the exponential growth of umbilical cord (UC) biobanking in recent decades. UC blood and tissue provide a rich source of primitive hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for clinical transplantation, offering distinct advantages over alternative adult stem cell sources. However, to fully realize the therapeutic potential of UC-derived stem cells and establish a comprehensive global UC-biobanking network, it is imperative to optimize and standardize UC processing, cryopreservation methods, quality control protocols, and regulatory frameworks, alongside developing effective consent provisions. This review aims to comprehensively explore recent advancements in UC biobanking, focusing on the establishment of rigorous safety and quality control procedures, the standardization of biobanking operations, and the optimization and automation of UC processing and cryopreservation techniques. Additionally, the review examines the expanded clinical applications of UC stem cells, addresses the challenges associated with umbilical cord biobanking and UC-derived stem cell therapies, and discusses the promising role of artificial intelligence (AI) in enhancing various operational aspects of biobanking, streamlining data processing, and improving data analysis accuracy while ensuring compliance with safety and quality standards. By addressing these critical areas, this review seeks to provide insights into the future direction of UC biobanking and its potential to significantly impact regenerative medicine.
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Affiliation(s)
- Sahar AlOraibi
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sebastien Taurin
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sfoug Alshammary
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
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10
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Lombardo G, Lechanteur C, Briquet A, Seidel L, Willems E, Servais S, Baudoux E, Kerre T, Zachee P, Herman J, Janssen A, Muller J, Baron F, Beguin Y. Co-infusion of mesenchymal stromal cells to prevent GVHD after allogeneic hematopoietic cell transplantation from HLA-mismatched unrelated donors after reduced-intensity conditioning: a double-blind randomized study and literature review. Stem Cell Res Ther 2024; 15:461. [PMID: 39627816 PMCID: PMC11613890 DOI: 10.1186/s13287-024-04064-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/14/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have immunomodulatory and hematopoiesis-supporting properties that could potentially benefit hematopoietic stem cell (HSC) engraftment and decrease the incidence and/or severity of graft-versus-host disease (GVHD). METHODS Based on our previous pilot study, we established a multicenter, prospective, randomized, double-blind trial evaluating the efficacy of co-infusing third-party MSC (1.5-3 × 106/kg) versus placebo on the day of HSC transplantation (HCT) to prevent GVHD in recipients of HLA-mismatched unrelated donors after reduced-intensity conditioning. RESULTS The study planned to include 120 patients to improve 1-year overall survival (OS) from 55 to 77% but was stopped after 9 years for low recruitment (n = 38). One-year OS was 74% in the MSC group and 80% in the placebo group. In multivariate analysis, the incidence of grade II-IV acute GVHD was significantly lower in patients receiving MSC (HR 0.332, 95% CI 0.124-0.890, p = 0.0284). No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival at 1 year or long-term, or hematopoietic and immune reconstitution. CONCLUSIONS Despite premature study closure, the suggested beneficial effect of MSC co-transplantation for the prevention of acute GVHD in HLA-mismatched HCT warrants further investigation.
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Affiliation(s)
- Gérôme Lombardo
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Laurence Seidel
- Center for Biostatistics and Research Methods, CHU and University of Liège, Liège, Belgium
| | - Evelyne Willems
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Sophie Servais
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Etienne Baudoux
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium
| | - Tessa Kerre
- Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium
| | - Pierre Zachee
- Department of Clinical Hematology, ZNA Stuivenberg, Antwerp, Belgium
| | - Julie Herman
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Audrey Janssen
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Joséphine Muller
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Frédéric Baron
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium
| | - Yves Beguin
- Department of Clinical Hematology, CHU of Liège, 1 Avenue de L'hôpital, 4000, Liège, Belgium.
- Laboratory of Cell and Gene Therapy, CHU and University of Liège, Liège, Belgium.
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11
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Olivieri A, Mancini G. Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD. Cells 2024; 13:1524. [PMID: 39329708 PMCID: PMC11431085 DOI: 10.3390/cells13181524] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/27/2024] [Accepted: 09/03/2024] [Indexed: 09/28/2024] Open
Abstract
Whereas aGVHD has strong inflammatory components, cGVHD displays autoimmune and fibrotic features; incidence and risk factors are similar but not identical; indeed, the aGVHD is the main risk factor for cGVHD. Calcineurin Inhibitors (CNI) with either Methotrexate (MTX) or Mycophenolate (MMF) still represent the standard prophylaxis in HLA-matched allogeneic stem cell transplantation (HSCT); other strategies focused on ATG, Post-Transplant Cyclophosphamide (PTCy), Abatacept and graft manipulation. Despite the high rate, first-line treatment for aGVHD is represented by corticosteroids, and Ruxolitinib is the standard second-line therapy; investigational approaches include Microbiota transplant and the infusion of Mesenchymal stem cells. GVHD is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. It is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. Extracorporeal Photopheresis (ECP) is still an option used for steroid refractoriness or to achieve a steroid-sparing. For Ruxolitinib-refractory cGVHD, Belumosudil and Axatilimab represent the most promising agents. Bronchiolitis obliterans syndrome (BOS) still represents a challenge; among the compounds targeting non-immune effectors, Alvelestat, a Neutrophil elastase inhibitor, seems promising in BOS. Finally, in both aGVHD and cGVHD, the association of biological markers with specific disease manifestations could help refine risk stratification and the availability of reliable biomarkers for specific treatments.
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Affiliation(s)
- Attilio Olivieri
- Clinica di Ematologia, Università Politecnica delle Marche Ancona, 60126 Ancona, Italy
| | - Giorgia Mancini
- Department of Hematology, AOU delle Marche Ancona, 60126 Ancona, Italy;
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12
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Braidotti S, Granzotto M, Curci D, Faganel Kotnik B, Maximova N. Advancing Allogeneic Hematopoietic Stem Cell Transplantation Outcomes through Immunotherapy: A Comprehensive Review of Optimizing Non-CAR Donor T-Lymphocyte Infusion Strategies. Biomedicines 2024; 12:1853. [PMID: 39200317 PMCID: PMC11351482 DOI: 10.3390/biomedicines12081853] [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: 07/04/2024] [Revised: 08/07/2024] [Accepted: 08/11/2024] [Indexed: 09/02/2024] Open
Abstract
Optimized use of prophylactic or therapeutic donor lymphocyte infusions (DLI) is aimed at improving clinical outcomes in patients with malignant and non-malignant hematological diseases who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). Memory T-lymphocytes (CD45RA-/CD45RO+) play a crucial role in immune reconstitution post-HSCT. The infusion of memory T cells is proven to be safe and effective in improving outcomes due to the enhanced reconstitution of immunity and increased protection against viremia, without exacerbating graft-versus-host disease (GVHD) risks. Studies indicate their persistence and efficacy in combating viral pathogens, suggesting a viable therapeutic avenue for patients. Conversely, using virus-specific T cells for viremia control presents challenges, such as regulatory hurdles, cost, and production time compared to CD45RA-memory T lymphocytes. Additionally, the modulation of regulatory T cells (Tregs) for therapeutic use has become an important area of investigation in GVHD, playing a pivotal role in immune tolerance modulation, potentially mitigating GVHD and reducing pharmacological immunosuppression requirements. Finally, donor T cell-mediated graft-versus-leukemia immune responses hold promise in curbing relapse rates post-HSCT, providing a multifaceted approach to therapeutic intervention in high-risk disease scenarios. This comprehensive review underscores the multifaceted roles of T lymphocytes in HSCT outcomes and identifies avenues for further research and clinical application.
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Affiliation(s)
- Stefania Braidotti
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy;
| | - Marilena Granzotto
- Azienda Sanitaria Universitaria Giuliano Isontina (ASU GI), 34125 Trieste, Italy;
| | - Debora Curci
- Advanced Translational Diagnostic Laboratory, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy;
| | - Barbara Faganel Kotnik
- Department of Hematology and Oncology, University Children’s Hospital, 1000 Ljubljana, Slovenia;
| | - Natalia Maximova
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy;
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13
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[Chinese expert consensus on the diagnosis and treatment of chronic graft-versus-host disease (2024)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:713-726. [PMID: 39307718 PMCID: PMC11535560 DOI: 10.3760/cma.j.cn121090-20240611-00217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Indexed: 12/06/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation, which significantly impacts patients' survival and quality of life. In recent years, notable progress has been made in the diagnosis, prevention, and treatment of cGVHD, driven by the emergence of novel therapies such as targeted drugs and the advancement of clinical research. This consensus, based on the latest developments in cGVHD research and growing data from evidence-based medicine, has been revised and updated from the "Chinese consensus on the diagnosis and management of chronic graft-versus-host disease (2021)" to better guide clinical practice.
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14
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Mo XD, Huang XJ. [The present and future of haploidentical hematopoietic stem cell transplantation in China]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:625-628. [PMID: 39231765 PMCID: PMC11388121 DOI: 10.3760/cma.j.cn121090-20240215-00061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Indexed: 09/06/2024]
Abstract
The lack of donors is the biggest obstacle to the widespread use of hematopoietic stem cell transplantation. The establishment and improvement of new transplantation schemes have made haploid hematopoietic stem cell transplantation a clinical routine, benefiting a large number of patients with hematological diseases. Haploid donors have become the most important source of donors for allogeneic hematopoietic stem cell transplantation in China. This article focuses on the current situation and future development trends of haploid hematopoietic stem cell transplantation in China, in order to increase the understanding of clinical doctors on haploid hematopoietic stem cell transplantation.
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Affiliation(s)
- X D Mo
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X J Huang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
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15
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Mendiratta M, Mohanty S, Sahoo RK. Umbilical Cord-Derived Mesenchymal Stromal Cells For Prevention of Chronic Graft-vs-Host Disease. JAMA Oncol 2024; 10:986-987. [PMID: 38814632 DOI: 10.1001/jamaoncol.2024.1521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, 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, All India Institute of Medical Sciences, New Delhi, India
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16
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Huang R, Zhang X. Umbilical Cord-Derived Mesenchymal Stromal Cells For Prevention of Chronic Graft-vs-Host Disease-Reply. JAMA Oncol 2024; 10:987-988. [PMID: 38814587 DOI: 10.1001/jamaoncol.2024.1524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Affiliation(s)
- Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China
- Jinfeng Laboratory,Chongqing, China
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17
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Zhu Y, Huang C, Zheng L, Li Q, Ge J, Geng S, Zhai M, Chen X, Yuan H, Li Y, Jia W, Sun K, Li Y, Ye T, Zhao Z, Liu H, Liu Z, Jiang H. Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study. Stem Cell Res Ther 2024; 15:122. [PMID: 38679727 PMCID: PMC11057094 DOI: 10.1186/s13287-024-03707-2] [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: 01/08/2024] [Accepted: 03/24/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. METHODS In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. RESULTS In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups. CONCLUSION Intravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty. TRIAL REGISTRATION Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011 .
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Affiliation(s)
- Yingqian Zhu
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Ce Huang
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai Municipality, 200032, China
| | - Liang Zheng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Qingqing Li
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Jianli Ge
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - ShaSha Geng
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Miaomiao Zhai
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Xin Chen
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Huixiao Yuan
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yang Li
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Wenwen Jia
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Keping Sun
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yan Li
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Tong Ye
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Zhengmei Zhao
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Hailiang Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Zhongmin Liu
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University, Shanghai, 200120, China.
| | - Hua Jiang
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
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Song Z, Cui X, Zhang Z, Liu R, Shi X. Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients. Med Clin (Barc) 2024; 162:244-249. [PMID: 38044188 DOI: 10.1016/j.medcli.2023.07.029] [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: 02/10/2023] [Revised: 07/24/2023] [Accepted: 07/27/2023] [Indexed: 12/05/2023]
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. MATERIAL AND METHOD NCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. RESULTS From January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10-34.41)×108/kg, and the median CD34+ count was 13.7 (8.95-22)×106/kg. Neutrophil reconstitution occurred 12 days (11-14 days) after transplantation, and the median platelet reconstitution time was 12 days (9-14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II-IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5-2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation. CONCLUSION This study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT. Transplantation should be performed at an early stage for the survival quality of pediatric patients.
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Affiliation(s)
- Zeliang Song
- Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China
| | - Xiaodai Cui
- Department of Key Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Zhaoxia Zhang
- Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China
| | - Rong Liu
- Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China.
| | - Xiaodong Shi
- Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing 100020, China.
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19
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Huang R, Chen T, Wang S, Wang J, Su Y, Liu J, Zhang Y, Ma X, Wen Q, Kong P, Zhang C, Gao L, Zhong JF, Gao L, Zhang X. Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant: An Open-Label Randomized Clinical Trial. JAMA Oncol 2024; 10:220-226. [PMID: 38153755 PMCID: PMC10870190 DOI: 10.1001/jamaoncol.2023.5757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 09/08/2023] [Indexed: 12/29/2023]
Abstract
Importance Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD. Objective To determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD. Design, Setting, and Participants This open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months. Interventions The enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group). Main Outcome and Measure The cumulative incidence of severe chronic GVHD. Results Of 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04). Conclusions and Relevance The results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT. Trial Registration Chinese Clinical Trial Registry: ChiCTR-IIR-16007806.
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Affiliation(s)
- Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Ting Chen
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Sanbin Wang
- Department of Hematology, 920th Hospital of Joint Logistics Support Force, Yunnan, China
| | - Jishi Wang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Yi Su
- Department of Hematology, the General Hospital of Western Theater Command, Sichuan, China
| | - Jing Liu
- Department of Hematology, the Third Xiangya Hospital of Central South University, Hunan, China
| | - Yanqi Zhang
- Department of Health Statistics, College of Military Preventive Medicine, Army Medical University, Chongqing, China
| | - Xiangyu Ma
- Department of Epidemiology, College of Military Preventive Medicine, Army Medical University, Chongqing, China
| | - Qin Wen
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Peiyan Kong
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Cheng Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jiang F. Zhong
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- Jinfeng Laboratory, Chongqing, China
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20
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Xie Q, Gu J. Therapeutic and Safety Promise of Mesenchymal Stem Cells for Liver Failure: From Preclinical Experiment to Clinical Application. Curr Stem Cell Res Ther 2024; 19:1351-1368. [PMID: 37807649 DOI: 10.2174/011574888x260690230921174343] [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: 05/04/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 10/10/2023]
Abstract
Liver failure (LF) is serious liver damage caused by multiple factors, resulting in severe impairment or decompensation of liver synthesis, detoxification, metabolism, and biotransformation. The general prognosis of LF is poor with high mortality in non-transplant patients. The clinical treatments for LF are mainly internal medicine comprehensive care, artificial liver support system, and liver transplantation. However, none of the above treatment strategies can solve the problems of all liver failure patients and has its own limitations. Mesenchymal stem cells (MSCs) are a kind of stem cells with multidirectional differentiation potential and paracrine function, which play an important role in immune regulation and tissue regeneration. In recent years, MSCs have shown multiple advantages in the treatment of LF in pre-clinical experiments and clinical trials. In this work, we reviewed the biological characteristics of MSCs, the possible molecular mechanisms of MSCs in the treatment of liver failure, animal experiments, and clinical application, and also discussed the existing problems of MSCs in the treatment of liver failure.
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Affiliation(s)
- Qiong Xie
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
| | - Jundong Gu
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin, 300457, China
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21
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Singh AK, Prasad P, Cancelas JA. Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis. Front Cell Dev Biol 2023; 11:1325291. [PMID: 38169927 PMCID: PMC10759248 DOI: 10.3389/fcell.2023.1325291] [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: 10/21/2023] [Accepted: 11/23/2023] [Indexed: 01/05/2024] Open
Abstract
Hematopoietic stem cell (HSC) transplantation-based treatments are in different phases of clinical development, ranging from current therapies to a promise in the repair and regeneration of diseased tissues and organs. Mesenchymal stromal/stem cells (MSCs), which are fibroblast-like heterogeneous progenitors with multilineage differentiation (osteogenic, chondrogenic, and adipogenic) and self-renewal potential, and exist in the bone marrow (BM), adipose, and synovium, among other tissues, represent one of the most widely used sources of stem cells in regenerative medicine. MSCs derived from bone marrow (BM-MSCs) exhibit a variety of traits, including the potential to drive HSC fate and anti-inflammatory and immunosuppressive capabilities via paracrine activities and interactions with the innate and adaptive immune systems. The role of BM-MSC-derived adipocytes is more controversial and may act as positive or negative regulators of benign or malignant hematopoiesis based on their anatomical location and functional crosstalk with surrounding cells in the BM microenvironment. This review highlights the most recent clinical and pre-clinical findings on how BM-MSCs interact with the surrounding HSCs, progenitors, and immune cells, and address some recent insights on the mechanisms that mediate MSCs and adipocyte metabolic control through a metabolic crosstalk between BM microenvironment cells and intercellular mitochondrial transfer in normal and malignant hematopoiesis.
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Affiliation(s)
- Abhishek K. Singh
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Parash Prasad
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Jose A. Cancelas
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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22
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Xu ZL, Huang XJ. Haploidentical transplants with a G-CSF/ATG-based protocol: Experience from China. Blood Rev 2023; 62:101035. [PMID: 36404244 DOI: 10.1016/j.blre.2022.101035] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022]
Abstract
Haploidentical donor stem cell transplantation (haplo-SCT) has made great advances in recent decades. The granulocyte colony-stimulating factor (G-CSF)- and antithymocyte globulin (ATG)-based protocol, which is known as the Beijing Protocol, represents one of the current T-cell repletion strategies in haplo-SCT. The key elements of the Beijing Protocol for graft versus host disease (GvHD) prophylaxis include G-CSF inducing T-cell tolerance and altering graft cell components, as well as ATG administration exerting an immunoregulatory effect for intensive prophylaxis. This review will summarize the GvHD incidence, the underlying novel mechanism for GvHD prophylaxis, how to optimize GvHD prophylaxis, and the recent advances of the Beijing Protocol, mainly focusing on the issues of GvHD.
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Affiliation(s)
- Zheng-Li Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
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23
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Zhang X, He J, Zhao K, Liu S, Xuan L, Chen S, Xue R, Lin R, Xu J, Zhang Y, Xiang AP, Jin H, Liu Q. Mesenchymal stromal cells ameliorate chronic GVHD by boosting thymic regeneration in a CCR9-dependent manner in mice. Blood Adv 2023; 7:5359-5373. [PMID: 37363876 PMCID: PMC10509672 DOI: 10.1182/bloodadvances.2022009646] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 06/15/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Mature donor T cells within the graft contribute to severe damage of thymic epithelial cells (TECs), which are known as key mediators in the continuum of acute GVHD (aGVHD) and cGVHD pathology. Mesenchymal stromal cells (MSCs) are reportedly effective in the prevention and treatment of cGVHD. In our previous pilot clinical trial in patients with refractory aGVHD, the incidence and severity of cGVHD were decreased, along with an increase in levels of blood signal joint T-cell receptor excision DNA circles after MSCs treatment, which indicated an improvement in thymus function of patients with GVHD, but the mechanisms leading to these effects remain unknown. Here, we show in a murine GVHD model that MSCs promoted the quantity and maturity of TECs as well as elevated the proportion of Aire-positive medullary TECs, improving both CD4+CD8+ double-positive thymocytes and thymic regulatory T cells, balancing the CD4:CD8 ratio in the blood. In addition, CCL25-CCR9 signaling axis was found to play an important role in guiding MSC homing to the thymus. These studies reveal mechanisms through which MSCs ameliorate cGVHD by boosting thymic regeneration and offer innovative strategies for improving thymus function in patients with GVHD.
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Affiliation(s)
- Xin Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiabao He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Ke Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Shiqi Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Shan Chen
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Rongtao Xue
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Jun Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Yan Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Hua Jin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
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24
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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: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.
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Affiliation(s)
- Ting Lin
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunfan Yang
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xinchuan Chen
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
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25
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Yan L, Li J, Zhang C. The role of MSCs and CAR-MSCs in cellular immunotherapy. Cell Commun Signal 2023; 21:187. [PMID: 37528472 PMCID: PMC10391838 DOI: 10.1186/s12964-023-01191-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/07/2023] [Indexed: 08/03/2023] Open
Abstract
Chimeric antigen receptors (CARs) are widely used by T cells (CAR-T cells), natural killer cells dendritic cells and macrophages, and they are of great importance in cellular immunotherapy. However, the use of CAR-related products faces several challenges, including the poor persistence of cells carrying CARs, cell dysfunction or exhaustion, relapse of disease, immune effector cell-associated neurotoxicity syndrome, cytokine release syndrome, low efficacy against solid tumors and immunosuppression by the tumor microenvironment. Another important cell therapy regimen involves mesenchymal stem cells (MSCs). Recent studies have shown that MSCs can improve the anticancer functions of CAR-related products. CAR-MSCs can overcome the flaws of cellular immunotherapy. Thus, MSCs can be used as a biological vehicle for CARs. In this review, we first discuss the characteristics and immunomodulatory functions of MSCs. Then, the role of MSCs as a source of exosomes, including the characteristics of MSC-derived exosomes and their immunomodulatory functions, is discussed. The role of MSCs in CAR-related products, CAR-related product-derived exosomes and the effect of MSCs on CAR-related products are reviewed. Finally, the use of MSCs as CAR vehicles is discussed. Video Abstract.
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Affiliation(s)
- Lun Yan
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Jing Li
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Cheng Zhang
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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26
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Dong X, Wu W, Pan P, Zhang XZ. Engineered Living Materials for Advanced Diseases Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023:e2304963. [PMID: 37436776 DOI: 10.1002/adma.202304963] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/04/2023] [Accepted: 07/11/2023] [Indexed: 07/13/2023]
Abstract
Natural living materials serving as biotherapeutics exhibit great potential for treating various diseases owing to their immunoactivity, tissue targeting, and other biological activities. In this review, the recent developments in engineered living materials, including mammalian cells, bacteria, viruses, fungi, microalgae, plants, and their active derivatives that are used for treating various diseases are summarized. Further, the future perspectives and challenges of such engineered living material-based biotherapeutics are discussed to provide considerations for future advances in biomedical applications.
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Affiliation(s)
- Xue Dong
- Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P. R. China
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 400037, P. R. China
| | - Wei Wu
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 400037, P. R. China
| | - Pei Pan
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Xian-Zheng Zhang
- Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P. R. China
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
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27
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Maldonado VV, Patel NH, Smith EE, Barnes CL, Gustafson MP, Rao RR, Samsonraj RM. Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy. J Biol Eng 2023; 17:44. [PMID: 37434264 DOI: 10.1186/s13036-023-00361-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 06/19/2023] [Indexed: 07/13/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have been carefully examined to have tremendous potential in regenerative medicine. With their immunomodulatory and regenerative properties, MSCs have numerous applications within the clinical sector. MSCs have the properties of multilineage differentiation, paracrine signaling, and can be isolated from various tissues, which makes them a key candidate for applications in numerous organ systems. To accentuate the importance of MSC therapy for a range of clinical indications, this review highlights MSC-specific studies on the musculoskeletal, nervous, cardiovascular, and immune systems where most trials are reported. Furthermore, an updated list of the different types of MSCs used in clinical trials, as well as the key characteristics of each type of MSCs are included. Many of the studies mentioned revolve around the properties of MSC, such as exosome usage and MSC co-cultures with other cell types. It is worth noting that MSC clinical usage is not limited to these four systems, and MSCs continue to be tested to repair, regenerate, or modulate other diseased or injured organ systems. This review provides an updated compilation of MSCs in clinical trials that paves the way for improvement in the field of MSC therapy.
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Affiliation(s)
- Vitali V Maldonado
- Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA
| | - Neel H Patel
- Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA
| | - Emma E Smith
- Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA
| | - C Lowry Barnes
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Raj R Rao
- Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA
- Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR, USA
| | - Rebekah M Samsonraj
- Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA.
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
- Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR, USA.
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Wang J, Metheny L. Umbilical cord blood derived cellular therapy: advances in clinical development. Front Oncol 2023; 13:1167266. [PMID: 37274288 PMCID: PMC10232824 DOI: 10.3389/fonc.2023.1167266] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/04/2023] [Indexed: 06/06/2023] Open
Abstract
While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.
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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: 38] [Impact Index Per Article: 19.0] [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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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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31
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Loisel S, Lansiaux P, Rossille D, Ménard C, Dulong J, Monvoisin C, Bescher N, Bézier I, Latour M, Cras A, Farge D, Tarte K. Regulatory B Cells Contribute to the Clinical Response After Bone Marrow-Derived Mesenchymal Stromal Cell Infusion in Patients With Systemic Sclerosis. Stem Cells Transl Med 2023; 12:194-206. [PMID: 36928395 PMCID: PMC10108721 DOI: 10.1093/stcltm/szad010] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/09/2023] [Indexed: 03/18/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered as a central mechanism for their clinical benefit, very few data are available on the impact of MSCs on immune cell subsets in vivo. In the current extended study of a phase I/II clinical trial exploring the injection of a single dose of allogeneic bone marrow-MSCs (alloBM-MSCs) in patients with severe SSc (NCT02213705), we performed a longitudinal in-depth characterization of circulating immune cells in 19 MSC-treated patients, including 14 responders and 5 non-responders. By a combination of flow cytometry and transcriptomic analyses, we highlighted an increase in circulating CD24hiCD27posCD38lo/neg memory B cells, the main IL-10-producing regulatory B cell (Breg) subset, and an upregulation of IL10 expression in ex-vivo purified B cells, specifically in responder patients, early after the alloBM-MSC infusion. In addition, a deeper alteration of the B-cell compartment before alloBM-MSC treatment, including a higher expression of profibrotic cytokines IL6 and TGFβ by sorted B cells was associated with a non-responder clinical status. Finally, BM-MSCs were able to directly upregulate IL-10 production in activated B cells in vitro. These data suggest that cytokine-producing B cells, in particular Breg, are pivotal effectors of BM-MSC therapeutic activity in SSc. Their quantification as activity biomarkers in MSC potency assays and patient selection criteria may be considered to reach optimal clinical benefit when designing MSC-based clinical trials.
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Affiliation(s)
- Séverine Loisel
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Pauline Lansiaux
- Unité de Médecine Interne (UF 04), CRMR Maladies auto-immunes et thérapie cellulaire (MATHEC), Centre de Référence des Maladies auto-immunes systémiques Rares d’Ile-de-France, AP-HP, Hôpital St-Louis, Paris, France
- Université de Paris Cité, IRSL, Recherche clinique appliquée à l’hématologie, URP 3518, Paris, France
| | - Delphine Rossille
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Cédric Ménard
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Joëlle Dulong
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Céline Monvoisin
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Nadège Bescher
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Isabelle Bézier
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Maëlle Latour
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
| | - Audrey Cras
- Cell Therapy Unit, Saint Louis Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France
- UMR1140, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France
| | - Dominique Farge
- Unité de Médecine Interne (UF 04), CRMR Maladies auto-immunes et thérapie cellulaire (MATHEC), Centre de Référence des Maladies auto-immunes systémiques Rares d’Ile-de-France, AP-HP, Hôpital St-Louis, Paris, France
- Université de Paris Cité, IRSL, Recherche clinique appliquée à l’hématologie, URP 3518, Paris, France
- Department of Medicine, McGill University, Montreal, Canada
| | - Karin Tarte
- SITI, CHU Rennes, Etablissement Français du Sang Bretagne, Rennes, France
- INSERM UMR 1236, Université Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France
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Hong T, Wang R, Yang G, Wang X, Zeng L, Yang S, Wei J, Gao Q, Zhang X. Human umbilical cord mesenchymal stem cells ameliorate acute graft versus host disease by elevating phytosphingosine. Exp Hematol 2023:S0301-472X(23)00070-X. [PMID: 36931619 DOI: 10.1016/j.exphem.2023.03.002] [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: 11/12/2022] [Revised: 02/28/2023] [Accepted: 03/08/2023] [Indexed: 03/17/2023]
Abstract
Acute graft-versus-host disease (aGVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT) and even leads to death after HSCT. Human umbilical cord mesenchymal stem cells (HUCMSCs) are effective in aGVHD treatment and have mild side effects, but the underlying mechanisms remain unclear. Phytosphingosine (PHS) is known to prevent loss of moisture from the skin; regulate epidermal cell growth, differentiation, and apoptosis; and exert bactericidal and anti-inflammatory effects. In this study, our results revealed the efficacy of HUCMSCs in alleviating aGVHD in a murine model, with striking changes in metabolism and significantly elevated PHS levels due to sphingolipid metabolism. In vitro, PHS reduced CD4+ T cell proliferation, enhanced apoptosis and reduced T helper 1 (Th1) cell differentiation. Transcriptional analysis of donor CD4+ T cells treated with PHS revealed significant decreases in transcripts regulating proinflammatory pathways, such as NF-κB. In vivo, the administration of PHS significantly ameliorated aGVHD development. Collectively, these beneficial effects indicate proof-of-concept that sphingolipid metabolites could be a safe and effective means to prevent aGVHD in the clinic.
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Affiliation(s)
- Tao Hong
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China
| | - Guancui Yang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637002, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China
| | - Lingyu Zeng
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221008, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China
| | - Jin Wei
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637002, China
| | - Qiangguo Gao
- Department of Cell Biology, College of Basic Medicine, Army Medical University, Chongqing, 400038, China..
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China; Jinfeng Laboratory, Chongqing, 401329, China..
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Li X, Xiao Y, Wang X, Huang R, Wang R, Deng Y, Rao J, Gao Q, Yang S, Zhang X. Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca 2+ -dependent gap junction intercellular communication. Chin Med J (Engl) 2023; 136:194-206. [PMID: 36801891 PMCID: PMC10106204 DOI: 10.1097/cm9.0000000000002554] [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: 07/27/2022] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. METHODS Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca 2+ -related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. RESULTS Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca 2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. CONCLUSIONS Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.
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Affiliation(s)
- Xiaoping Li
- Department of Hematology, 920th Hospital of Joint Logistic Support Force of People's Liberation, Kunming, Yunnan 650000, China
| | - Yunshuo Xiao
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Yi Deng
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Jun Rao
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Qiangguo Gao
- Department of Cell Biology College of Basic Medicine, Army Medical University, Chongqing 400038, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
- Jinfeng Laboratory, Chongqing 401329, China
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Wang X, Liu Q, Zhang X. Editorial: The role of hematopoietic and immune microenvironment in hematopoietic stem cell transplantation. Front Immunol 2023; 14:1139193. [PMID: 36742326 PMCID: PMC9893921 DOI: 10.3389/fimmu.2023.1139193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 01/20/2023] Open
Affiliation(s)
- Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China,Jinfeng Laboratory, Chongqing, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China,Jinfeng Laboratory, Chongqing, China,*Correspondence: Xi Zhang,
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Cheng X, Huang R, Huang S, Fan W, Yuan R, Wang X, Zhang X. Recent advances in ocular graft-versus-host disease. Front Immunol 2023; 14:1092108. [PMID: 36761771 PMCID: PMC9905686 DOI: 10.3389/fimmu.2023.1092108] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.
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Affiliation(s)
- Xianjing Cheng
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Shiqin Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Wei Fan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Rongdi Yuan
- Department of Ophthalmology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.,School of Medicine, Chongqing University, Chongqing, China.,Jinfeng Laboratory, Chongqing, China
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36
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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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Xue E, Minniti A, Alexander T, Del Papa N, Greco R. Cellular-Based Therapies in Systemic Sclerosis: From Hematopoietic Stem Cell Transplant to Innovative Approaches. Cells 2022; 11:3346. [PMID: 36359742 PMCID: PMC9658618 DOI: 10.3390/cells11213346] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 08/28/2023] Open
Abstract
Systemic sclerosis (SSc) is a systemic disease characterized by autoimmune responses, vasculopathy and tissue fibrosis. The pathogenic mechanisms involve a wide range of cells and soluble factors. The complexity of interactions leads to heterogeneous clinical features in terms of the extent, severity, and rate of progression of skin fibrosis and internal organ involvement. Available disease-modifying drugs have only modest effects on halting disease progression and may be associated with significant side effects. Therefore, cellular therapies have been developed aiming at the restoration of immunologic self-tolerance in order to provide durable remissions or to foster tissue regeneration. Currently, SSc is recommended as the 'standard indication' for autologous hematopoietic stem cell transplantation by the European Society for Blood and Marrow Transplantation. This review provides an overview on cellular therapies in SSc, from pre-clinical models to clinical applications, opening towards more advanced cellular therapies, such as mesenchymal stem cells, regulatory T cells and potentially CAR-T-cell therapies.
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Affiliation(s)
- Elisabetta Xue
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
| | - Antonina Minniti
- Department of Rheumatology, ASST G. Pini-CTO, 20122 Milan, Italy
| | - Tobias Alexander
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, 10117 Berlin, Germany
| | | | - Raffaella Greco
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
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Cheng XJ, Yuan RD, Zhang X. [Treatment of chronic ocular graft versus host disease]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:877-880. [PMID: 36709206 PMCID: PMC9669625 DOI: 10.3760/cma.j.issn.0253-2727.2022.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Indexed: 01/25/2023]
Affiliation(s)
- X J Cheng
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China School of Medicine Chongqing University, Chongqing 400030, China
| | - R D Yuan
- Ophthalmology Department, Xinqiao Hospital of Army Medical University, Chongqing 400037, China
| | - X Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, PLA Blood Disease Center, Chongqing Key Discipline of Medicine, Chongqing 400037, China School of Medicine Chongqing University, Chongqing 400030, China
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Nachmias B, Zimran E, Avni B. Mesenchymal stroma/stem cells: Haematologists' friend or foe? Br J Haematol 2022; 199:175-189. [PMID: 35667616 PMCID: PMC9796884 DOI: 10.1111/bjh.18292] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 01/07/2023]
Abstract
Mesenchymal stromal cells (MSCs) are non-haematopoietic cells found in fetal and adult organs, that play important roles in tissue repair, inflammation and immune modulation. MSCs residing in the bone marrow interact closely with haematopoietic cells and comprise an important component of the microenvironment supporting haematopoiesis, in both health and disease states. Since their identification in 1970, basic scientific and preclinical research efforts have shed light on the role of MSCs in the regulation of haematopoiesis and evoked interest in their clinical application in haematopoietic stem cell transplantation (HSCT) and malignant haematology. Over the last two decades, these research efforts have led to numerous clinical trials, which have established the safety of MSC therapy; however, the optimal mode of administration and the benefit remain inconclusive. In this paper, we will review the clinical experience with use of MSCs in HSCT for enhancement of engraftment, prevention and treatment of graft-versus-host disease and haemorrhagic cystitis. Then, we will discuss the contradictory evidence regarding tumour-promoting versus tumour-suppressing effects of MSCs in haematological malignancies, which may have relevance for future clinical applications.
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Affiliation(s)
- Boaz Nachmias
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Eran Zimran
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
| | - Batia Avni
- Division of Hematology and Bone Marrow Transplantation & Cancer ImmunotherapyHadassah Medical Center and Hebrew UniversityJerusalemIsrael
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40
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Trends in using mesenchymal stromal/stem cells (MSCs) in treating corneal diseases. Ocul Surf 2022; 26:255-267. [DOI: 10.1016/j.jtos.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 10/03/2022] [Accepted: 10/07/2022] [Indexed: 12/05/2022]
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41
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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: 86] [Impact Index Per Article: 28.7] [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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42
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Beyond the horizon: the newly found sinner disturbing mesenchymal stromal niche. BLOOD SCIENCE 2022; 4:179-180. [DOI: 10.1097/bs9.0000000000000119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 05/05/2022] [Indexed: 11/26/2022] Open
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Wang X, Huang R, Zhang X, Zhang X. Current status and prospects of hematopoietic stem cell transplantation in China. Chin Med J (Engl) 2022; 135:1394-1403. [PMID: 35866344 PMCID: PMC9481431 DOI: 10.1097/cm9.0000000000002235] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Indexed: 11/25/2022] Open
Abstract
ABSTRACT Hematopoietic stem cell transplantation (HSCT) is a highly effective and unique medical procedure for the treatment of most hematological malignancies. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then, the field has evolved and expanded worldwide. The first successful allogenic HSCT (allo-HSCT) in China was conducted in 1981. Although the development of allo-HSCT in China lagged, China has since made considerable contributions to the process of HSCT worldwide, with more than 10,000 HSCTs performed annually. In particular, haploid HSCT (haplo-HSCT) technology represented in the Beijing Protocol has demonstrated similar efficacy to human leukocyte antigen-matched HSCT and has gradually become the pre-dominant choice for allo-HSCT in China. Currently, the number of haplo-HSCT procedures exceeds 5000 per year, and the Beijing Protocol has been greatly improved by implementing updated individualized strategies for controlling complications, relapse, and infection management. In addition, innovative haplo-HSCT technologies developed by different medical transplantation centers, such as Soochow, Zhejiang, Fujian, Chongqing, and Anhui, have emerged, providing inspiration for the refinement of global practice. This review will focus on the current activity in this field and highlight important trends that are vital in China's allo-HSCT process, examining the current viewpoint and future directions.
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Affiliation(s)
- Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
| | - Xiaohui Zhang
- Peking University People's Hospital & Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China
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44
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[Chinese consensus on diagnosis and treatment of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation (2022)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:441-447. [PMID: 35968585 PMCID: PMC9800223 DOI: 10.3760/cma.j.issn.0253-2727.2022.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Indexed: 12/24/2022]
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Zhu L, Liu J, Kong P, Gao S, Wang L, Liu H, Zhang C, Gao L, Feng Y, Chen T, Gao L, Zhang X. Analysis of the Efficacy and Safety of Avatrombopag Combined With MSCs for the Treatment of Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2022; 13:910893. [PMID: 35693772 PMCID: PMC9184517 DOI: 10.3389/fimmu.2022.910893] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/29/2022] [Indexed: 01/05/2023] Open
Abstract
Platelet graft failure (PGF) is a frequent and serious complication after Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacks effective treatment strategies, which could affect the prognosis of patients and even cause death. The exact underlying mechanism of PGF remains unclear, and lacks standard treatment. Here, we conduct a retrospective study to evaluate the efficacy and safety of avatrombopag combined with mesenchymal stem cells (MSCs) in 16 patients with thrombocytopenia after allo-HSCT. Patients were administered the following treatment regimen: 20 mg/d avatrombopag; if the PLT count was less than 50×10^9/L for at least 2 weeks, the dose was increased to 40 mg/d; if the PLT count was 200-400×10^9/L, the dose was reduced; and if the PLT count was greater than 400×10^9/L, avatrombopag was terminated. Umbilical cord MSCs (1×10^6 cells/kg) infusion was performed every week for 4-6 weeks. Among the 16 patients, 13 patients (81.3%) achieved a complete response (CR), 2 patients (12.5%) got a partial response (PR), and 1 patient (6.3%) had no response (NR). The median time to obtain CR was 32 (7-426) days after treatment with avatrombopag combined with umbilical cord MSCs. The time to reach 20×10^9/L≤ PLT <50×10^9/L in the 2 patients with PR was 52 and 230 days after treatment, respectively. One patient had a severe pulmonary infection and died of cytomegalovirus pneumonia. Overall, our results indicated that combination of avatrombopag with MSCs can promote platelet recovery after transplantation, thereby improving the survival rate of patients and improving the quality of life of patients after transplantation, and providing a new method and strategy for the treatment of thrombocytopenia after allo-HSCT.
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46
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Ding L, Han DM, Yan HM, Zhou JX, Zheng XL, Zhu L, Xue M, Liu J, Mao N, Guo ZK, Ning HM, Wang HX, Zhu H. Infusion of haploidentical HSCs combined with allogenic MSCs for the treatment of ALL patients. Bone Marrow Transplant 2022; 57:1086-1094. [PMID: 35468947 DOI: 10.1038/s41409-022-01688-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/09/2022] [Accepted: 04/12/2022] [Indexed: 11/09/2022]
Abstract
Although haploidentical stem cell transplantation (haplo-HSCT) offers almost all acute lymphoblastic leukaemia (ALL) patients an opportunity for immediate transplantation, it exhibits a higher incidence of graft failure and graft versus host disease (GVHD). Mesenchymal stem cells (MSCs) are characterised by their haematopoiesis-promoting and immunomodulatory capacity. Thus, we designed a combination of haplo-HSCT and MSCs for ALL patients. ALL patients (n = 110) were given haploidentical HSCs combined with allogenic MSCs, and ALL patients without MSC infusion (n = 56) were included as controls. The 100-day cumulative incidences of grade ≥2 acute GVHD (aGVHD) and grade ≥3 aGVHD were 40.00% and 9.09% compared to 42.32% (P = 0.79) and 22.79% (P = 0.03) in patients without MSC infusion, respectively. The 3-year cumulative incidences of chronic GVHD (cGVHD) and extensive cGVHD were 22.27% and 10.27% compared to 32.14% (P = 0.19) and 22.21% (P = 0.04) in patients without MSC infusion, respectively. No significant differences in the 3-year relapse incidence, nonrelapse mortality, leukaemia-free survival or overall survival in groups with and without MSC cotransplantation were observed. Multivariate analysis showed that MSC infusion contributed to a lower risk of developing extensive cGVHD. Our data suggested that haplo-HSCT combined with MSCs may provide an effective and safe treatment for ALL patients.
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Affiliation(s)
- Li Ding
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China. .,Department of Experimental Hematology& Biochemistry, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, P.R. China.
| | - Dong-Mei Han
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Hong-Min Yan
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Jie-Xin Zhou
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Xiao-Li Zheng
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Ling Zhu
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Mei Xue
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Jing Liu
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China
| | - Ning Mao
- Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, P.R. China
| | - Zi-Kuan Guo
- Department of Experimental Hematology& Biochemistry, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, P.R. China.,Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, P.R. China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Hong-Mei Ning
- Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, P.R. China.,The Fifth Medical Center of Chinese PLA General Hospital, East Street 8, Beijing, 100071, People's Republic of China
| | - Heng-Xiang Wang
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, P.R. China.
| | - Heng Zhu
- Department of Experimental Hematology& Biochemistry, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, P.R. China. .,Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, P.R. China. .,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China. .,Graduate School of Anhui Medical University, Road Meishan 81, Hefei, 230032, Anhui, P.R. China.
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Sheng XF, Li H, Hong LL, Zhuang H. Combination of Haploidentical Hematopoietic Stem Cell Transplantation with Umbilical Cord-Derived Mesenchymal Stem Cells in Patients with Severe Aplastic Anemia: a Retrospective, Controlled Study. Turk J Haematol 2022; 39:117-129. [PMID: 35448935 PMCID: PMC9160692 DOI: 10.4274/tjh.galenos.2022.2022.0084] [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: 12/01/2022] Open
Abstract
Objective: We retrospectively compared the outcomes of patients with severe aplastic anemia (SAA) who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) combined or not combined with umbilical cord-derived mesenchymal stem cells (UC-MSCs). Materials and Methods: A total of 101 patients with SAA were enrolled in this study and treated with haplo-HSCT plus UC-MSC infusion (MSC group, n=47) or haplo-HSCT alone (non-MSC group, n=54). Results: The median time to neutrophil engraftment in the MSC and non-MSC group was 11 (range: 8-19) and 12 (range: 8-23) days, respectively (p=0.049), with a respective cumulative incidence (CI) of 97.82% and 97.96% (p=0.101). Compared to the non-MSC group, the MSC group had a lower CI of chronic graft-versus-host disease (GVHD) (8.60±0.25% vs. 24.57±0.48%, p=0.048), but similar rates of grades II-IV acute GVHD (23.40±0.39% vs. 24.49±0.39%, p=0.849), grades III-IV acute GVHD (8.51±0.17% vs. 10.20±0.19%, p=0.765), and moderate-severe chronic GVHD (2.38±0.06% vs. 7.45±0.18%, p=0.352) were observed. The estimated 5-year overall survival (OS) rates were 78.3±6.1% and 70.1±6.3% (p=0.292) while the estimated 5-year GVHD-free, failure-free survival (GFFS) rates were 76.6±6.2% and 56.7±6.9% (p=0.045) in the MSC and non-MSC groups, respectively. Conclusion: In multivariate analysis, graft failure was the only adverse predictor for OS. Meanwhile, graft failure, grades III-IV acute GVHD, and moderate-severe chronic GVHD could predict worse GFFS. Our results indicated that haplo-HSCT combined with UC-MSCs infusion was an effective and safe option for SAA patients.
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Affiliation(s)
- Xian-Fu Sheng
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Hui Li
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Li-Li Hong
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Haifeng Zhuang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Abstract
Human mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are important adult stem cells for regenerative medicine, largely due to their regenerative characteristics such as self-renewal, secretion of trophic factors, and the capability of inducing mesenchymal cell lineages. MSCs also possess homing and trophic properties modulating immune system, influencing microenvironment around damaged tissues and enhancing tissue repair, thus offering a broad perspective in cell-based therapies. Therefore, it is not surprising that MSCs have been the broadly used adult stem cells in clinical trials. To gain better insights into the current applications of MSCs in clinical applications, we perform a comprehensive review of reported data of MSCs clinical trials conducted globally. We summarize the biological effects and mechanisms of action of MSCs, elucidating recent clinical trials phases and findings, highlighting therapeutic effects of MSCs in several representative diseases, including neurological, musculoskeletal diseases and most recent Coronavirus infectious disease. Finally, we also highlight the challenges faced by many clinical trials and propose potential solutions to streamline the use of MSCs in routine clinical applications and regenerative medicine.
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49
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Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol 2022; 13:839844. [PMID: 35371003 PMCID: PMC8973075 DOI: 10.3389/fimmu.2022.839844] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, All Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
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50
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Zhao K, Lin R, Fan Z, Chen X, Wang Y, Huang F, Xu N, Zhang X, Zhang X, Xuan L, Wang S, Lin D, Deng L, Nie D, Weng J, Li Y, Zhang X, Li Y, Xiang AP, Liu Q. Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial. J Hematol Oncol 2022; 15:22. [PMID: 35255929 PMCID: PMC8900437 DOI: 10.1186/s13045-022-01240-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/19/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD. METHODS A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse. RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610). CONCLUSIONS MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .
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Affiliation(s)
- Ke Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhiping Fan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yu Wang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Fen Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Na Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Xin Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shunqing Wang
- Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Dongjun Lin
- Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Lan Deng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Danian Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jianyu Weng
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yonghua Li
- Department of Hematology, General Hospital of Southern Theatre Command, Guangzhou, 440104, China
| | - Xiaohui Zhang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - A P Xiang
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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